Drug–drug interaction profile of ritlecitinib as perpetrator and victim through cytochrome P450

Vivek S Purohit; Yeamin Huh; Martin E Dowty; Anna Plotka; Alexandre Lejeune; Hindu Kalluru; Brian Hee

doi:10.1002/bcp.70069

. 2025 May 7;91(8):2316–2326. doi: 10.1002/bcp.70069

Drug–drug interaction profile of ritlecitinib as perpetrator and victim through cytochrome P450

Vivek S Purohit ^1,^8,^✉, Yeamin Huh ¹, Martin E Dowty ^2,⁷, Anna Plotka ³, Alexandre Lejeune ⁴, Hindu Kalluru ⁵, Brian Hee ⁶

PMCID: PMC12304827 PMID: 40331456

Abstract

Aims

To assess the effect of a potent cytochrome P450 (CYP) 3A inhibitor and CYP inducer on the pharmacokinetics of ritlecitinib, a JAK3/TEC family kinase inhibitor, and assess the effect of ritlecitinib on the pharmacokinetics of CYP substrates (midazolam, efavirenz, tolbutamide, caffeine and oral contraceptives [ethinyl oestradiol and levonorgestrel]) in healthy adults.

Methods

Seven clinical drug–drug interaction studies were analysed. Pharmacokinetic parameters for drugs as measured in blood plasma were used to estimate the drug interaction potential with ritlecitinib as a perpetrator or victim.

Results

Midazolam exposure (area under plasma concentration–time curve from time 0 to infinity [AUC_inf]) and peak exposure (maximum concentration [C_max]) were increased by ≈169% and ≈80.1%, respectively, in the presence of ritlecitinib. Efavirenz exposure (AUC_0–72) and peak exposure (C_max) were similar in the presence and absence of ritlecitinib coadministration. Tolbutamide pharmacokinetic parameters (AUC_inf and C_max) were not affected by multiple ritlecitinib doses. In the presence of ritlecitinib, AUC_inf and C_max of caffeine increased by ≈165% and ≈10%, respectively. AUC_inf and C_max of ethinyl oestradiol decreased by ≈18% and ≈12%, respectively, following coadministration of multiple ritlecitinib 200 mg once‐daily doses, but no relevant change was observed following multiple 50 mg once‐daily doses. Ritlecitinib doses did not affect the pharmacokinetics of levonorgestrel. Coadministration following multiple itraconazole doses increased ritlecitinib AUC_inf by ≈15%. Coadministration following multiple rifampicin doses decreased AUC_inf of ritlecitinib by ≈45%.

Conclusions

Ritlecitinib is a moderate inhibitor of CYP3A and CYP1A2. Strong CYP inducers can reduce ritlecitinib concentrations, but not to clinically relevant levels leading to lack of benefit.

Keywords: cytochrome P450, drug metabolism, drug–drug interaction, pharmacokinetics, ritlecitinib

What is already known about this subject

Ritlecitinib is a kinase inhibitor indicated for the treatment of severe alopecia areata at a 50 mg once‐daily dose.
Ritlecitinib is cleared primarily through metabolism via both glutathione conjugation and cytochrome P450 (CYP) family enzyme‐mediated oxidation.
Patients with alopecia areata may require medications as treatment for other conditions or comorbidities.

What this study adds

Ritlecitinib is a moderate inhibitor of CYP3A and CYP1A2. Concomitant use of ritlecitinib with some CYP3A and CYP1A2 substrates with narrow therapeutic indices should be accompanied by additional monitoring and necessary dosage adjustment per label,
Strong CYP inducers and inhibitors did not induce clinically relevant changes to ritlecitinib pharmacokinetics.

1. INTRODUCTION

Concomitant use of different medications is common; therefore, understanding pharmacokinetic (PK) drug–drug interactions (DDIs) is an important factor to consider during drug development. The US Food and Drug Administration and European Medicines Agency provide guidance on what drugs are important to test for potential DDIs during the course of drug development, as this information will help inform label warnings and information. ¹ , ²

Ritlecitinib is an oral, selective, dual inhibitor of JAK3 and the TEC family kinases. Treatment with ritlecitinib can affect downstream pathways implicated in the pathology of inflammatory diseases such as alopecia areata (AA) or vitiligo; affected pathways include cytokine signalling (interleukin [IL]‐2, IL‐7, IL‐9, IL‐15 and IL‐21) ³ , ⁴ , ⁵ , ⁶ , ⁷ and CD8⁺ T‐cell and natural killer cell functioning. ⁸ , ⁹ , ¹⁰ In June 2023 in the USA and July 2023 in the EU, ritlecitinib was approved as a treatment for severe AA in both adult and adolescent patients. ¹¹ , ¹² Patients with AA may receive concomitant medications as treatments for other conditions or comorbidities ¹³ ; therefore, it is important to identify DDI risk with ritlecitinib.

Ritlecitinib is cleared from the body primarily through metabolism via both glutathione conjugation and cytochrome P450 (CYP) family enzyme‐mediated oxidation. ¹⁴ However, no single pathway contributes >25% to the metabolism of ritlecitinib. Glutathione conjugation is predicted to contribute ≈24% to the metabolic disposition of ritlecitinib, while CYPs are predicted to contribute ≈47% collectively toward the metabolic disposition of ritlecitinib with contributions from (in order of magnitude of contribution) CYP3A4, CYP2C8/CYP1A2 and CYP2C9 (Table S1). ¹⁴ Previously, it was reported that ritlecitinib is an inhibitor of organic cation transporter 1 (OCT1), but not breast cancer resistance protein or organic anion transporter 3 or P1B. ¹⁵ Ritlecitinib has also been shown to be a time dependent inhibitor of CYP3A and CYP1A2 in vitro (Table S1).

