Lack of Differences in the Pharmacokinetics of Therapeutic Monoclonal Antibodies Between Japanese and Non‐Japanese Individuals

Abstract

Evaluation of the pharmacokinetics (PK) of new drugs in Japanese individuals is regularly requested by the Japanese regulatory agency prior to participation in global clinical trials or for bridging approaches for regulatory approval. However, the need for PK assessments in the Japanese population may be less compelling for monoclonal antibodies (mAbs) compared to other drugs, given that the intrinsic properties of immunoglobulin G molecules are generally considered ethnically insensitive. This prompted an evaluation of the currently available evidence for potential PK differences for mAbs between Japanese and Non‐Japanese populations. We reviewed 137 mAbs approved in the United States, of which 101 were also approved in Japan, to evaluate whether PK differences between Japanese and non‐Japanese individuals have been reported. PK was found to be similar between Japanese and non‐Japanese, predominantly Caucasians/Whites, for 59 out of 101 mAbs. Although PK differences were identified for 26 out of 101 mAbs approved in Japan, these differences were largely attributed to body weight differences between Japanese and non‐Japanese populations. After adjusting for these body weight differences, most mAbs demonstrated no meaningful PK differences across the ethnic groups. Importantly, the observed differences were reported not to translate into clinically meaningful impact on pharmacodynamics, safety, and efficacy to warrant different dosing recommendations. No differences in dosing recommendations could be detected for any of the 101 mAbs approved in Japan compared to the United States. Overall, these data suggest a lack of a convincing scientific rationale for the necessity of dedicated PK studies in Japanese versus non‐Japanese individuals for mAbs.

Introduction

Clinical drug development in the 21st century is, in many cases, a global endeavor. ¹ Pharmaceutical companies are frequently faced with the need to manage a highly complex clinical trial portfolio that concurrently satisfies regulatory requirements in multiple jurisdictions, where the focus is usually on the pharmaceutical markets in Europe, Asia, and North America. ² Thus, requirements for trials are largely determined by the regulations and guidance of the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency of Japan (PMDA), and the National Medical Products Administration of China (NMPA). Since the release of the Japanese regulatory guidance, “Basic Principles on Global Clinical Trials” in 2007 by PMDA, based on the bridging concept described in the International Council for Harmonization (ICH) E5 guideline, ³ , ⁴ there has been a marked increase in the number of clinical trials in Japan. ⁵ , ⁶ , ⁷ , ⁸ The guidance acknowledges that although foreign data may sometimes be sufficient to evaluate safety or pharmacokinetics (PK), or support dose selection based on similar approved drugs, it nevertheless recommends conducting PK studies in Japanese subjects as part of the bridging strategy when ethnic, regional, or cultural factors could influence PK and/or pharmacodynamics. ³ , ⁹ Accordingly, the guidance recommends that Phase 1 studies should routinely be conducted in Japanese healthy volunteers or patients to assess PK and safety and to compare these findings with clinical data obtained in non‐Japanese populations before Japanese patients join late‐phase global clinical trials (GCTs) or in parallel with GCTs. ⁵ The purpose of these studies is to identify PK and safety differences early in drug development to ensure effective and safe dose regimens are recommended for the Japanese population, thereby promoting efficient and rapid drug development in Japan and facilitating that new drugs can be made available to Japanese patients without a delay from the rest of the world. Since then, the 2007 PMDA guidance has been updated twice, in 2012 and 2014. ¹⁰ These updates again emphasized the need to conduct Japanese phase 1 studies before Japanese patients can participate in a GCT.

Over the last three decades, monoclonal antibodies (mAbs) have become a major part of our pharmacopoeia and the backbone of pharmacotherapeutic interventions in numerous indications, ¹¹ and still constitute a major fraction of all clinical drug development projects. In 2011, Zhou et al stated that mAbs are less likely to be ethnically sensitive compared to small molecules and questioned the need for dedicated ethnic sensitivity studies following mAb administration to healthy Japanese subjects, supported by evidence in a comparison that showed the same or very similar dosing regimens for all 12 mAbs approved in the United States and Japan by January 2011. ¹² These findings were further corroborated in 2014 by Chiba et al and in 2015 by Matsushima et al. ⁹ , ¹³ These authors demonstrated that the PK of 11 of 24 mAbs approved in Japan and the United States as of May 2013 were comparable based on available exposure metrics (maximum concentration [C_max] and area under the curve [AUC]) and the conventional bioequivalence criterion for exposure metric ratios of 90% confidence intervals (CI) in the range 0.8‐1.25.

The work by Zhou et al, Chiba et al, and Matsushima et al was published a decade ago. ⁹ , ¹² , ¹³ Since, then, the number of approved mAbs has reached 137 in the United States, of which 101 were also approved in Japan as of December 2025. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ Based on this substantially expanded database on PK comparisons between Japanese and non‐Japanese individuals for mAbs, the objective of this review is to re‐evaluate whether the PK of mAbs is different in Japanese and corresponding non‐Japanese individuals, and whether the available scientific evidence warrants the routine performance of dedicated PK studies in Japan during clinical development of mAbs.

Methods

mAbs Approved in the United States and Japan

As of 2026, 137 therapeutic mAbs have been approved in the United States from June 1986 to December 2025, of which 101 have also been approved in Japan (Table 1). ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ These data were obtained from the approved drugs sections on the US FDA (“Novel drug approval at FDA”) ²² and PMDA (“List of approved products”) websites. ²³

Table 1.

Therapeutic Monoclonal Antibodies Approved in the United States and Japan From 1986 to 2025 and the Availability of Comparisons of Their Pharmacokinetics in Japanese Versus Non‐Japanese Individuals