The key in vitro study results that helped define the choice of clinical DDI studies are summarized in Table S1 and Supplemental Methods. Due to in vitro evidence that ritlecitinib can cause time‐dependent inhibition vs. CYP3A and CYP1A2 and that there was potential for ritlecitinib to induce CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19, the sensitive index CYP substrates midazolam, efavirenz, tolbutamide and caffeine were selected for study using US Food and Drug Administration guidance. ¹ Additionally, the oral contraceptives (OCs) ethinyl oestradiol (EE) and levonorgestrel (LN), being frequently prescribed and potential commonly concomitant medications, were chosen to be studied as potential victims (medications with PK that may be affected by ritlecitinib). Based on CYP3A contributions to clearance, studies with itraconazole, a potent CYP inhibitor, and rifampicin, a CYP (and glutathione S‐transferase) inducer, as potential perpetrators (medications that impact the PK of ritlecitinib) were also planned.

This manuscript describes the results and interpretation of the DDI studies conducted for ritlecitinib both as a victim and perpetrator to define its DDI potential through the CYP pathways. As perpetrator, the effects of ritlecitinib on the PKs of various relevant sensitive CYP probe substrates were evaluated (including midazolam, efavirenz, tolbutamide, caffeine, and OCs EE and LN). ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ As a victim, the effect of the potent probe CYP inhibitor itraconazole ²¹ and inducer rifampicin ²² on the PK of ritlecitinib was evaluated.

2. METHODS

2.1. Clinical study design, study participants and treatments

Seven clinical DDI studies were included in the analysis: 5 evaluated the effect of ritlecitinib (as perpetrator) on the PK of sensitive or clinically important CYP substrates and 2 evaluated the effect of a selective CYP3A4 inhibitor (itraconazole) or a pan‐CYP inducer (rifampicin) on the PK of ritlecitinib (as victim).

Protocols from all studies were reviewed and approved by the institutional review boards or ethics committees of the participating investigational centre. The studies were conducted in accordance with the International Council for Harmonization Guideline for Good Clinical Practice and the Declaration of Helsinki. All participants provided informed consent.

2.1.1. Midazolam and efavirenz study

This was a phase 1, randomized, 2‐way crossover, multiple‐dose, open‐label study of the effect of ritlecitinib on midazolam and efavirenz PK in healthy participants. Healthy adults (defined as no clinically relevant abnormalities) aged 18–55 years with a body mass index (BMI) of 17.5–30.5 kg/m² and a total body weight of >50 kg were eligible for the study. Twelve participants were randomized to 1 of 2 treatment sequences with 2 periods (Figure S1). Treatment sequence 1 consisted of a dose of oral midazolam 2 mg and efavirenz 50 mg on Day 1 (Period 1) following ≥10 h of overnight fasting. After a washout of ≥10 days, participants received oral ritlecitinib 200 mg once daily (QD) for 11 days, with a dose of oral midazolam 2 mg and efavirenz 50 mg on Day 10 (Period 2). Participants assigned to treatment sequence 2 received the same dosages, but with periods reversed.

The primary objective was to estimate the effect of multiple doses of ritlecitinib on the PK of a dose of oral midazolam and efavirenz; the primary endpoints were area under the plasma concentration–time curve from time 0 to infinity (AUC_inf) of midazolam and the area under the plasma concentration–time profile from time 0 to the quantifiable concentration 72 h postdose (AUC_0–72) of efavirenz. Truncated AUC was used for efavirenz due to its long half‐life consistent with established precedent. ²³ , ²⁴ Midazolam and efavirenz are components of the Basel cocktail for DDI studies where it was demonstrated that their concomitant administration as single doses is unlikely to have an interaction. ²³

2.1.2. Tolbutamide study

This was a phase 1, 2‐period, multiple‐dose, open‐label, single‐fixed sequence study to estimate the effect of ritlecitinib on tolbutamide PK in healthy participants aged ≥18 years. The study consisted of 2 treatment periods (Figure S1). On Day 1 of Period 1, a dose of tolbutamide 500 mg was administered. Immediately following Period 1, on Days 1–9 in Period 2, participants received ritlecitinib 200 mg QD. On Day 10, participants simultaneously received ritlecitinib 200 mg and tolbutamide 500 mg.

The primary objective was to estimate the effect of multiple doses of ritlecitinib on the PK of a dose of oral tolbutamide; the primary endpoints were AUC_inf and maximum concentration (C_max) of tolbutamide.

2.1.3. Caffeine study

This was a phase 1, 2‐period, fixed‐sequence, multiple‐dose, open‐label study of the effect of multiple doses of ritlecitinib on the PK of a dose of oral caffeine in healthy participants as previously described in Liu et al (Figure S1). ¹⁴ This manuscript provides a summary of this study to provide a more complete picture of the DDI profile of ritlecitinib.

2.1.4. OC study 1

A phase 1, randomized, 2‐way crossover, open‐label study of the effect of multiple doses of ritlecitinib 200 mg QD on single‐dose OC PK in healthy female participants of nonchildbearing potential (defined as postmenopausal, had undergone a hysterectomy and/or oophorectomy, and/or had ovarian failure). Healthy females aged 18–55 years with a BMI of 17.5–35.0 kg/m² and a total body weight of >50 kg were eligible for the study. Participants who were of childbearing potential (including participants with tubal ligations) were excluded from the study. Twelve participants were randomized to 2 treatment sequences. Each treatment sequence consisted of 2 periods (Figure S2). In Treatment Sequence 1 Period 1 Day 1, participants received 1 Portia tablet (EE 30 μg and LN 150 μg) orally. Period 2 followed immediately, with no washout, in which participants received oral ritlecitinib 200 mg QD for 9 days. On Day 10, oral ritlecitinib 200 mg and an oral Portia tablet were administered simultaneously. On Day 11, only ritlecitinib 200 mg was administered. In Treatment Sequence 2 Period 1, participants received ritlecitinib 200 mg QD for 9 days. On Day 10, ritlecitinib 200 mg and a Portia tablet were administered simultaneously. On Day 11, only ritlecitinib 200 mg was administered. Following Day 11, participants underwent a washout period of ≥10 days. In Period 2, participants received a Portia tablet on Day 1.