Antibody INN Name	Trade Name	Target; Format	Indication/Disease	Manufacturer/Sponsor	US FDA Approval Year	Japan PMDA Approval Year	Japanese Versus Non‐Japanese PK Difference	Ref
Abciximab	Reopro	GPIIb/IIIa; chimeric IgG1 Fab	Prevention of blood clots in angioplasty	Centocor	1994	NA	Not known	21
Adalimumab	Humira	TNF; human IgG1	Rheumatoid arthritis	Abbvie/Abbott	2002	2008	No	24
Aducanumab	Aduhelm	Amyloid beta; human IgG1	Alzheimer's disease	Biogen	2021	NA	Not known	15
Alemtuzumab	MabCampath, Campath‐1H; Lemtrada	CD52; humanized IgG1	Chronic myeloid leukemia # , multiple sclerosis	Genzyme/Sanofi	2014; 2001 #	2014	No	25
Alirocumab	Praluent	PCSK9; human IgG1	Familial hypercholesterolemia, atherosclerotic cardiovascular disease	Regeneron/Sanofi	2015	2016	Yes	26
Amivantamab	Rybrevant	EGFR, cMET; human bispecific IgG1	NSCLC w/ EGFR exon 20 insertion mutations	Janssen Pharmaceutical	2021	2024	No	27
Anifrolumab	Saphnelo	IFNAR1; human IgG1	Systemic lupus erythematosus	AstraZeneca	2021	2021	No	28 , 29
Ansuvimab	Ebanga	Ebola virus; human IgG1	Ebola infection	Ridgeback Biotherapeutics	2020	NA	Not known	30
Atezolizumab	Tecentriq	PD‐L1; humanized IgG1	Bladder cancer	Genentech/Chugai Pharmaceutical	2016	2018	No	31 , 32
Atoltivimab, Maftivimab, and Odesivimab‐ebgn	Inmazeb	Ebola virus; mixture of three human IgG1	Ebola virus infection	Regeneron	2020	NA	Not known	33
Avelumab	Bavencio	PD‐L1; human IgG1	Advanced solid tumors	EMD Serono	2017	2017	Yes	34 , 35
Axatilimab	Niktimvo	CSF‐1R; humanized IgG4	cGVHD	Incyte Corporation	2024	NA	No	36
Basiliximab	Simulect	IL‐2R; chimeric IgG1	Prevention of kidney transplant rejection	Novartis/Ciba‐Geigy Japan	1998	2002	Not known	21
Belimumab	Benlysta	BLyS inhibitor; human IgG1	Systemic lupus erythematosus	Human Genome Sciences/GlaxoSmithKline	2011	2017	Yes	37 , 38
Benralizumab	Fasenra	IL‐5Rα; humanized IgG1	Asthma	AstraZeneca	2017	2018	Yes	39
Bevacizumab	Avastin	VEGF; humanized IgG1	Colorectal cancer	Genentech/Chugai Pharmaceutical	2004	2007	No	40
Bezlotoxumab	Zinplava	Clostridium difficile enterotoxin B; human IgG1	Prevention of Clostridium difficile infection recurrence	Merck	2016	2017	Yes	41
Bimekizumab	Bimzelx	IL‐17A,F; humanized IgG1	Psoriasis	UCB Pharma	2023	2022	Not known	42
Blinatumomab	Blincyto	CD19, CD3; murine bispecific tandem scFv	Acute lymphoblastic leukemia	Amgen/Astellas	2014	2018	No	43
Brodalumab	Siliq, Lumicef	IL‐17R; human IgG2	Plaque psoriasis	Valeant Pharmaceuticals/ Kyowa Kirin	2017	2016	No	44 , 45
Brolucizumab	Beovu	VEGF‐A; humanized scFv	Macular degeneration	Novartis	2019	2020	Not known	46
Burosumab	Crysvita	FGF23; human IgG1	X‐linked hypophosphatemia	Ultragenyx Pharmaceutical/ Kyowa Kirin	2018	2019	Insufficient data	47
Canakinumab	Ilaris	IL‐1β; human IgG1	Muckle–Wells syndrome	Novartis	2009	2011	Yes	48 , 49
Caplacizumab	Cablivi	von Willebrand factor; humanized nanobody	Acquired thrombotic thrombocytopenic	Ablynx/Sanofi	2019	2022	Not known	16
Casirivimab + imdevimab	Regen‐cov, Ronapreve	SARS‐CoV‐2; human IgG1	COVID‐19	Regeneron/ Chugai Pharmaceutical	2020 (EUA)	2021	Not known	16
Cemiplimab	Libtayo	PD‐1; human IgG4	Cutaneous squamous cell carcinoma	Regeneron/ Sanofi	2018	2022	Not known	50
Certolizumab pegol	Cimzia	TNF; humanized Fab, pegylated	Crohn's disease	UCB Pharma	2008	2012	No	51
Cetuximab	Erbitux	EGFR; chimeric IgG1	Colorectal cancer	ImClone Systems/ Merck KGaA	2004	2008	No	52 , 53
Clesrovimab	Enflonsia	RSV F fusion protein; human IgG1	RSV	Merck Sharp Dohme	2025	NA	Not known	54
Concizumab	Alhemo	TFPI; humanized IgG4	Hemophilia A and B	Novo Nordisk Pharma	2024	2023	No	55
Cosibelimab	Unloxcyt	PD‐L1; human IgG1	mCSCC, laCSCC	Checkpoint Therapeutics	2024	NA	Not known	56
Crizanlizumab	Adakveo	P‐selectin; humanized IgG2	Sickle cell disease	Novartis	2019	NA	Not known	57
Crovalimab	Piasky	Complement C5; humanized IgG1	Paroxysmal nocturnal hemoglobinuria	Genentech/ Chugai Pharmaceutical	2024	2024	Not known	58
Daclizumab	Zenapax; Zinbryta	IL‐2R; humanized IgG1	Prevention of kidney transplant rejection; multiple sclerosis	Abbvie/Biogen	2016; 1997 #	NA	No	59
Daratumumab	Darzalex	CD38; human IgG1	Multiple myeloma	Janssen	2015	2017	Not known	60
Denosumab	Prolia	RANK‐L; human IgG2	Bone loss	Amgen/Daiichi Sankyo	2010	2012	No	61
Depemokimab	Exdensur	IL‐5; humanized IgG1	Eosinophilic asthma	GlaxoSmithKline	2025	2025	No	62
Dinutuximab	Qarziba; Unituxin	GD2; chimeric IgG1	Neuroblastoma	United Therapies/Ohara Pharmaceutical	2015	2021	Not known	63
Donanemab	Kisunla	Pyroglutamate‐modified amyloid‐β (Aβ) plaques; humanized IgG1	Alzheimer's disease	Eli Lilly	2024	2024	Not known	64
Dostarlimab	Jemperli	PD‐1; humanized IgG4	Endometrial cancer	GlaxoSmithKline	2021	NA	Not known	65
Dupilumab	Dupixent	IL‐4Rα; human IgG4	Atopic dermatitis	Regeneron/Sanofi	2017	2018	Yes	66 , 67
Durvalumab	Imfinzi	PD‐L1; human IgG1	Bladder cancer	AstraZeneca	2017	2018	Insufficient data	68
Eculizumab	Soliris	C5; humanized IgG2/4	Paroxysmal nocturnal hemoglobinuria	Alexion Pharmaceuticals	2007	2010	Yes	69
Efalizumab	Raptiva	CD11a; humanized IgG1	Psoriasis	Genentech	2003 #	NA	Not known	21
Elotuzumab	Empliciti	SLAMF7; humanized IgG1	Multiple myeloma	Bristol‐Myers Squibb	2015	2016	Yes	70
Elranatamab	Elrexfio	BCMA, CD3; humanized IgG2	Multiple myeloma	Pfizer	2023	2024	No	71 , 72
Emapalumab	Gamifant	IFNγ; human IgG1	Primary hemophagocytic lymphohistiocytosis	Novimmune	2018	NA	Not known	73
Emicizumab	Hemlibra	Factor IXa, X; bispecific humanized IgG4	Hemophilia A	Genentech/Chugai Pharmaceutical	2017	2018	No	74
Epcoritamab	Epkinly	CD20, CD3; bispecific humanized IgG1	relapsed or refractory diffuse large B cell lymphoma	Genmab	2023	2023	Insufficient data	75
Eptinezumab	Vyepti	CGRP; humanized IgG1	Migraine prevention	Lundbeck/ Seattle Bio Pharmaceuticals	2020	NA	Not known	76
Erenumab	Aimovig	CGRP receptor; human IgG2	Migraine prevention	Amgen	2018	2021	Not known	77
Evinacumab	Evkeeza	Angiopoietin‐like 3; human IgG4	Homozygous familial hypercholesterolemia	Fierce Pharma/Ultragenyx	2021	2024	No	78
Evolocumab	Repatha	PCSK9; human IgG2	High cholesterol	Amgen/ Astellas	2015	2016	No	79 , 80
Faricimab	Vabysmo	VEGF‐A, Ang‐2; human/humanized IgG1 kappa/lambda, with domain crossover	Wet age‐related macular degeneration, diabetic macular edema	Chugai Pharmaceutical/Genentech	2022	2022	Insufficient data	81
Fremanezumab	Ajovy	CGRP; human IgG2	Migraine prevention	Teva Pharmaceuticals/Otsuka Pharmaceutical	2018	2021	No	82
Galcanezumab	Emgality	CGRP; human IgG4	Migraine prevention	Eli Lilly	2018	2021	No	83
Garadacimab	Andembry	Activated factor XII; human IgG4	Hereditary angioedema	CSL Behring	2025	2025	No	84
Glofitamab	Columvi	CD20, CD3e; bispecific 2+1 IgG1 CrossMab	Diffuse large B‐cell lymphoma	Genentech	2023	NA	Not known	85
Golimumab	Simponi	TNF; human IgG1	Rheumatoid and psoriatic arthritis and ankylosing spondylitis	Janssen/Centocor Ortho Biotech	2009	2011	No	86
Guselkumab	Tremfya	IL‐23 P19; human IgG1	Plaque psoriasis	Janssen	2017	2018	No	87 , 88
Ibalizumab	Trogarzo	CD4; humanized IgG4	HIV infection	TaiMed Biologics	2018	NA	Not known	89
Idarucizumab	Praxbind	Dabigatran; humanized Fab	Reversal of dabigatran‐induced anticoagulation	Boehringer Ingelheim	2015	2016	Yes	90 , 91
Inebilizumab	Uplizna	CD19; humanized IgG1	Neuromyelitis optica and neuromyelitis optica spectrum disorders	Viela Bio/Mitsubishi Tanabe Pharma	2020	2021	No	92 , 93
Infliximab	Remicade	TNF; chimeric IgG1	Crohn's disease and rheumatoid arthritis	Centocor/Tanabe Seiyaku	1998	2002	No	94 , 95
Ipilimumab	Yervoy	CTLA‐4; human IgG1	Metastatic melanoma	Bristol‐Myers Squibb	2011	2015	No	96 , 97
Isatuximab	Sarclisa	CD38; chimeric IgG1	Multiple myeloma	Sanofi	2020	2020	No	98 , 99
Ixekizumab	Taltz	IL‐17a; humanized IgG4	Psoriasis	Eli Lilly	2016	2016	No	100
Lanadelumab	Takhzyro	Plasma kallikrein; human IgG1	Hereditary angioedema attacks	Dyax /Takeda	2018	2022	No	101
Lebrikizumab	Ebglyss	IL‐13; humanized IgG4	Atopic dermatitis	Eli Lilly	2024	2024	Not known	102
Lecanemab	Leqembi	Amyloid beta protofibrils; humanized IgG1	Alzheimer's disease	Eisai and Biogen	2023	2023	Yes	103 , 104
Linvoseltamab	Lynozyfic	BCMA; human IgG4	Relapsed or refractory multiple myeloma	Regeneron Pharmaceuticals	2025	NA	Not known	105
Margetuximab	Margenza	HER2; chimeric IgG1	HER2+ breast cancer	MacroGenics	2020	NA	Not known	106
Marstacimab	Hympavzi	TFPI; human IgG1	Hemophilia A and B	Pfizer	2024	2024	No	107
Mepolizumab	Nucala	IL‐5; humanized IgG1	Severe eosinophilic asthma	GlaxoSmithKline	2015	2016	No	108
Mirikizumab	Omvoh	IL23p19; humanized IgG4	Ulcerative colitis and Crohn's disease	Eli Lilly	2023	2023	No	109
Mogamulizumab	Poteligeo	CCR4; humanized IgG1	Cutaneous T cell lymphoma	Kyowa Kirin	2018	2012	No	110
Mosunetuzumab	Lunsumio	CD20, CD3; humanized bispecific IgG1	Follicular lymphoma	Genentech/ Chugai Pharmaceutical	2022	2024	No	111 , 112
Muromonab‐CD3	Orthoclone Okt3	CD3; murine IgG2a	Reversal of kidney transplant rejection	Janssen/Cilag	1986 #	NA	Not known	17
Narsoplimab	Yartemlea	MASP‐2; human IgG4	HSCT‐TMA	Omeros	2025	NA	Not known	113
Natalizumab	Tysabri	α4 integrin; humanized IgG4	Multiple sclerosis	Biogen	2004	2014	Yes	114
Naxitamab	Danyelza	GD2; humanized IgG1	High‐risk neuroblastoma and refractory osteomedullary disease	Y‐mabs Therapeutics	2020	NA	Not known	21
Necitumumab	Portrazza	EGFR; human IgG1	Non‐small cell lung cancer	Eli Lilly	2015	2019	No	115 , 116
Nemolizumab	Nemluvio/Mitchga	IL‐31RA; humanized IgG2	Atopic dermatitis and prurigo nodularis	Galderma Laboratories LP/Maruho	2024	2022	No	117
Nipocalimab	Imaavy	FcRn; human IgG1	Myasthenia gravis; wAIHA; Sjögren's disease	Janssen Pharmaceutical	2025	2025	Yes	118
Nirsevimab	Beyfortus	RSV; human IgG1	RSV infection	AstraZeneca	2023	2024	Yes	119
Nivolumab	Opdivo	PD‐1; human IgG4	Melanoma; non‐small cell lung cancer	Bristol‐Myers Squibb/Ono Pharmaceutical	2014	2014	Yes	120 , 121
Obiltoxaximab	Anthim	Protective antigen of B. anthracis exotoxin; chimeric IgG1	Prevention of inhalational anthrax	Elusys Therapeutics	2016	NA	Not known	19
Obinutuzumab	Gazyva	CD20; humanized IgG1; glycoengineered	Chronic lymphocytic leukemia	Genentech/Chugai Pharmaceutical	2013	2018	No	122
Ocrelizumab	Ocrevus	CD20; humanized IgG1	Multiple sclerosis	Genentech	2017	NA	Not known	18
Ofatumumab	Arzerra	CD20; human IgG1	Chronic lymphocytic leukemia	GlaxoSmithKline	2009	2013	Yes	123
Olaratumab	Lartruvo	PDGFRα; human IgG1	Soft tissue sarcoma	Eli Lilly	2016 #	NA	No	124 , 125
Omalizumab	Xolair	IgE; humanized IgG1	Asthma	Genentech/Novartis	2003	2009	Yes	126
Palivizumab	Synagis	RSV; humanized IgG1	Prevention of respiratory syncytial virus infection	Swedish Orphan/Dainabot	1998	2002	No	127
Panitumumab	Vectibix	EGFR; human IgG2	Colorectal cancer	Amgen/Takeda	2006	2010	No	128
Pembrolizumab	Keytruda	PD‐1; humanized IgG4	Melanoma	Merck	2014	2016	No	129 , 130
Penpulimab	Penpulimab‐kcqx	PD‐1; humanized IgG1	NPC	Akeso Biopharma	2025	NA	Not known
Pertuzumab	Perjeta	HER2; humanized IgG1	Breast cancer	Genentech/Chugai Pharmaceutical	2012	2013	No	131 , 132
Pozelimab	Veopoz	Complement 5; human IgG4	CHAPLE disease	Regeneron	2023	NA	Not known	133
Ramucirumab	Cyramza	VEGFR2; human IgG1	Gastric cancer	Eli Lilly	2014	2015	No	134 , 135
Ranibizumab	Lucentis	VEGF; humanized IgG1 Fab	Macular degeneration	Genentech/Novartis	2006	2009	No	136 , 137
Ravulizumab	Ultomiris	C5; humanized IgG2/4	Paroxysmal nocturnal hemoglobinuria	Alexion Pharmaceuticals	2018	2019	Not known	16
Raxibacumab	Abthrax	B. anthracis PA; human IgG1	Anthrax infection	Human Genome Sciences	2012	NA	Not known	138
Relatlimab	Opdualag (relatlimab + nivolumab combo)	LAG‐3; human IgG4	Melanoma	Bristol‐Myers Squibb	2022	NA	Not known	139
Reslizumab	Cinqaero, Cinqair	IL‐5; humanized IgG4	Asthma	Teva Pharmaceuticals	2016	NA	Not known	140
Retifanlimab	Zynyz	PD‐1; humanized IgG4	Merkel cell carcinoma	Incyte	2023	2025	Yes	141
Risankizumab	Skyrizi	IL‐23p19; humanized IgG1	Plaque psoriasis	Abbvie	2019	2019	Yes	142
Rituximab	MabThera, Rituxan	CD20; chimeric IgG1	Non‐Hodgkin lymphoma	Genentech/Bayer Yakuhin	1997	2008	Yes	143
Romosozumab	Evenity	Sclerostin; humanized IgG2	Osteoporosis in postmenopausal women at risk of fracture	Amgen/Astellas	2019	2019	Yes	144
Rozanolixizumab	Rystiggo	FcRn; humanized IgG4	Generalized myasthenia gravis	UCB Pharma	2023	2023	Yes	145
Sarilumab	Kevzara	IL‐6R; human IgG1	Rheumatoid arthritis	Sanofi	2017	2017	Yes	146
Satralizumab	Enspryng	IL‐6R; humanized IgG2	Neuromyelitis optica and neuromyelitis optica spectrum disorders	Genentech/Chugai Pharmaceutical	2020	2020	Not known	15
Secukinumab	Cosentyx	IL‐17a; human IgG1	Psoriasis	Novartis	2015	2014	No	147
Sibeprenlimab	Voyxact	APRIL; humanized IgG2	IgA nephropathy	Otsuka Pharmaceutical	2025	NA	No	148
Siltuximab	Sylvant	IL‐6; chimeric IgG1	Castleman disease	Janssen	2014	NA	No	149 , 150
Spesolimab	Spevigo	IL‐36 receptor; humanized IgG1	Generalized pustular psoriasis	Boehringer Ingelheim	2022	2022	No	151
Sutimlimab	Enjaymo	C1s; humanized IgG4	Cold agglutinin disease	Bioverativ/Sanofi	2022	2022	Yes	152 , 153
Tafasitamab	Monjuvi, Minjuvi	CD19; humanized IgG1	Diffuse large B‐cell lymphoma	MorphoSys/ Incyte Biosciences Japan	2020	2025	No	154
Talquetamab	Talvey	G protein–coupled receptor 5D, CD3; bispecific humanized IgG4	Multiple myeloma	Janssen	2023	2025	Not known	155
Teclistamab	Tecvayli	BCMA, CD3; bispecific humanized IgG4	Multiple myeloma	Janssen	2022	2024	No	156
Teplizumab	Tzield	CD3; humanized IgG1	Delay onset of type 1 diabetes	Provention Bio	2022	NA	Not known	157
Teprotumumab	Tepezza	IGF‐1R; human IgG1	Thyroid eye disease	Horizon Therapeutics. Amgen	2020	2024	Not known	158
Tezepelumab	Tezspire	Thymic stromal lymphopoietin; human IgG2	Severe asthma	AstraZeneca	2021	2022	No	159 , 160
Tildrakizumab	Ilumya	IL‐23p19; humanized IgG1	Plaque psoriasis	Merck/Sun Pharma Japan	2018	2020	No	161
Tislelizumab	Tevimbra	PD‐1; humanized IgG4	Esophageal squamous cell carcinoma	BeiGene	2024	2025	Not known	16
Tixagevimab, cilgavimab	Evusheld	SARS‐CoV‐2; human IgG1	COVID‐19	AstraZeneca	2021 (EUA)	2022	No	162
Tocilizumab	RoActemra,Actemra	IL‐6R; humanized IgG1	Rheumatoid arthritis	Genentech/Chugai Pharmaceutical	2010	2005	No	163
Toripalimab	Loqtorzi, Tuoyi	PD‐1; humanized IgG4	Nasopharyngeal carcinoma, esophageal squamous cell carcinoma	Coherus BioSciences	2023	NA	Not known	164
Tositumomab‐I131	Bexxar	CD20; murine IgG2a	Non‐Hodgkin lymphoma	GlaxoSmithKline	2003 #	NA	Not known	21
Tralokinumab	Adtralza	IL‐13; human IgG4	Atopic dermatitis	Leo Pharma	2021	2022	Yes	165
Trastuzumab	Herceptin	HER2; humanized IgG1	Breast cancer	Genentech/Roche	1998	2013	No	166 , 167
Tremelimumab	Imjudo	CTLA‐4; human IgG2A	Antineoplastic; liver cancer	AstraZeneca	2022	2022	Not known	168
Ublituximab	Briumvi	CD20; chimeric IgG1	Multiple sclerosis	TG Therapeutics	2022	NA	Not known	169
Ustekinumab	Stelara	IL‐12/23; human IgG1	Psoriasis	Janssen/Centocor Ortho Biotech	2009	2011	Yes	170
Vedolizumab	Entyvio	α4β7 integrin; humanized IgG1	Ulcerative colitis; Crohn's disease	Takeda	2014	2018	No	171 , 172 , 173
Zanidatamab	Ziihera	HER2; humanized IgG1	Biliary tract cancer	Jazz Pharmaceuticals Ireland Limited	2024	NA	No	174
Zenocutuzumab	Bizengri	HER2 & HER3; humanized IgG1	NSCLC; pancreatic adenocarcinoma	Merus	2024	NA	Not known	175
Zolbetuximab	Vyloy	Claudin‐18.2; chimeric IgG1	Gastric or gastroesophageal junction adenocarcinoma	Astellas	2024	2024	No	176