The primary objective was to estimate the effect of multiple doses of ritlecitinib 200 mg QD on the PK of single‐dose OC steroids EE and LN in healthy female participants; the primary endpoint was AUC_inf of EE. Other endpoints included the area under the plasma concentration–time profile from time 0 to the time of the last quantifiable concentration (AUC_last) of LN.

2.1.5. OC study 2

This was a phase 1, randomized, 2‐way crossover, open‐label study of the effect of multiple doses of ritlecitinib 50 mg QD on the PK of a single‐dose combination OC in healthy female participants. Healthy females (as determined by medical evaluation) aged 18–60 years of nonchildbearing potential (as described above) with a BMI of 17.5–35.0 kg/m² and a total body weight of >50 kg were eligible for the study. Participants who were of childbearing potential were excluded from the study. Two treatment sequences were administered (Figure S2). In Treatment Sequence 1 Period 1 Day 1, a Portia tablet was administered, with no washout between Periods 1 and 2. In Period 2, participants received ritlecitinib 50 mg QD for 9 days. On Day 10, ritlecitinib 50 mg and 1 Portia tablet were administered simultaneously. Participants then received ritlecitinib 50 mg QD on Days 11–13. In Treatment Sequence 2 Period 1, participants received ritlecitinib 50 mg QD for 9 days. On Day 10, ritlecitinib 50 mg and 1 Portia tablet were administered simultaneously. Participants then received ritlecitinib 50 mg QD on Days 11–13. A washout period of ≥10 days followed Period 1. Period 2 consisted of 1 Portia tablet.

The study's primary objective was to estimate the effect of multiple doses of ritlecitinib 50 mg QD on the PK of single‐dose OC steroids EE and LN in healthy female participants; the primary endpoint was AUC_inf of EE. Other endpoints included AUC_last of LN.

2.1.6. Itraconazole study

A phase 1, open‐label, fixed‐sequence, 2‐period study was conducted to investigate the effect of multiple oral doses of itraconazole on the PK of a dose of oral ritlecitinib in healthy participants. Healthy adult participants aged 18–55 years with a BMI of 17.5–30.5 kg/m² and a total body weight of >50 kg were eligible for the study. Participants received 2 treatments in a fixed sequence of 2 periods (Figure S3). On Day 1 of Period 1 after ≥10 h of overnight fasting, all participants received ritlecitinib 30 mg in the morning. Period 1 was immediately followed by Period 2 with no washout as ritlecitinib has a very short half‐life (<2 h). In Period 2 on Days 1–3, participants received a 200‐mg oral solution of itraconazole in the morning. On Day 4, following an overnight fast of ≥10 h, a 200‐mg oral solution of itraconazole followed by ritlecitinib 30 mg was administered. On Day 5, participants once again received a 200‐mg oral solution of itraconazole. Drugs were administered as 20 mL of an itraconazole 10‐mg/mL oral solution and 3 10‐mg ritlecitinib tablets, respectively.

The study's primary objective was to estimate the effect of multiple doses of itraconazole on the PK of a 30‐mg oral dose of ritlecitinib; the primary endpoints were AUC_inf and C_max of ritlecitinib.

2.1.7. Rifampicin study

This was a phase 1, open‐label, 2‐period, single fixed‐sequence study to evaluate the effect of repeat‐dose oral rifampicin on single‐dose ritlecitinib PK after a 50‐mg oral dose in healthy participants. Healthy adults aged 18–55 years with a BMI of 17.5–30.5 kg/m² and a total body weight of >50 kg were eligible for the study. Two treatments were administered in 1 fixed sequence (Figure S3). In the morning of Day 1 of Period 1, following an overnight fast of ≥10 h, participants received ritlecitinib 50 mg, followed by a 4‐h fast. Period 2 directly followed Period 1 with no washout as ritlecitinib has a very short half‐life (<2 h). On Days 1–7, rifampicin 600 mg QD was administered ≈1 h before the morning meal. In the morning of Day 8 after ≈8 h of overnight fasting, participants received rifampicin 600 mg 2 h prior to a dose of oral ritlecitinib 50 mg followed by a 4‐h fast. Ritlecitinib was provided as a 50‐mg tablet, and rifampicin as 2 300‐mg capsules.

The primary objective of the study was to estimate the effect of repeat‐dose rifampicin on the PK of a 50‐mg oral dose of ritlecitinib; the primary endpoints were AUC_inf and C_max of ritlecitinib.

2.2. Blood collection

For the OC studies, at prespecified timepoints, 6‐mL blood samples were collected from each participant to provide a minimum of 2 mL of plasma. For all other studies, 3‐mL blood samples were collected to provide a minimum of 1.2 mL of plasma.

2.3. Analytical methods for drugs in plasma

Plasma sample analyses for respective drug concentrations are summarized in Supplemental Methods.

2.4. Statistical methods and PK parameters

PK parameters for each drug were calculated for each participant and treatment using noncompartmental analysis of concentration–time data. Samples below the lower limit of quantitation were set to 0 for the analysis. Actual sample collection times were used for the PK analysis.

Natural log–transformed PK values (AUC_inf, AUC_0–72, AUC_last and C_max) were calculated using oNCA version 2.2.4. Estimates of the adjusted mean differences (test − reference) and corresponding 90% confidence intervals (CIs) were obtained from the model. The adjusted mean difference and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (test/reference) and 90% CIs for the ratios. Test treatments were coadministered drugs, while the reference treatment was a single dose of drug administered alone.

3. RESULTS

3.1. Ritlecitinib as perpetrator

3.1.1. Midazolam (CYP3A substrate) and efavirenz (CYP2B6 substrate) study

Overall, 12 participants were assigned to treatment. One participant discontinued during Period 1 and did not receive a dose of midazolam 2 mg and efavirenz 50 mg in Period 2. There were 11 male and 1 female participant (Table 1). Four were White and 8 Black. Mean age was 39.7 years, with a range between 27 and 52 years. Mean weight was 83.7 kg, with a range of 63.1–103.4 kg.

TABLE 1.

Patient demographics.

	Ritlecitinib as perpetrator					Ritlecitinib as victim
	Midazolam and efavirenz study	Tolbutamide study	Caffeine study	Oral contraceptive study 1	Oral contraceptive study 2	Itraconazole study	Rifampicin study
Male, n (%)	11 (91.7)	9 (75)	8 (66.7)	‐	‐	10 (83.3)	12 (100)
Female, n (%)	1 (8.3)	3 (25)	4 (33.3)	12 (100)	29 (100)	2 (16.7)	0
Age, mean (SD), years	39.7 (8.0)	40.3 (12.8)	38.0 (8.4)	53.1 (1.9)	53.2 (4.2)	35.5 (9.9)	36.5 (11.8)
Age, range, years	27–52	23–57	27–55	50‐56 ^a	43‐60	23‐54	20‐55
Race, n (%)
Asian	0	1 (8.3)	0	0	0	0	1 (8.3)
Black	8 (66.7)	4 (33.3)	8 (66.7)	0	2 (6.9)	1 (8.3)	1 (8.3)
Native Hawaiian/other Pacific Islander	0	0	0	0	0	0	1 (8.3)
White	4 (33.3)	7 (58.3)	4 (33.3)	12 (100)	27 (93.1)	11 (91.7)	8 (66.7)
Not reported	0	0	0	0	0	0	1 (8.3)
Hispanic or Latino	4 (33.3)	2 (16.7)	1 (8.3)	12 (100)	29 (100)	1 (8.3)	1 (8.3)
Weight, mean (SD), kg	83.7 (12.4)	75.3 (12.5)	79.0 (10.6)	76.8 (9.4)	71.6 (9.4)	72.4 (7.5)	79.9 (12.5)
Weight, range, kg	63.1–103.4	59.5–93.4	61.5–96.7	60.7–92.4	54.3–96.3	59.5–82.6	56.6–107.6
BMI, mean (SD), kg/m²	26.3 (2.8)	25.1 (1.7)	25.4 (2.9)	29.2 (2.1)	27.9 (3.1)	24.7 (2.6)	25.0 (2.95)
BMI, range, kg/m²	22.2–30.5	21.8–28.2	20.7–29.4	25.4–32.8	22.9–34.5	22.1–29.8	19.5–29.6

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Abbreviations: BMI, body mass index; SD, standard deviation.

^{^a}

Database collected only birth year, resulting in 1 of the participants categorized as aged 56 years when she was still 55 years at the time of screening.

Coadministration of multiple doses of ritlecitinib increased PK parameters of midazolam. Midazolam exposure (AUC_inf, Figure 1a) and peak exposure (C_max) were increased by 2.7‐ and 1.8‐fold, respectively, in the presence of ritlecitinib (Table 2). The ratios (90% CIs) of geometric means for midazolam after coadministration with multiple doses of ritlecitinib and a dose of efavirenz compared with a dose of efavirenz without ritlecitinib were 269.4% (216.1–335.9%) for AUC_inf and 180.8% (148.1–220.6%) for C_max.

(A) Box and whisker plot of individual and geometric mean of plasma midazolam AUC_inf *vs.* treatment with ritlecitinib 200 mg once daily (QD); (B) box and whisker plot of individual and geometric mean of plasma caffeine AUC_inf vs. treatment with ritlecitinib 200 mg QD; (C) box and whisker plot of individual and geometric mean of plasma ritlecitinib AUC_last vs. treatment with rifampicin 600 mg QD. Circles represent individual subject values. Stars represent geometric mean. The box plot provides median and 25%/75% quartiles with whiskers to the last point within 1.5 times the interquartile range.

TABLE 2.

Change in PK parameters of coadministered drugs and oral contraceptive steroids in the presence of ritlecitinib.

	Ritlecitinib dose	AUC_inf ^a	AUC_last ^a	AUC_0–72 ^a	C_max ^b
Effect of ritlecitinib on PK of midazolam and efavirenz
Midazolam ^c (CYP3A substrate)	Adjusted geometric mean (test, 200 mg QD × 11 days)	55.0	53.3	–	14.4
	Adjusted geometric mean (reference)	20.4	19.8	–	8.0
	Ratio, % (test/reference) of adjusted geometric means (90% CI)	269.4 (216.1–335.9)	269.3 (215.8–336.1)	–	180.8 (148.1–220.6)
Efavirenz ^c (CYP2B6 substrate)	Adjusted geometric mean (test, 200 mg QD × 11 days)	–	5544	5542	264.5
	Adjusted geometric mean (reference)	–	5559	5559	299.9
	Ratio, % (test/reference) of adjusted geometric means (90% CI)	–	99.7 (95.3–104.4)	99.7 (95.2–104.4)	88.2 (77.1–101.0)
Effect of ritlecitinib on PK of tolbutamide
Tolbutamide ^c (CYP2C9 substrate)	Adjusted geometric mean (test, 200 mg QD × 10 days)	602 900	580 700	–	45 570
	Adjusted geometric mean (reference)	608 600	591 000	–	44 240
	Ratio, % (test/reference) of adjusted geometric means (90% CI)	99.1 (92.0–106.6)	98.3 (92.8–104.1)	–	103.0 (96.7–109.8)
Effect of ritlecitinib on PK of caffeine
Caffeine ^c (CYP1A2 substrate)	Adjusted geometric mean (test, 200 mg QD × 9 days)	41 530	38 580	–	2372
	Adjusted geometric mean (reference)	15 660	14 780	–	2162
	Ratio, % (test/reference) of adjusted geometric means (90% CI)	265.1 (234.−1300.3)	261.0 (232.5−293.1)	–	109.7 (103.9−115.9)
Effect of ritlecitinib on PK of EE and LN (study 1)
EE ^c	Adjusted geometric mean (test, 200 mg QD × 11 days)	656.3	586.2	–	60.6
	Adjusted geometric mean (reference)	799.9	679.8	–	68.8
	Ratio, % (test/reference) of adjusted geometric means (90% CI)	82.1 (75.8−88.8)	86.2 (81.1−91.7)	–	88.1 (77.7−99.8)
LN ^c	Adjusted geometric mean (test, 200 mg QD × 11 days)	–	26 840	–	3026
	Adjusted geometric mean (reference)	–	23 810	–	2936
	Ratio, % (test/reference) of adjusted geometric means (90% CI)	–	112.7 (104.2–122.0)	–	103.1 (97.3–109.2)
Effect of ritlecitinib on PK of EE and LN (study 2)
EE ^c	Adjusted geometric mean (test, 50 mg QD × 13 days)	733.3	604.8	–	63.8
	Adjusted geometric mean (reference)	746.6	658.0	–	69.1
	Ratio, % (test/reference) of adjusted geometric means (90% CI)	98.2 (90.6–106.5)	91.9 (84.4–100.1)	–	92.3 (84.0–101.3)
LN ^c	Adjusted geometric mean (test, 50 mg QD × 13 days)	–	29 580	–	2320
	Adjusted geometric mean (reference)	–	33 670	–	2897
	Ratio, % (test/reference) of adjusted geometric means (90% CI)	–	87.9 (82.7–93.4)	–	80.1 (73.1–87.8)