Ang‐2, Angiotensin II; APRIL, A proliferation inducing ligand; B. anthracis PA, Bacillus anthracis–protective antigen; BCMA, B‐cell maturation antigen; BLyS, B‐lymphocyte stimulator; C1s, complement component C1s; C5, complement 5; CCR4, carbon catabolite repression 4; CD, cluster of differentiation; CGRP, calcitonin gene–related peptide; cGVHD, chronic graft‑versus‑host disease; CHAPLE, complement hyperactivation, angiopathic thrombosis and protein‐losing enteropathy; c‐MET, receptor tyrosine kinase; COVID‐19, coronavirus disease of 2019; CSF‐1R, colony‑stimulating factor‑1 receptor; CTLA‐4, cytotoxic T‐lymphocyte‐associated protein; EGFR, epidermal growth factor receptor; EUA, emergency‐use authorization; Fab, fragment antigen‐binding; FcRn, neonatal Fc receptor; FGF23, fibroblast growth factor 23; GD‐2, disialoganglioside 2; GPIIb/IIIa, glycoprotein IIb/IIIa; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; HIV, human immunodeficiency virus; HSCT‐TMA, hematopoietic stem cell transplant–associated thrombotic microangiopathy; IFNAR1, interferon alpha and beta receptor subunit 1; IFNγ, interferon‐gamma; IgE, immunoglobulin E; IgG, immunoglobulin G; IGF‐1R, insulin‐like growth factor 1 receptor; IL, interleukin; laCSCC, locally advanced cutaneous squamous cell carcinoma; LAG‐3, lymphocyte‐activation gene 3; MASP‐2, mannan‐binding lectin‐associated serine protease 2; mCSCC, metastatic cutaneous squamous cell carcinoma; NA, not approved; NPC, non‐keratinizing nasopharyngeal carcinoma; NSCLC, non‐small cell lung cancer; PCSK9, proprotein convertase subtilisin/kexin type 9; PD‐1, programmed cell death protein 1; PD‐L1, programmed death‐ligand 1; PDGFRα, platelet‐derived growth factor receptor α; PK, pharmacokinetics; RANK‐L, receptor activator of nuclear factor kappa beta ligand; RSV, respiratory syncytial virus; SARS‐COV‐2, severe acute respiratory syndrome coronavirus 2; scFv, single‐chain variable fragment; SLAMF7, signaling lymphocytic activation molecule family member 7; TFPI, tissue factor pathway inhibitor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; wAIHA, warm autoimmune hemolytic anemia.