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Abbreviations: AUC, area under the plasma concentration–time curve; CI, confidence interval; C_max, maximum concentration; EE, ethinyl oestradiol; LN, levonorgestrel; PK, pharmacokinetics; QD, once daily.

^{^a}

Studies measuring the PK parameters AUC_inf, AUC_last and AUC_0–72 of midazolam, efavirenz, tolbutamide and caffeine reported results in units of ng h/mL. Studies measuring the PK parameters AUC_inf and AUC_last of ethinyl oestradiol and levonorgestrel reported results in units of pg h/mL.

^{^b}

Studies measuring the PK parameter C_max for midazolam, efavirenz, tolbutamide and caffeine reported results in units of ng/mL. Studies measuring the PK parameter C_max for EE and LN reported results in units of pg/mL.

^{^c}

Descriptive statistics of all reported PK parameters are provided in Table S2.

Efavirenz exposure (AUC_0–72) and peak exposure (C_max) were similar in the presence and absence of ritlecitinib coadministration. The ratios (90% CIs) of geometric means for efavirenz after multiple doses of ritlecitinib and a dose of midazolam compared with a dose of efavirenz without ritlecitinib were 99.7% (95.2–104.4%) for AUC_0–72 and 88.2% (77.1–101.0%) for C_max (Table 2).

3.1.2. Tolbutamide (CYP2C9 substrate) study

Overall, 12 participants were assigned to the study, and all received tolbutamide treatment alone in Period 1. In Period 2, 10 participants received treatment and completed the study. Nine participants were male and 3 were female; 7 were White, 4 were Black and 1 was Asian (Table 1). Mean age was 40.3 years, with a range between 23.0 and 57.0 years. Mean weight was 75.3 kg, with a range between 59.5 and 93.4 kg.

Tolbutamide PK parameters (AUC_inf, AUC_last and C_max) were not affected by multiple doses of ritlecitinib (Table 2). The ratios of the geometric means (90% CI) for AUC_inf, AUC_last and C_max for tolbutamide when coadministered with ritlecitinib compared with tolbutamide administered alone were 99.1% (92.0–106.6%), 98.3% (92.8–104.1%) and 103.0% (96.7–109.8%), respectively.

3.1.3. Caffeine (CYP1A2 substrate) study

A total of 12 participants were enrolled; all 12 received treatment and completed the study as previously described. ¹⁴ Eight participants were male and 4 were female; 4 participants were White and 8 Black (Table 1). Mean age was 38.0 years (range, 27–55 years), and mean weight was 79.0 kg (range, 61.5–96.7 kg).

Coadministration of caffeine (a substrate of CYP1A2) in the presence of steady‐state levels of ritlecitinib increased caffeine exposure (AUC_inf, Figure 1b) compared with caffeine administered alone (Table 2). In the presence of ritlecitinib, the ratios of geometric means (90% CI) for AUC_inf and C_max for caffeine when coadministered with ritlecitinib were 265.1% (234.1–300.3%) and 109.7% (103.9–115.9%), respectively, as previously published. ¹⁴

3.1.4. OC (EE and LN) study 1

In total, 12 female participants were assigned to treatment. All 12 received and completed 2 treatment sequences. All participants were Hispanic or Latina (Table 1). Mean age was 53.1 years, with a range of 50 to 55 years at the time of the screening visit. Mean weight for participants was 76.8 kg, with a range of 60.7 to 92.4 kg.

AUC_inf and C_max of EE decreased by ≈18% and 12%, respectively, following coadministration of multiple doses of ritlecitinib (Table 2). The ratios of the geometric means (90% CI) for AUC_inf and C_max for EE were 82.1% (75.8–88.8%) and 88.1% (77.7–99.8%) when administered in the presence and absence of ritlecitinib, respectively. Multiple doses of ritlecitinib did not affect PK parameters for LN (Table 2). The ratios of geometric means (90% CI) of LN AUC_last and C_max were 112.7% (104.2–122.0%) and 103.1% (97.3–109.2%), respectively.

3.1.5. OC (EE and LN) study 2

Overall, 29 female participants were assigned to treatment, and 28 completed both treatments; 1 participant only received Treatment B. Five participants discontinued before study treatment completion. Of the participants, 27 were White and 2 were Black (Table 1). Mean age was 53.2 years, with a range of 43–60 years; mean weight was 71.6 kg (range, 54.3–96.3 kg).

Multiple doses of ritlecitinib 50 mg resulted in a lack of effect on the PK of a dose of OC steroids (Table 2). Coadministration of ritlecitinib and OC steroids compared with administration of OC steroids alone resulted in ratios of the geometric means (90% CI) of AUC_inf and C_max of 98.2% (90.6–106.5%) and 92.3% (84.0–101.3%), respectively, for EE. The ratios of the adjusted geometric means (90% CI) of AUC_last and C_max were 87.9% (82.7–93.4%) and 80.1% (73.1–87.8%), respectively, for LN.