^# Withdrawn or marketing discontinued for the indication approved.

Clinical Pharmacokinetic Data for mAbs Approved in the United States and Japan

To investigate whether studies had been conducted in Japan in addition to clinical studies in other ethnic groups, an English literature search was performed for the 137 mAbs. This search was performed in Google Scholar (scholar.google.com) using the following keywords:“[Name of the mAb],” “[pharmacokinetics],” “[Japanese],” “[Asians],” “[non‐Japanese],” “[Caucasians],” “[non‐Asians],” “[population pharmacokinetic/pharmacodynamic],” and “[safety/efficacy analysis].” The corresponding non‐Japanese studies were defined as those that sponsors/authors used to compare the PK between Japanese and non‐Japanese individuals. Study population (number of participants, healthy volunteers, or patients), trial design (Phases 1, 2, or 3 trial; doses; and route of administration), and PK analysis strategy (non‐compartmental analysis [NCA], population pharmacokinetic [PopPK], or population pharmacokinetic/pharmacodynamic [PopPK/PD]) were recorded for each study. Further metrics were collected from the available data: body weight (BW); maximum plasma concentration, C_max; time to reach C_max (t_max); AUC from zero to infinity (AUC_inf), zero to the last measurable concentration (AUC_last), or during a dosing interval (AUC_tau); terminal half‐life (t_1/2); clearance (CL); and volume of distribution (V_d). Ratios of the mean/median values of C_max and AUC_inf/AUC_last/AUC_tau in Japanese versus non‐Japanese individuals were calculated.

The categorization of mAbs in exhibiting differences in PK between Japanese and non‐Japanese individuals or not is solely based on the actually reported conclusions in the referenced documents. For the benefit of the reader, the respective underlying PK parameters are also provided for further interpretation.

Results

mAbs With Reported Differences in PK Between Japanese and Non‐Japanese Individuals

This section lists 26 mAbs where differences in PK were found between Japanese and non‐Japanese individuals, along with the underlying reasons as reported in the FDA reviews and/or publications.

Alirocumab

Alirocumab (Praluent) is an IgG1 mAb approved in the United States and Japan for atherosclerotic cardiovascular disease. ²⁶ The PK of alirocumab was investigated in Phase 2/3 trial patients (186 [24.5%] Japanese and 576 [75.9% Whites]) who received alirocumab at 50, 75, or 150 mg every 2 weeks. A 23% (50 mg dose) to 60% (150 mg dose) higher AUC_ss were observed in Japanese compared to White patients. The authors reported the difference in exposure was caused by lower BW of Japanese (61.7‐66.7 kg) versus White patients (79.9‐88.8 kg), since BW was identified as a significant covariate in a PopPK analysis affecting alirocumab PK in both populations. However, after BW normalization, exposures between the two groups were reported as comparable, and therefore, no dose adjustment was required. ²⁶

Avelumab

Avelumab (Bavencio) is an anti‐programmed cell death ligand‐1 (PD‐L1) IgG1 mAb for the treatment of melanoma and cancers of the lung, kidney, head and neck, bladder, stomach, and breast. ¹⁷⁷ A Phase 1 study was conducted in 17 Japanese patients that received a 3 mg/kg (n = 5), 10 mg/kg (n = 6), or 20 mg/kg (n = 6) dose by intravenous (IV) infusion ³⁴ and 49 White patients received the same doses, 3 mg/kg (n = 13), 10 mg/kg (n = 15), or 20 mg/kg (n = 2). ³⁵ The authors reported that no significant difference was observed in systemic exposures of avelumab. The point estimates for AUC_inf ratios (Japanese vs White) were 1.01, 1.09, and 0.84 at the dose of 3, 10, and 20 mg/kg, respectively. C_max was 1.25‐ and 1.7‐fold greater in Japanese than in White patients at the 3 and 10 mg/kg doses of avelumab, respectively. C_max was, however, comparable between the groups at the dose of 20 mg/kg, with a point estimate of 1.05. The authors attributed the observed C_max difference to lower mean BW and lower blood volume in Japanese patients or differences in disease characteristics/tumor types, or sampling variability due to the small number of Japanese patients (n = 5 or 6) at the 3 or 10 mg/kg avelumab doses. The safety and efficacy of avelumab in Japanese participants was reported to be consistent with that of the White population. Hence, the authors concluded that the observed C_max differences did not significantly impact the PK, safety, or efficacy of avelumab that require any dose adjustments.

Belimumab

Belimumab (Benlysta) is an IgG1 mAb approved in the United States and Japan for systemic lupus erythematosus. The PK was evaluated in two Phase 1 studies in 8 Japanese patients who received IV infusions of 1 mg/kg (n = 4) or 10 mg/kg (n = 4) and 57 non‐Japanese patients (25 [43.85%] Whites, 30 [53.6%] African Americans, and 2 [3.5%] Asians) who received the same doses of belimumab. ³⁷ , ³⁸ The authors reported C_max to be similar between the two groups with point estimates (Japanese vs non‐Japanese) of 0.91 and 0.92 at the doses of 1 and 10 mg/kg, respectively. However, AUC_inf was reported to be higher in Japanese compared to non‐Japanese subjects. Point estimates for AUC_inf ratio were 1.37 and 1.5 at 1 and 10 mg/kg, respectively. This was supported by a 1.53‐ and 1.56‐fold lower CL in the Japanese compared to the non‐Japanese patients at 1 and 10 mg/kg, respectively. t_1/2 was also slightly higher in Japanese subjects compared to the non‐Japanese subjects (1 mg/kg: 12.4 vs 8.46 days; and 10 mg/kg: 15.7 vs 9.64 days in Japanese vs non‐Japanese, respectively). V_d was comparable at 1 mg/kg: 80.1 versus 73.3 mL/kg, and 10 mg/kg: 76.2 versus 69.2 mL/kg in Japanese versus non‐Japanese, respectively. The authors attributed the PK differences to lower BW in Japanese patients compared to non‐Japanese patients, and interpreted them as not clinically relevant to warrant dose adjustments based on ethnicity. ³⁷ , ³⁸

Benralizumab

Benralizumab (Fasenra) is an anti‐IL‐5 IgG1 mAb approved in the United States and Japan for the treatment of asthma. A PopPK analysis was performed with concentrations from two Phase 1 studies in 48 Japanese healthy volunteers (BW 63.7‐65.0 kg) with IV or subcutaneous (SC) administration and four studies in 152 White patients (BW 72.4‐85.5 kg). ³⁹ The final model was a two‐compartment model with first‐order elimination from the central compartment and first‐order absorption from the SC dosing site. The authors identified ethnicity as a significant covariate on volume of the central compartment (V_c), with Japanese subjects having, on average, a 34% greater V_c than White patients, but individual V_c values mostly overlapped between Japanese subjects and White patients. The authors did not provide an explanation for the observed difference in V_c. In addition, ethnicity had no impact on CL, AUC, and C_max. ³⁰

Bezlotoxumab

Bezlotoxumab (Zinplava) is an IgG1 mAb approved in the United States and Japan for preventing the recurrence of Clostridium difficile infection. A PopPK model was developed with concentrations from 1587 participants (1507 [95%] Caucasians and 80 [5%] Japanese) in Phase 1/3 trials. ⁴¹ The PK was described using a two‐compartment model with linear elimination and allometric scaling for clearance and volume by BW. The sponsor identified Japanese ethnicity as a significant covariate on CL and V_c, with a 9.5% lower CL and 14% lower V_c in Japanese compared to Caucasians. These differences resulted in <20% lower exposure (AUC_inf was ∼8%‐15% lower and C_max was ∼6% lower) in the Japanese compared to the Caucasians. The sponsor attributed these differences in CL, V_c, and exposure to BW differences between the Japanese and Caucasian subjects, and these were considered not clinically meaningful to warrant any dose adjustments. ⁴¹

Canakinumab

Canakinumab (Ilaris) is an anti‐IL‐1β mAb approved in the United States and Japan for cryopyrin‐associated periodic syndrome (CAPS) and other indications, including gouty arthritis, rheumatoid arthritis (RA), psoriasis, and asthma. ⁴⁸ A PopPK model was developed using concentrations from multiple patient studies with 368 (61.2%) gout, 60 (16.3%) CAPS, 52 (8.6%) RA, 25 (4.2%) asthma, and 23 (3.8%) psoriasis patients, as well as 73 healthy volunteers (48 [8.0%] Japanese and 25 [4.2%] non‐Japanese). ⁴⁹ A two‐compartmental model with first‐order absorption and linear elimination best described the PK. The sponsor identified BW as a significant covariate on CL, V_c, and volume of peripheral compartment (V_p). After accounting for BW, CL differed by ∼17%, with non‐Japanese subjects (0.17 L/day) having a slower clearance compared to Japanese subjects (0.19 L/day). However, the sponsor did not consider this difference clinically significant for canakinumab PK, and therefore, no dose adjustments were needed. ⁴⁹