3.2. Ritlecitinib as victim

3.2.1. Itraconazole (selective CYP3A inhibitor) study

Overall, 12 participants were assigned to treatment, and all were treated and completed the study. There were 10 male and 2 female participants (Table 1). Eleven participants were White and 1 was Black, and 1 female participant was Hispanic or Latina. Mean age was 35.5 years, with a range between 23 and 54 years. Mean weight for participants was 72.4 kg, with a range of 59.5 to 82.6 kg.

Coadministration of multiple 200‐mg doses of itraconazole increased ritlecitinib AUC_inf by ≈15% (Table 3). Peak ritlecitinib exposure (C_max) was similar when ritlecitinib was coadministered with itraconazole relative to a 30‐mg ritlecitinib dose alone. When ritlecitinib was coadministered with multiple doses of itraconazole compared with administration of ritlecitinib alone, the ratios of adjusted geometric means (90% CI) for ritlecitinib's AUC_inf and C_max were 115.1% (104.6–126.7%) and 102.5% (82.8–127.0%), respectively.

TABLE 3.

Change in PK parameters of coadministered ritlecitinib in the presence of itraconazole and rifampicin.

	Dose of coadministered drug	AUC_inf (ng h/mL)	AUC_last (ng h/mL)	C_max (ng/mL)
Effect of itraconazole (CYP3A inhibitor) on PK of ritlecitinib
Ritlecitinib ^a 30 mg	Adjusted geometric mean (test, 200 mg QD × 5 days)	308.0	303.9	156.5
	Adjusted geometric mean (reference)	267.5	264.2	152.6
	Ratio, % (test/reference) of adjusted geometric means (90% CI)	115.1 (104.6–126.7)	115.1 (104.4–126.7)	102.5 (82.8–127.0)
Effect of rifampicin (CYP3A inducer) on PK of ritlecitinib
Ritlecitinib ^a 50 mg	Adjusted geometric mean (test, 600 mg QD × 8 days)	250.5	249.4	204.4
	Adjusted geometric mean (reference)	449.3	448.1	272.3
	Ratio, % (test/reference) of adjusted geometric means (90% CI)	55.8 (51.9–59.9)	55.7 (51.9–59.7)	75.1 (63.3–89.1)

Open in a new tab

Abbreviations: AUC, area under the plasma concentration–time curve; CI, confidence interval; C_max, maximum concentration; PK, pharmacokinetics; QD, once daily.

^{^a}

Descriptive statistics of all reported PK parameters are provided in Table S3.

3.2.2. Rifampicin (CYP inducer) study

A total of 12 participants were enrolled and received treatment. Two participants completed Period 1 but withdrew from Period 2. All 12 participants were male; 8 were White, 1 was Black, 1 was Asian, 1 was Native Hawaiian or other Pacific Islander, and 1 did not report his race (Table 1). One participant was Hispanic or Latino. Mean age was 36.5 years, with a range between 20 and 55 years. Mean weight was 79.9 kg, with a range of 56.6–107.6 kg.

The presence of rifampicin decreased plasma exposure (AUC_last, Figure 1c) of ritlecitinib compared with ritlecitinib administered alone (Table 3). The ratios of the geometric means (90% CI) for ritlecitinib AUC_inf and C_max were 55.8% (51.9–59.9%) and 75.1% (63.3–89.1%), respectively, when ritlecitinib was coadministered with multiple doses of rifampicin compared with ritlecitinib administration alone.

4. DISCUSSION

This manuscript summarizes 7 phase 1, open‐label DDI studies investigating the effect of ritlecitinib on CYP substrate PK and the effect of CYP inhibitors and inducers on the PK of ritlecitinib.

Ritlecitinib is a moderate inhibitor of the CYP3A and CYP1A2 pathways and can increase systemic exposures of drugs metabolized by CYP3A or CYP1A2. Midazolam and caffeine are sensitive probe substrates for CYP3A and CYP1A2, respectively. Ritlecitinib increased midazolam AUC_inf and C_max by ≈2.7‐ and 1.8‐fold, respectively, and increased caffeine AUC_inf and C_max by ≈2.7‐ and 1.1‐fold, respectively. Conversely, ritlecitinib did not impact systemic exposures of drugs metabolized by CYP2B6 or CYP2C9 and did not produce clinically meaningful changes in the AUC_0–72 and C_max of efavirenz, a sensitive probe for CYP2B6, ² , ²³ , ²⁵ or in the AUC_inf and C_max of tolbutamide, a sensitive probe substrate for CYP2C9.

The perpetrator studies for ritlecitinib were conducted at a dose of 200 mg as this was the highest dose for ritlecitinib in the confirmatory trials ²⁶ and represents a worst‐case scenario. Even though the approved dose for ritlecitinib is 50 mg, ²⁷ the data from ritlecitinib 200 mg as perpetrator in drug interaction studies represent a conservative assessment and provide valuable actionable information on the DDI risk of ritlecitinib on concomitant medications. Translating the risk of DDI from a dose of 200 mg QD to the approved dose of 50 mg QD, at which increases in exposure are anticipated due to an interaction, it can be envisaged that the magnitude of exposure change may be lower, but the risk of higher exposures still exists. Hence, caution should be exercised for drugs with narrow therapeutic indexes that are substrates of CYP3A and CYP1A2 for which changes in concentrations may lead to adverse events.