Dupilumab

Dupilumab (Dupixent) is an IgG4 anti‐IL‐4 mAb approved in the United States and Japan for atopic dermatitis. A Phase 1 trial in healthy volunteers (12 Japanese and 12 non‐Japanese) was conducted at SC dupilumab doses of 150 mg and 300 mg. ⁶⁶ The authors reported that at 150 mg, exposures (AUC_last and C_max) were similar between Japanese and non‐Japanese subjects. At the 300 mg dose, there was an increase in exposure in Japanese subjects compared to non‐Japanese subjects. The point estimates for the mean AUC_last and C_max ratios (Japanese vs non‐Japanese) were 1.17 and 1.18, respectively. However, the individual values in the Japanese subjects were within the ranges of C_max and AUC_last in the non‐Japanese subjects. The authors attributed the higher exposure to a lower BW of the Japanese (52.1‐78.3 kg) compared to the non‐Japanese subjects (58.0‐95.1 kg). Once corrected for BW, the authors observed no differences in the PK. ⁶⁶ Additionally, results from a Phase 2b trial suggested PK was comparable in Japanese and non‐Japanese patients after accounting for BW differences. ⁶⁷ Across all Phase 1/2 trials, dupilumab showed no clinically relevant differences in the PK between Japanese and non‐Japanese individuals, and therefore, no dose adjustments were required.

Eculizumab

Eculizumab (Soliris) is an IgG2/4 mAb, approved in the United States and Japan for paroxysmal nocturnal hemoglobinuria. A PopPK analysis was conducted with concentrations from 62 Phase 3 patients (3 [5%] Japanese and 59 [95%] Whites). ⁶⁹ A linear two‐compartment model with first‐order elimination best described the PK. The sponsor reported that exposure (AUC_inf and C_max) was higher in Japanese compared to White patients. The point estimates for AUC_inf and C_max ratios were 1.34 and 1.40, respectively. CL and inter‐compartmental clearance (Q) were slightly lower in the Japanese (0.0054 and 0.149 L/h) than in the White patients (0.008 and 0.22 L/h). However, other PK parameters (V_c, V_p, and t_1/2) were comparable between the groups. The sponsor attributed the higher exposure in Japanese compared to White patients as likely due to the lower BW of the Japanese individuals. Pharmacodynamic responses appeared to be similar between Japanese and White patients; however, the data were limited to three Japanese patients. Overall, no dose adjustments were considered necessary for Japanese patients. ⁶⁹

Elotuzumab

Elotuzumab (Empliciti) is an IgG1 mAb approved in the United States and Japan for multiple myeloma. A PopPK model was developed with concentrations from 420 patients (343 [81.7%] non‐Japanese and 77 [18.3%] Japanese) in Phase 1/2/3 studies. ⁷⁰ PK was best characterized by a linear two‐compartment model with parallel linear (non‐specific) and non‐linear (Michaelis–Menten type) elimination from the central compartment and an additional target‐mediated elimination from the peripheral compartment. The sponsor identified Japanese ethnicity as a significant covariate on V_c, with a 15% lower V_c in Japanese patients compared to non‐Japanese patients, whereas Japanese ethnicity was not a significant predictor of non‐specific CL. The sponsor did not find any evidence to suggest any ethnicity‐related differences in Michaelis–Menten or target‐mediated elimination. While the impact of Japanese ethnicity on V_c was unexplained, the overall difference in AUC between Japanese and non‐Japanese was <20%, and the sponsor did not consider it clinically relevant. Further, model‐based simulations showed that all model‐predicted exposure metrics (C_{avg, ss}, C_{max, ss}, and C_{min, ss}) were similar between Japanese and non‐Japanese patients. The sponsor concluded that a lack of Japanese ethnicity has no impact on the elotuzumab PK/exposure to warrant any dose adjustments. ⁷⁰

Idarucizumab

Idarucizumab (Praxbind) is approved in the United States and Japan as a reversal agent for dabigatran. A PopPK model was developed with concentrations from 140 (63.6%) Caucasians and 80 (36.3%) Japanese healthy volunteers in Phase 1 trials. ⁹⁰ , ⁹¹ Idarucizumab disposition was best described with a linear three‐compartment model. The investigators identified Japanese ethnicity as a significant covariate on PK, with ∼11% lower CL in Japanese subjects resulting in 11% higher AUC relative to the Caucasian subjects. The investigators reported the observed difference was due to the lower BW of Japanese (∼61‐65 kg) compared to Caucasians (∼80 kg). After BW normalization, the exposure difference was reported to be negligible, and therefore no dose adjustments were recommended. ⁹⁰ , ⁹¹

Lecanemab

Lecanemab (Leqembi) is an IgG1 mAb approved in the United States and Japan for Alzheimer's disease. A PopPK analysis was conducted from phase 1/2 trial data in 725 subjects (626 [86.3%] Whites, 26 [3.6%] Black/African Americans, 15 [2.1%] Asians [excluding Chinese and Japanese], 50 [6.9%] Japanese, and 8 [1.1%] American Indian/Alaskan). ¹⁰³ , ¹⁰⁴ Lecanemab PK was described by a two‐compartment model. The authors identified Japanese ethnicity as a significant covariate on V_p, with ∼0.45‐fold lower V_p in Japanese compared to the non‐Japanese subjects. The effect of Japanese ethnicity (90% CI) on lecanemab AUC_ss and C_{max, ss}, however, was within the bioequivalence criteria of 0.80‐1.25. Hence, the authors did not consider Japanese ethnicity to have a clinically meaningful impact on lecanemab exposure to warrant any dose adjustments. ¹⁰³ , ¹⁰⁴

Natalizumab

Natalizumab (Tysabri) is an IgG4 mAb approved in the United States and Japan for multiple sclerosis. ¹¹⁴ Mean C_max was 84.8 and 121.4 mg/mL, and t_1/2 was 10.4 and 15.2 days in American and Japanese patients, respectively, after a single‐dose of natalizumab in Phase 2/3 trials. Natalizumab was also administered as multiple doses using extended‐interval dosing (EID) regimens ranging from 4 to 16 weeks. The mean C_max observed in American and Japanese patients were 15.3 and 47.0 mg/mL with a 4‐week, 2.01 and 11.0 mg/mL with an 8‐week, 0.78 and 5.19 mg/mL with a 10‐week, 0.30 and 2.69 mg/mL with a 12‐week, and 0.05 and 0.74 mg/mL with a 16‐week EID, respectively. C_max was consistently higher in the Japanese compared to the American patients with single‐dose or EID natalizumab regimens. The authors reported that the difference was the result of ∼20% lower BW of Japanese patients (∼57.6 kg) compared to American patients (∼72 kg). Overall, despite the observed PK differences, several studies demonstrated the safety and efficacy to be similar between the two populations, and therefore, the same dosing regimen was approved in both countries. ¹¹⁴ , ¹⁷⁸ , ¹⁷⁹

Nipocalimab

Nipocalimab (Imaavy) is an anti‐neonatal Fc receptor (FcRn) IgG1 mAb approved in the United States and Japan for rare autoimmune diseases. A PopPK model was developed using concentrations from Phase 1/2/3 studies in 422 patients (183 Whites, 24 Japanese, 49 Chinese, and 166 Others). A two‐compartment model parameterized in terms of CL, V_c, V_p, Q, and rate of internalization (target‐mediated elimination) of the FcRn‐nipocalimab complex best described the PK. The sponsors identified Japanese ethnicity as a significant covariate on V_c, with V_c ∼14% higher in Japanese patients compared with White patients. However, this difference did not translate into clinically meaningful differences in steady‐state exposures. Model‑derived comparisons of exposure demonstrated that geometric mean ratios (Japanese vs Whites) and corresponding 90% CI for steady‑state exposures (C_{max, ss}: 0.93 [0.87‐0.99] and AUC_{tau, ss}: 0.91 [0.85‐0.97]) were fully contained within the 0.80‐1.25 range. Overall, the authors concluded that no dose adjustment is required for Japanese patients. ¹¹⁸

Nirsevimab

Nirsevimab (Beyfortus) is an IgG1 mAb approved in the United States and Japan for respiratory syncytial virus infection. A PopPK analysis was conducted from Phase 1/2/3 trial data which included 2836 subjects (1389 [64.8%] Whites, 620 [21.9%] Black/African Americans, 88 [3.1%] Asians [75% Japanese], 66 [2.3%] American Indians/Alaskans, 17 [0.6%] Native Hawaiians/Pacific Islanders, 34 [1.2%] multiple ethnicity, 168 [5.9%] other ethnicities, and 4 [0.1%] unknown ethnicity). ¹¹⁹ A linear two‐compartment model with first‐order absorption and first‐order elimination from the central compartment best described the PK. The sponsor found the group including Asians to be a statistically significant covariate for CL and V_c, with a ∼9% lower CL and 22.6% lower V_c compared to the White and Native Hawaiian/Pacific Islander population. In a subsequent exposure–response analysis, the sponsor identified Japanese status and AUC quartiles as potential predictors in a Kaplan–Meier analysis. The final exposure–response model, a Cox proportional hazards model, however, included only AUC quartiles as predictors. Thus, the sponsor did not consider the effect of Japanese ethnicity on PK to be clinically relevant to warrant any dose adjustments. ¹¹⁹

Nivolumab

Nivolumab (Opdivoag) is an IgG4 anti‐PD‐1 mAb approved in the United States and Japan for non‐small cell lung cancer. A PopPK analysis was conducted using concentrations from 34 Japanese patients receiving 240 mg every 2 weeks of nivolumab. PK was described using a two‐compartment, zero‐order IV infusion, and time‐varying clearance model. ¹⁸⁰ The authors reported that mean nivolumab CL in Japanese patients (0.0064 L/h) was lower than values in PopPK analyses of previous clinical trials in non‐Japanese patients (0.0094 L/h [CV 35%], ¹²⁰ 0.011 L/h [CV 31%], ¹⁸¹ and 0.0088 L/h [CV 31%] ¹²¹ ). The authors stated that the difference in CL was due to the lower BW of the Japanese population (62.7 kg) than that of the past reports (79.1, 80, and 78.5 kg). These studies had reported BW as a covariate of CL. Another PopPK model was used to assess the impact of race (Asian vs non‐Asian) on nivolumab exposure. The analysis included 387 patients, 28 (84.75%) Asians (including 15.85% Japanese), and 59 (15.24%) non‐Asians. ¹⁸¹ The authors reported nivolumab exposures (C_{min, ss}, C_{max, ss}, and C_{avg, ss}) at 240 mg every 2 weeks were higher in Asian patients (51, 115, and 72 µg/mL, respectively) due to their lower BW compared to the non‐Asians (35.6, 86.4, and 53.5 µg/mL, respectively). The authors reported the higher exposures in Asians to not have an impact on the safety of nivolumab, which further supported the use of the same dosing regimen in both populations.

Ofatumumab

Ofatumumab (Arzerra) is an anti‐CD20 IgG1κ mAb in the United States and Japan for lymphocytic leukemia. A Phase 2 trial was conducted in 43 patients (21 [48.8%] Japanese and 22 [51.2%] White Russians) who received 20 mg every 4 weeks ofatumumab subcutaneously for 24‐48 weeks. ¹²³ Trough concentrations (C_trough) were compared between the two groups at pre‐defined time‐points. Mean C_trough was higher in Japanese patients than in Russian patients. The point estimate ratios (Japanese vs Russians subjects) for C_trough were 1.79, 1.46, 1.75, and 1.27 on days 2, 5, 7 and 14, respectively, and 1.32, 1.73, 1.31, 1.04, 1.34, and 1.18 on weeks 4, 12, 24, 28, 36, and 48, respectively. The sponsor attributed C_trough differences to lower BW in the Japanese (∼54.1 kg) compared with the Russian patients (∼62.4 kg). Overall, the sponsor stated that the observed PK differences did not affect the safety or efficacy of ofatumumab across the groups to warrant dose adjustments. ¹²³

Omalizumab

Omalizumab (Xolair) is an IgG1 mAb approved in the United States and Japan for allergic asthma. It selectively and reversibly binds to human IgE, forming an omalizumab‐IgE immune complex, thus decreasing free IgE levels. A PopPK/PD analysis was conducted to determine the impact of Japanese ethnicity on the PK of omalizumab and the free IgE profile (pharmacodynamics). ¹²⁶ Concentrations from 12 studies in 3229 patients (322 (9.97%) Japanese and 2907 (90.02%) non‐Japanese (2325 [80%] Caucasians, 239 [8%] Blacks, 26 [1%] Oriental, and 317 [11%] Others) were included in the analysis. A one‐compartment model of reversible omalizumab‐IgE binding and turnover best described the disposition of free omalizumab, free IgE, and omalizumab‐IgE complex. The sponsor identified Japanese ethnicity as a significant covariate on clearances of free drug (CL) and drug‐IgE complex (CL_c), V_d, and drug‐IgE binding constant (K_d). CL and CL_c were 12% and 13% higher, and V_d was 16% smaller in Japanese compared to Caucasian patients, respectively. Also, omalizumab bound to IgE with greater affinity in the Japanese subjects, with an ∼19% lower K_d than for Caucasians. The effect of Japanese ethnicity was further explored using simulated steady‐state PK/PD profiles of Japanese and Caucasian patients. The authors stated that although clearance was faster and drug exposure was lower in the Japanese compared to the Caucasians, the more potent IgE binding in the Japanese patients resulted in the same degree of free IgE suppression as in the Caucasian patients. Therefore, the authors concluded Japanese ethnicity to not have a clinically meaningful effect on the pharmacodynamics/efficacy of omalizumab that requires dosage adjustment. ¹²⁶

Retifanlimab

Retifanlimab (Zynyz) is an IgG4 anti‐PD‐L1 mAb developed for squamous cell carcinoma. A Phase 1/1b study at a 500‐mg every 4 weeks IV dose of retifanlimab was conducted in 6 Japanese patients and 40 Western patients. ¹⁴¹ In Japanese patients, the mean C_max, AUC_tau, and AUC_inf following the first dose were 31%, 47%, and 66% higher, and the mean concentration observed at the end of the 4‐week dosing interval (C_{tau, ss}) was 43% higher compared to the Western patients. Although retifanlimab exposures were higher in Japanese relative to Western patients, mean CL and V_d were comparable in the two populations when normalized for BW (Japanese: 0.00310 L/day/kg and 0.0955 L/kg, respectively; Western: 0.00405 L/day/kg and 0.0857 L/kg, respectively). Therefore, the sponsor did not recommend dose adjustments based on ethnicity. ¹⁴¹

Risankizumab

Risankizumab (Skyrizi) is an anti‐IL‐23 IgG1 mAb approved in the United States and Japan for plaque psoriasis. A Phase 1 study compared PK in 12 White and 12 Japanese healthy volunteers who received 18 mg or 300 mg risankizumab subcutaneously (n = 6 per group). ¹⁴² Japanese and White subjects had average BW of 62 kg and 79 kg, respectively. For risankizumab at either dose levels, the t_max was 7 days for both ethnic groups. Similarly, t_1/2 was also comparable across ethnic groups (18 mg: 32.5 days Japanese vs 30.5 days Whites; and 300 mg: 29.7 days Japanese vs 28.7 days Whites). There was a significant difference in C_max and AUC_inf between the Japanese and White subjects. The point estimates (90% CI) for the C_max and AUC_inf ratios (Japanese/Whites) were 1.32 (1.03‐1.69) and 1.31 (1.10‐1.56), respectively. The authors stated that this exposure difference was reported to be the result of lower BW for the Japanese compared with the White subjects. After accounting for BW differences, the authors reported risankizumab exposures to be comparable across the two groups (C_max: 0.84 [0.61‐1.14] and AUC_inf: 1.02 [0.81‐1.30]); thus, alternative dosage regimens based on ethnicity were not required. ¹⁴²

Rituximab

Rituximab (Rituxan) is an anti‐CD20 IgG1 mAb approved in the United States and Japan for non‐Hodgkin lymphoma. A Phase 1 trial in 8 Japanese patients evaluated rituximab at 375 mg/m² every 4 weeks IV, ¹⁸² while Phase 1 and 2 trials in the United States used the same dose in 10 and 37 patients, respectively. ¹⁴³ , ¹⁸³ The sponsor reported that C_max was significantly lower in Japanese patients compared to the US patients, at 78.8% in Phase 1 and 81.6% in Phase 2 trials, respectively. t_1/2 was significantly higher in the Japanese (15.8 days) than in the US subjects (3.19 days in Phase 1 and 8.41 days in Phase 2). The observed PK differences were attributed to differences in CD20 expression rather than ethnicity. Further, the sponsor reported that the safety/efficacy profiles of rituximab were similar between the US and Japanese individuals, and therefore, no dose adjustments were necessary. ¹⁴³ , ¹⁸²

Romosozumab

Romosozumab (Evenity) is an IgG2 mAb approved in the United States and Japan for osteoporosis. A PopPK analysis was conducted with concentrations from 11 trials in 1459 healthy subjects and postmenopausal women with osteoporosis (743 [50.9%] Whites, 64 [4.38%] Blacks, 102 [7%] Hispanics, 30 [2.05%] Asians, 208 [14.25%] Japanese, and 312 [21.3%] Others). ¹⁴⁴ A three‐compartment model with linear distribution to peripheral compartments and parallel linear elimination from the central compartment and target‐mediated non‐linear elimination from the peripheral compartments, along with a saturable, FcRn‐mediated SC absorption, was used to describe the PK of romosozumab. The sponsor identified Japanese ethnicity as a significant covariate for CL (point estimate 1.11). However, an exposure–response analysis indicated that the impact of Japanese ethnicity on the PK resulted in <20% change in C_{max, ss} and AUC_ss, which did not impact the efficacy/safety of romosozumab to a clinically relevant extent. Therefore, the sponsor did not recommend dosage adjustments based on Japanese ethnicity. ¹⁴⁴

Rozanolixizumab

Rozanolixizumab (Rystiggo) is an IgG4 anti‐FcRn mAb approved in the United States and Japan for myasthenia gravis. A Phase 1 study was conducted in Japanese, Chinese, and Caucasian healthy adults at 3, 7, and 10 mg/kg. ¹⁴⁵ The sponsor reported that exposures tend to be lower in Japanese and Chinese compared to Caucasians. The sponsor stated the difference was due to the lower BW of Chinese and Japanese subjects. After accounting for BW differences, PopPK/PD analysis revealed that ethnicity was not a significant covariate for the PK/PD of rozanolixizumab. In the final PopPK/PD analysis, the subjects were grouped as either Asian (Chinese and Japanese) or non‐Asian (Caucasians), and no significant differences in CL or Vd were found between the two groups that warrant any dose adjustments. ¹⁴⁵