Alopecia areata typically first manifests within the first 4 decades of life, ²⁸ , ²⁹ a period during which patients frequently use OCs. Given the potential for induction identified for several CYPs, OCs are important clinically relevant concomitant medications. Hence, a DDI study with OCs as victim was planned at ritlecitinib doses of 200 and 50 mg QD. The OC DDI studies were conducted prior to the knowledge of the clinically approved dose. The first OC DDI study was conducted at the highest dose being evaluated in the ritlecitinib AA trials (200 mg QD), followed by a second study at a lower dose of 50 mg QD. At a dose of 200 mg QD, ritlecitinib decreased the PK parameters for EE whereas LN was not affected. At the clinically approved ²⁷ dose of 50 mg QD, ritlecitinib did not produce a clinically meaningful change in the PK parameters of EE and LN. Hence, ritlecitinib doses of ≤50 mg are not expected to affect the efficacy of OCs containing EE or LN.

These studies had some limitations. Within each study, only 1 selected dose of ritlecitinib and victim drug or OC combination was evaluated. Overall, these results indicate that ritlecitinib usage concomitantly with drugs that are metabolized via CYP3A and CYP1A2 for which small changes in concentration may lead to serious adverse side effects should be associated with additional monitoring and dosage adjustment in accordance with approved product labelling of respective substrates when used with ritlecitinib.

The DDI studies in which ritlecitinib was evaluated as a victim were conducted with 30‐ or 50‐mg doses in line with the objective of minimizing systemic exposures in healthy participants in anticipation of increased exposure due to a drug interaction. Ritlecitinib exposures increase approximately dose‐proportionally up to 200 mg. ²⁷ , ³⁰ As a victim of DDI, ritlecitinib exposure was not decreased to clinically relevant levels when concomitantly administered with the CYP inducer rifampicin. The clinical relevance of exposure changes was assessed based on the typical exposure range (defined as 0.5‐ to 2‐fold of mean exposure for a dose; see Supplemental Methods). The ≈45% reduction in exposure is unlikely to lead to complete efficacy loss, as 30‐mg doses have shown significant benefit in efficacy trials ²⁶ and are within the typical exposure range. Concomitant administration with potent selective CYP3A inhibitor itraconazole resulted in ≈15% increase in exposure, which is considered marginal and is within the typical exposure range.

Based on the drugs tested in DDI studies described here and some frequently prescribed concomitant medications, a nonexhaustive list of drugs that may have potential DDIs with ritlecitinib include midazolam ³¹ (for anxiety or sleep disorders), quinidine ³² (for heart rhythm disturbances), colchicine ³³ (for prophylaxis of and/or treatment of gout), dihydroergotamine and ergotamine ³⁴ (for migraines), theophylline ³⁵ (for asthma), tizanidine ³⁶ (muscle relaxant) and pirfenidone ³⁷ (for idiopathic pulmonary fibrosis). Additionally, concomitant use of ritlecitinib and medications with narrow therapeutic indices for the treatment of schizophrenia and chronic psychosis such as pimozide ³⁸ should also receive attention for potential DDIs. The PK of some immunomodulators or immunosuppressants such as cyclosporine, everolimus, tacrolimus and sirolimus ³⁹ may also be impacted by ritlecitinib, which could lead to a potential tolerability issue. Healthcare providers should refer to the label of potential concomitant medications to assess potential DDIs.

AUTHOR CONTRIBUTIONS

Vivek S. Purohit and Yeamin Huh drafted the manuscript. Vivek S. Purohit, Yeamin Huh, Martin E. Dowty, Anna Plotka and Alexandre Lejeune designed the trials. Brian Hee managed the PK samples and analysis. Hindu Kalluru and Anna Plotka conducted the NCA and statistical analysis. All authors reviewed and contributed to the manuscript.

CONFLICT OF INTEREST STATEMENT

At the time of the study, all authors were employees of and may own shares/stock options in Pfizer Inc.

Supporting information

TABLE S1 In vitro results.

TABLE S2 Descriptive summary of plasma PK parameters of coadministered drugs and oral contraceptive steroids in the presence of ritlecitinib.

TABLE S3 Descriptive summary of plasma PK parameters of coadministered drugs and oral contraceptive steroids in the presence of ritlecitinib.

FIGURE S1 Treatment flow diagram for drug–drug interaction studies with ritlecitinib as perpetrator.

FIGURE S2 Treatment flow diagram for drug–oral contraceptive interaction studies with ritlecitinib as perpetrator.

FIGURE S3 Treatment flow diagram for drug–drug interaction studies with ritlecitinib as victim.

BCP-91-2316-s001.docx^{(586.2KB, docx)}

ACKNOWLEDGEMENTS

Editorial/medical writing support was provided by Carolyn Maskin, PhD, of Nucleus Global, and was funded by Pfizer Inc. The authors would like to thank Dr. Julia Kaplan for providing primary bioanalytical oversight for all studies.

Purohit VS, Huh Y, Dowty ME, et al. Drug–drug interaction profile of ritlecitinib as perpetrator and victim through cytochrome P450. Br J Clin Pharmacol. 2025;91(8):2316‐2326. doi: 10.1002/bcp.70069

Funding information This study was sponsored by Pfizer Inc.

The authors confirm that the principal investigators for the 7 clinical trials discussed in the article are Sylvester Pawlak (midazolam and efavirenz study), Juan Perez‐Moralez (oral contraceptive study 1), Jeffrey Levy (oral contraceptive study 2), Smita Goodman (tolbutamide study), Mona Shahbazi (caffeine study) and Constantino Kantaridis (itraconazole and rifampicin studies) and that they had direct clinical responsibility for their respective patients.

DATA AVAILABILITY STATEMENT

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

TABLE S1 In vitro results.

TABLE S2 Descriptive summary of plasma PK parameters of coadministered drugs and oral contraceptive steroids in the presence of ritlecitinib.

TABLE S3 Descriptive summary of plasma PK parameters of coadministered drugs and oral contraceptive steroids in the presence of ritlecitinib.

FIGURE S1 Treatment flow diagram for drug–drug interaction studies with ritlecitinib as perpetrator.

FIGURE S2 Treatment flow diagram for drug–oral contraceptive interaction studies with ritlecitinib as perpetrator.

FIGURE S3 Treatment flow diagram for drug–drug interaction studies with ritlecitinib as victim.