Sarilumab

Sarilumab (Kevzara) is an anti‐IL‐6 IgG1 mAb approved in the United States and Japan for RA. In a Phase 1 study, 24 Japanese patients received single‐dose SC administration of sarilumab 50, 100, or 200 mg. The sponsor reported that exposure tended to be higher in Japanese patients than in Caucasians. The exposure difference was linked to the BW difference between Japanese (56.5 kg) and Caucasian patients (76.5 to 78.2 kg). Moreover, in a PopPK analysis with concentrations from 1554 Caucasians (88%), 105 Asians (24 Japanese; 6%), 60 Blacks (3%), and 51 Other race (3%) patients, the sponsor did not identify race (Caucasians vs non‐Caucasians) as a significant covariate influencing PK. Therefore, the sponsor concluded that the observed differences in exposure do not have a clinically significant impact on sarilumab PK that necessitates dose adjustments. ¹⁴⁶

Sutimlimab

Sutimlimab (Enjaymo) is an IgG4 mAb approved in the United States and Japan for hemolytic anemia. A PopPK model was developed with concentrations from 196 participants (30 Japanese and 166 non‐Japanese) in Phase 1/3 studies. ¹⁵² , ¹⁵³ The PK was best described by a two‐compartment model with parallel linear and nonlinear (Michaelis–Menten) clearance pathways. The sponsor identified Japanese ethnicity as a significant covariate on V_c and maximal elimination rate (V_max) for the nonlinear pathway. Japanese subjects had a 29% lower V_c and a 30% lower V_max compared to non‐Japanese subjects. AUC was 23% to 33% greater in the Japanese compared to the non‐Japanese. The sponsor demonstrated that ethnic differences did not affect the PK, safety, or efficacy of sutimlimab to a clinically significant extent, and therefore, no dose adjustment was necessary. ¹⁵² , ¹⁵³

Tralokinumab

Tralokinumab (Adtralza) is an anti‐IL‐13 IgG4 mAb approved in the United States and Japan for atopic dermatitis. A Phase 1, single‐dose study was conducted in 20 non‐Japanese (80% Whites) and 20 Japanese healthy volunteers who received 150 or 300 mg SC tralokinumab (n = 10 per group). ¹⁶⁵ The sponsor reported mean C_max in Japanese subjects was 42.6% and 24.5% greater for the 150 and 300 mg doses, respectively, with corresponding 37.2% and 38.9% higher AUC_inf values compared to the non‐Japanese subjects. The observed higher exposures in the Japanese were consistent with 28% and 31% lower CL compared to the non‐Japanese participants for the 150 and 300 mg doses, respectively. t_1/2 (150 mg: 20.02 days Japanese vs 19.2 days non‐Japanese and 300 mg: 20.95 days Japanese vs 19.4 days non‐Japanese) and t_max (150 mg: 6 days Japanese vs 5 days non‐Japanese and 300 mg: 5 days Japanese vs 5 days non‐Japanese) were comparable between the groups. The sponsor explained the observed differences by the lower BW of Japanese participants (∼63.5 kg), 15.3% lower than that of the non‐Japanese participants (∼75 kg). The sponsor did not consider the variability in PK parameters to be clinically relevant to justify dose adjustment, as the slight increase in exposure in Japanese participants did not translate into a meaningful difference in efficacy/safety of tralokinumab. ¹⁶⁵

Ustekinumab

Ustekinumab (Stelara) is an anti‐IL12/23 IgG1_k mAb approved in the United States and Japan for psoriasis. The sponsor compared the PK between 94 Japanese and US healthy adults who received a 45‐mg SC dose of ustekinumab. These comprised 6 (6.38%) Japanese, 71 (75.5%) non‐Japanese ≤80 kg, and 17 (18.08%) non‐Japanese >80 kg. ¹⁷⁰ The sponsor reported that exposures were comparable between the Japanese and non‐Japanese ≤80 kg participants with point estimates for AUC_inf and C_max ratios as 0.96 and 1.11, respectively. However, exposures were slightly higher in Japanese participants compared to the non‐Japanese >80 kg participants. The point estimates for AUC_inf and C_max ratios were 1.26 and 1.37, respectively. The sponsor related these differences to the differences in BW. The BW‐adjusted mean CL/F and V_d/F were comparable across the three groups. Estimates for CL/F and V_d/F in Japanese, non‐Japanese ≤80 kg, and non‐Japanese >80 kg participants were 0.000020, 0.000019, and 0.000020 L/h/kg and 0.11, 0.12, and 0.11 L/kg, respectively. After BW adjustments, the sponsor reported PK to be consistent across the groups, and no dose adjustments were recommended. ¹⁷⁰

mAbs With Reported Lack of Differences in PK Between Japanese and Non‐Japanese Individuals

For the 101 mAbs approved in the United States and Japan, the FDA/sponsors judged that the PK was similar between Japanese and non‐Japanese individuals for 59 mAbs. A summary of the available PK parameters for the two populations obtained from published FDA reviews and research articles is provided in Table S1.

The sponsors/authors reported 26 mAbs (mirikizumab, ¹⁰⁹ aniforlumab, ²⁸ , ²⁹ evinacumab, ⁷⁸ fremanezumab, ⁸² galcanezumab, ⁸³ lanadelumab, ¹⁰¹ tildrakizumab, ¹⁶¹ emicizumab, ⁷⁴ brodalumab, ⁴⁴ , ⁴⁵ olaratumab, ¹²⁴ , ¹²⁵ necitumumab, ¹¹⁵ , ¹¹⁶ evolocumab, ⁷⁹ , ⁸⁰ secukinumab, ¹⁴⁷ blinatumomab, ⁴³ , ¹⁸⁴ pembrolizumab, ¹²⁹ , ¹³⁰ ramucirumab, ¹³⁴ , ¹³⁵ pertuzumab, ¹³¹ , ¹³² ipilimumab, ⁹⁶ , ⁹⁷ , ¹⁸⁵ golimumab, ⁸⁶ certolizumab pegol, ⁵¹ adalimumab, ²⁴ trastuzumab, ¹⁶⁶ , ¹⁶⁷ nemolizumab, ¹¹⁷ marstacimab, ¹⁰⁷ zolbetuximab, ¹⁷⁶ and garadacimab ⁸⁴ ) with comparable PK parameters in both Japanese and non‐Japanese subjects along with point estimates for C_max and AUC ratios (Japanese vs non‐Japanese) to be within or close to the 0.8‐1.25 CI. Only seven mAbs had values beyond these ranges: mosunetuzumab (C_max ratio: 1.84), ¹¹¹ , ¹¹² cilgavimab (300 mg intramuscular [IM]–AUC_inf ratio: 1.37 and C_max ratio: 1.39), ¹⁶² guselkumab (30 mg SC–AUC ratio: 1.34 and C_max ratio: 1.31, 100 mg SC–AUC ratio: 1.47), ⁸⁷ , ⁸⁸ cetuximab (initial/weekly 500/250 mg/m²–AUC ratio: 1.4 and C_max ratio: 1.6), ⁵² , ⁵³ palivizumab (3 mg/kg IM–C_max ratio: 0.61), ⁹ , ¹³ , ¹²⁷ daclizumab (75 mg SC–C_max ratio: 1.39), ⁵⁹ and elranatamab (C_max ratio: 1.7). ⁷¹ , ⁷² There were some exceptions with comparable exposure metrics: tezepelumab t_max was significantly higher in Japanese (7‐10 days) versus non‐Japanese (3.9 days) healthy subjects, ¹⁵⁹ , ¹⁶⁰ and mepolizumab t_1/2 was significantly longer in Japanese healthy volunteers (36.1 days) compared to the White patients (18.5 days). ¹⁰⁸ , ¹⁸⁶ Despite these deviations in PK parameters, based on the magnitude of the differences and the totality of the available data, the sponsors/authors concluded PK to be similar between Japanese and non‐Japanese individuals with no necessity for changes to dosing regimens. The reason for these slight PK variations could be due to differences in clinical trial designs, except for cilgavimab, where the sponsor explicitly attributed the slightly higher exposures in Japanese participants to the lower BW of the Japanese compared to the Whites. ¹⁶²

The sponsors/authors conducted PopPK analyses for five mAbs (amivantamab, ²⁷ mogamulizumab, ¹¹⁰ panitumumab, ¹²⁸ bevacizumab, ¹³ , ⁴⁰ and depemokimab ⁶² ) and concluded that Japanese ethnicity was not a significant covariate to have a meaningful impact on the PK of these mAbs.

For three mAbs, spesolimab, ¹⁵¹ atezolizumab, ³¹ , ³² and vedolizumab, ¹⁷¹ , ¹⁷² , ¹⁷³ the sponsor/authors compared the PK at different dose levels and reported that the ranges of PK parameters in Japanese were, on average, close to the ranges reported in non‐Japanese individuals.

For the remaining 16 of 59 mAbs, the sponsor/authors described PK to be similar between Japanese and non‐Japanese, but did not report direct comparisons of PK parameters. ²⁵ , ³⁶ , ⁵⁵ , ⁶¹ , ⁹² , ⁹³ , ⁹⁴ , ⁹⁸ , ⁹⁹ , ¹⁰⁰ , ¹²² , ¹³⁶ , ¹³⁷ , ¹⁴⁸ , ¹⁴⁹ , ¹⁵⁰ , ¹⁵⁴ , ¹⁵⁶ , ¹⁶³ , ¹⁷⁴ , ¹⁸⁷

mAbs With Reported Lack of Sufficient Data to Identify Differences in PK Between Japanese and Non‐Japanese Individuals

For the four mAbs, epcoritamab, ⁷⁵ faricimab, ⁸¹ burosumab, ⁴⁷ and durvalumab ⁶⁸ (Table S2), the sponsors/authors reported that the PK differences between Japanese and non‐Japanese could not be identified with adequate statistical power due to an insufficient number of Japanese subjects investigated.

Most of the mAbs from Table 1 not listed in Sections 1‐3 were not approved in Japan, and therefore, we did not find evidence of clinical trials in Japanese individuals, or PK was not compared between the Japanese and other ethnicities in GCTs. For the remaining mAbs, it was not reported whether Japanese subjects were part of the Asian subgroup in clinical trials or PopPK analyses, and hence, potential PK differences between Japanese and other ethnicities are unknown.

Discussion

The regulatory requirements based on the ICH E5 guideline have proven to be a critical step for PMDA in implementing simultaneous global drug development that increased the participation of Japanese centers in GCTs and the approval of new drugs in Japan. ³ , ⁵ , ⁶ , ⁷ Evaluation of potential inter‐ethnic differences in PK and safety was mandated to confirm that risks in the Japanese population are equivalent with non‐Japanese groups and for interpretation of clinical data from bridging studies to allow extrapolation of non‐Japanese data for the development of new drugs. ⁵ Accordingly, sponsors usually conduct PK and safety studies in a small number of Japanese subjects for the determination of ethnic differences or similarities with non‐Japanese individuals and to meet the ethnic bridging requirement.

Here, we compared the PK between Japanese and other ethnicities for each of the mAbs currently approved in the United States and Japan. First, we found that the sponsors/authors stated the observed differences in the PK between Japanese and non‐Japanese were either due to differences in BW or target binding affinity. BW has often been identified as a significant covariate in PopPK analyses for mAbs. ¹⁸⁸ However, the sponsor/authors suggest that slight ethnic differences in BW, such as the difference between Japanese and Caucasians with 10%‐20%, result for most mAbs only in minor to moderate effects on exposure (PK) with no clinically relevant impact on safety and efficacy. Additionally, after BW adjustments, no apparent differences were observed in the exposure for most mAbs. The difference in target binding affinity depends on the disease status or stage and baseline target level, ¹⁸⁹ as seen with omalizumab. However, the pharmacodynamic outcome of greater target binding affinity in Japanese patients in this specific example was counterbalanced by slightly higher mAb exposures in Caucasians, resulting in no necessity for dose adjustments based on ethnicity.

To further explore whether specific drug target characteristics may be the underlying cause of the observed PK differences, we categorized the 26 mAbs with reported PK differences according to target biology (i.e., soluble vs membrane‐bound, shedding characteristics, and anatomical distribution such as vascular vs extravascular). This analysis did not identify any single dominant target characteristic consistently associated with ethnicity‐driven PK differences. Instead, the differences were sporadic and modest across all categories and, when interpreted in the context of overall variability, do not support a mechanistic link between target biology and ethnicity‐related PK differences. Moreover, no consistent trends were observed at the level of individual targets (Table 1), further supporting the absence of a target‐specific effect.

Second, a direct comparison of PK parameters showed no ethnic difference between Japanese and non‐Japanese individuals for 59 mAbs, with a few exceptions. Among these, 26 mAbs, regardless of their dosing scheme, administration routes, clinical trial stage, or disease condition, met the bioequivalence similarity criterion in both C_max and AUC, along with similarity in other PK parameters (t_1/2, t_max, CL, or V_d). Nine of these mAbs did not meet the predefined AUC and C_max criteria or showed slight differences in other PK parameters, but based on the degree of deviations and totality of data, the sponsors/authors judged their PK to be similar in Japanese versus non‐Japanese individuals with no necessary changes to dosing regimens. Furthermore, based on PopPK analyses for five mAbs, the sponsors/authors concluded that Japanese ethnicity did not have a clinically meaningful impact on PK and did not warrant any dose adjustments.

Our findings are similar to those previously reported by Zhou et al, ¹² Chiba et al, ¹³ and Matsushima et al ⁹ for much smaller mAb datasets. These authors also found differences in the PK because of the marked differences in the BW between Japanese and the US healthy volunteers, and concluded the difference was within safety margins, which did not necessitate different dosing regimens in the two populations, ¹² , ¹³ or the doses selected for Japanese patient trials were the same as those stated in the approved US labels. ¹³ Chiba et al demonstrated PK similarity between Japanese and Caucasians based on C_max and AUC ratios for the limited mAb data investigated in their publication to be within the PMDA‐established “similarity criterion” 0.6‐1.4 and 0.6‐1.3, respectively, ¹³ while Matsushima et al utilized the standard bioequivalence criterion for comparison. ⁹ Matsushima et al fitted PK profiles of various mAbs to a typical IgG pharmacokinetic model and showed that most mAbs exhibited similar PK behavior across the Japanese and non‐Japanese healthy subjects, and any deviations from this pattern did not result from inherent ethnic differences. ⁹ , ¹³ Further, a pharmacometric analysis of IgPro10 (proline‐stabilized, 10% IV IgG [IVIG] formulation) in Japanese and non‐Japanese patients with primary immunodeficiency reported that PK parameters of serum IgG were similar between the two populations. ¹⁹⁰

These results support the notion that mAbs are most likely ethnically insensitive compared to small‐molecule drugs because of the properties recognized by the ICH E5 guideline. These include minimal hepatic cytochrome P450 (CYP450) metabolism, low susceptibility to dietary absorption effects, and little potential for food and drug interactions. ¹²

The elimination of mAbs, as well as endogenous IgG, from the human body is largely mediated by nonspecific proteolytic catabolism by lysosomal degradation after intracellular uptake by pinocytosis, an unspecific fluid phase endocytosis, or by a receptor‐mediated endocytosis. ¹⁹¹ , ¹⁹² The latter may be facilitated by a variety of membrane‐standing receptor systems, including the Fcγ receptors expressed on many immune cells, and the pharmacologic target of the mAb, denoted as target‐mediated drug disposition (TMDD). ¹⁹³ , ¹⁹⁴ These elimination processes are further modulated by the interaction of mAbs with FcRn, a salvage pathway that may prevent some IgG molecules from undergoing lysosomal degradation, thereby providing a protective mechanism for IgGs in order to limit their degradation and facilitate their prolonged systemic residence time. ¹⁸⁹ , ¹⁹² , ¹⁹⁵ Although genetic polymorphisms have been described for FcγR ⁹⁵ , ¹⁹⁶ , ¹⁹⁷ and FcRn, ¹⁹⁸ their impact as a source of ethnic differences in mAb disposition has not been reported. Since mAbs and endogenous IgG undergo elimination via the same common non‐specific proteolytic degradation and no ethnic differences in the elimination of endogenous IgGs between Japanese and non‐Japanese individuals have been described, one could conclude that most mAbs are also likely to have no ethnicity‐specific differences in their elimination. ¹² , ¹³

Elimination of many mAbs is also facilitated through interaction of the complementarity‐determining region of the mAb with its specific target epitope, resulting in endocytosis of the mAb‐target complex and subsequent lysosomal degradation. This elimination process is referred to as TMDD. ¹⁹² TMDD is an important determinant for the PK of many mAbs and is primarily driven by factors such as dose of the mAb, target expression, binding affinity, and internalization efficiency, which may all vary across individuals but have not been shown to differ consistently by ethnicity. Based on the data reviewed in this manuscript, we did not identify evidence of ethnicity‐related differences in TMDD between Japanese and non‐Japanese populations. In cases where differences in target binding or baseline target expression levels were observed (e.g., omalizumab), these were attributable to disease characteristics rather than intrinsic ethnic factors and did not translate into clinically meaningful differences in pharmacodynamic response or dosing adjustments based on ethnicity. Importantly, TMDD is generally saturated at therapeutic dose levels for most mAbs as it is intended to block most of the target receptors. As a result, its influence on PK is very limited under clinical dosing conditions. ¹⁹² Consequently, TMDD is unlikely to contribute meaningfully to ethnic differences in PK or necessitate ethnicity‐specific dose adjustments.

Furthermore, mAbs are delivered by IV, SC, or intramuscular administration, ¹⁹¹ , ¹⁹² and thus dietary interference with absorption processes as a potential source of ethnicity‐related PK differences is considered irrelevant. Another factor that contributes to the differences in mAb PK or exposure is the development of immunogenicity in the form of anti‐drug antibodies (ADA). ¹⁹² , ¹⁹⁹ However, based on the available clinical data for all mAbs reviewed in this manuscript, we did not find evidence of ethnicity‐related differences in ADA incidence or its impact on PK between Japanese and non‐Japanese populations, and no ADA‐driven ethnicity‐specific dose adjustments appear to be warranted. It should be noted, however, that due to the small sample sizes of most PK assessments in Japanese individuals, these studies were not powered to detect any meaningful differences in ADA incidence and severity between Japanese and non‐Japanese individuals.

Conclusions

This work provides a detailed and systematic review of clinical studies evaluating PK differences between Japanese and other ethnicities for the currently approved mAbs. Our findings corroborate that there are essentially no or minimal differences in mAb PK between Japanese and non‐Japanese individuals, and these minor differences do not translate into a clinically meaningful impact on pharmacodynamics, safety, and efficacy. This is further substantiated by the fact that the same dosing regimens have been approved in the United States and Japan for all mAbs reviewed in this work. Based on our results, we suggest that the need for dedicated PK studies in the Japanese population for mAbs may need to be re‐evaluated, and question whether such studies could be waived when adequately justified for mAbs whose PK, safety, and efficacy have already been well‐characterized in other racial and ethnic populations.

Author Contributions

P.G. contributed to the conceptualization, data collection, writing, editing, and final approval of the manuscript. A.S. and B.M. contributed to the conceptualization, reviewing, editing, and final approval of the manuscript.

Conflicts of Interest

A.S. is an employee of Boehringer Ingelheim Pharmaceuticals. P.G. and B.M. have no conflicts of interest to declare.

Funding

No funding has been received in support of the writing of this article.

Supporting information

Supporting information