BCP-91-2316-s001.docx^{(586.2KB, docx)}

Data Availability Statement

[bcp70069-bib-0001] 1. Research USDoHaHSFaDACfDEa . Clinical drug interaction studies ‐ cytochrome P450 enzyme‐ and transporter‐mediated drug interactions: guidance for industry. Center for Drug Evaluation and Research. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions [Google Scholar]

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[bcp70069-bib-0003] 3. Chen C, Lu D, Sun T, Zhang T. JAK3 inhibitors for the treatment of inflammatory and autoimmune diseases: a patent review (2016‐present). Expert Opin Ther Pat. 2022;32(3):225‐242. doi: 10.1080/13543776.2022.2023129 [DOI] [PubMed] [Google Scholar]

[bcp70069-bib-0004] 4. Tosti A, Bellavista S, Iorizzo M. Alopecia areata: a long term follow‐up study of 191 patients. J am Acad Dermatol. 2006;55(3):438‐441. doi: 10.1016/j.jaad.2006.05.008 [DOI] [PubMed] [Google Scholar]

[bcp70069-bib-0005] 5. Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12(1):25‐36. doi: 10.1038/nrrheum.2015.167 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bcp70069-bib-0006] 6. Martins C, Migayron L, Drullion C, et al. Vitiligo skin T cells are prone to produce type 1 and type 2 cytokines to induce melanocyte dysfunction and epidermal inflammatory response through jak signaling. J Invest Dermatol. 2021;142(4):1194‐1205.e7. doi: 10.1016/j.jid.2021.09.015 [DOI] [PubMed] [Google Scholar]

[bcp70069-bib-0007] 7. Monteleone G, Monteleone I, Fina D, et al. Interleukin‐21 enhances T‐helper cell type I signaling and interferon‐gamma production in Crohn's disease. Gastroenterology. 2005;128(3):687‐694. doi: 10.1053/j.gastro.2004.12.042 [DOI] [PubMed] [Google Scholar]

[bcp70069-bib-0008] 8. Xu H, Jesson MI, Seneviratne UI, et al. PF‐06651600, a dual JAK3/TEC family kinase inhibitor. ACS Chem Biol. 2019;14(6):1235‐1242. doi: 10.1021/acschembio.9b00188 [DOI] [PubMed] [Google Scholar]

[bcp70069-bib-0009] 9. Faraj S, Kemp EH, Gawkrodger DJ. Patho‐immunological mechanisms of vitiligo: the role of the innate and adaptive immunities and environmental stress factors. Clin Exp Immunol. 2022;207(1):27‐43. doi: 10.1093/cei/uxab002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bcp70069-bib-0010] 10. Passeron T, King B, Seneschal J, et al. Inhibition of T‐cell activity in alopecia areata: recent developments and new directions. Front Immunol. 2023;14:1243556. doi: 10.3389/fimmu.2023.1243556 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bcp70069-bib-0011] 11. FDA Approves Pfizer's LITFULO™ (Ritlecitinib) for Adults and Adolescents With Severe Alopecia Areata 2023. https://www.pfizer.com/news/press-release/press-release-detail/fda-approves-pfizers-litfulotm-ritlecitinib-adults-and

[bcp70069-bib-0012] 12. Agency EM . Litfulo (ritlecitinib). https://www.ema.europa.eu/en/documents/overview/litfulo-epar-medicine-overview_en.pdf

[bcp70069-bib-0013] 13. Lee S, Lee H, Lee CH, Lee WS. Comorbidities in alopecia areata: a systematic review and meta‐analysis. J am Acad Dermatol. 2019;80(2):466‐477.e16. doi: 10.1016/j.jaad.2018.07.013 [DOI] [PubMed] [Google Scholar]

[bcp70069-bib-0014] 14. Liu J, Solan R, Wolk R, et al. Evaluation of the effect of ritlecitinib on the pharmacokinetics of caffeine in healthy participants. Br J Clin Pharmacol. 2023;89(7):2208‐2215. doi: 10.1111/bcp.15695 [DOI] [PubMed] [Google Scholar]

[bcp70069-bib-0015] 15. Wang X, Purohit V, Dowty ME, et al. Evaluation of the impact of ritlecitinib on organic cation transporters using sumatriptan and biomarkers as probes. J Clin Pharmacol. 2023;63(7):784‐797. doi: 10.1002/jcph.2215 [DOI] [PubMed] [Google Scholar]

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PERMALINK

Drug–drug interaction profile of ritlecitinib as perpetrator and victim through cytochrome P450

Vivek S Purohit

Yeamin Huh

Martin E Dowty

Anna Plotka

Alexandre Lejeune

Hindu Kalluru

Brian Hee

Abstract

Aims

Methods

Results

Conclusions

What is already known about this subject

What this study adds

1. INTRODUCTION

2. METHODS

2.1. Clinical study design, study participants and treatments

2.1.1. Midazolam and efavirenz study

2.1.2. Tolbutamide study

2.1.3. Caffeine study

2.1.4. OC study 1

2.1.5. OC study 2

2.1.6. Itraconazole study

2.1.7. Rifampicin study

2.2. Blood collection

2.3. Analytical methods for drugs in plasma

2.4. Statistical methods and PK parameters

3. RESULTS

3.1. Ritlecitinib as perpetrator

3.1.1. Midazolam (CYP3A substrate) and efavirenz (CYP2B6 substrate) study

TABLE 1.

FIGURE 1.

TABLE 2.

3.1.2. Tolbutamide (CYP2C9 substrate) study

3.1.3. Caffeine (CYP1A2 substrate) study

3.1.4. OC (EE and LN) study 1

3.1.5. OC (EE and LN) study 2

3.2. Ritlecitinib as victim

3.2.1. Itraconazole (selective CYP3A inhibitor) study

TABLE 3.

3.2.2. Rifampicin (CYP inducer) study

4. DISCUSSION

AUTHOR CONTRIBUTIONS

CONFLICT OF INTEREST STATEMENT

Supporting information

ACKNOWLEDGEMENTS

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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