Aprepitant and fosaprepitant drug interactions: a systematic review

Abstract

Aims

Aprepitant and fosaprepitant, commonly used for the prevention of chemotherapy‐induced nausea and vomiting, alter cytochrome P450 activity. This systematic review evaluates clinically significant pharmacokinetic drug interactions with aprepitant and fosaprepitant and describes adverse events ascribed to drug interactions with aprepitant or fosaprepitant.

Methods

We systematically reviewed the literature to September 11, 2016, to identify articles evaluating drug interactions involving aprepitant/fosaprepitant. The clinical significance of each reported pharmacokinetic drug interaction was evaluated based on the United States Food and Drug Administration guidance document on conducting drug interaction studies. The probability of an adverse event reported in case reports being due to a drug interaction with aprepitant/fosaprepitant was determined using the Drug Interaction Probability Scale.

Results

A total of 4377 publications were identified. Of these, 64 met inclusion eligibility criteria: 34 described pharmacokinetic drug interactions and 30 described adverse events ascribed to a drug interaction. Clinically significant pharmacokinetic interactions between aprepitant/fosaprepitant and bosutinib PO, cabazitaxel IV, cyclophosphamide IV, dexamethasone PO, methylprednisolone IV, midazolam PO/IV, oxycodone PO and tolbutamide PO were identified, as were adverse events resulting from an interaction between aprepitant/fosaprepitant and alcohol, anthracyclines, ifosfamide, oxycodone, quetiapine, selective serotonin reuptake inhibitors/serotonin‐norepinephrine reuptake inhibitors and warfarin.

Conclusions

The potential for a drug interaction with aprepitant and fosaprepitant should be considered when selecting antiemetic therapy.

What is Already Known about this Subject

• Aprepitant and fosaprepitant are moderate and weak CYP3A4 inhibitors, respectively. Aprepitant is also a weak CYP2C9 inducer.

• There are no systematic literature reviews describing interactions between aprepitant or fosaprepitant and other drugs.

What this Study Adds

• Using the FDA's definition, reports of clinically significant pharmacokinetic interactions between aprepitant and bosutinib, cabazitaxel, cyclophosphamide, dexamethasone, methylprednisolone, midazolam, oxycodone and tolbutamide were identified.

• Concurrent administration of aprepitant and the following drugs may lead to adverse events: alcohol (impaired cognition), ifosfamide (neurotoxicity), oxycodone (decreased respiratory rate, increased feeling of a ‘high’), quetiapine (somnolence), SSRI/SNRIs (vomiting) and warfarin (INR changes). Administration of fosaprepitant and anthracyclines via the same peripheral vein may cause a local reaction at the infusion site.

Tables of Links

TARGETS
GPCRs 2	Enzymes 3
NK1 receptor	CYP3A4
	CYP2C9

LIGANDS
alcohol	methylprednisolone
aprepitant	midazolam
bosutinib	ondansetron
cabazitaxel	oxycodone
cyclophosphamide	palonosetron
dexamethasone	paroxetine
digoxin	pazopanib
dinaciclib	prednisolone
docetaxel	quetiapine
dolasetron	tacrolimus
erlotinib	thiotepa
fosaprepitant	tolbutamide
granisetron	vinorelbine
ifosfamide	warfarin
melphalan

These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2, 3.

Introduction

A neurokinin‐1 antagonist such as oral (PO) aprepitant or its intravenous (IV) prodrug, fosaprepitant, together with a 5‐HT₃ antagonist and dexamethasone, are strongly recommended for prophylaxis of chemotherapy‐induced nausea and vomiting (CINV) in both adult and paediatric cancer patients receiving highly emetogenic chemotherapy 4, 5, 6, 7. However, aprepitant and fosaprepitant are moderate 8, 9 and weak inhibitors of CYP3A4 10, 11, respectively, and there is uncertainty regarding the clinical significance of potential interactions with CYP3A4 substrates. A moderate CYP3A4 inhibitor may increase the area under the concentration vs. time curve (AUC) of a victim drug by two‐ to up to five‐fold and a weak CYP3A4 inhibitor may increase AUC of a victim drug by 1.25‐ up to two‐fold 12. CYP3A4 inhibitors may also reduce the conversion of a prodrug to its active form 13. Aprepitant or fosaprepitant may therefore influence the toxicity and the efficacy of concomitantly administered drugs. Recommendations for CINV prevention in children with cancer caution against the use of aprepitant with antineoplastic agents which are CYP3A4 substrates 6, 14. However, avoidance of aprepitant due to potential interactions with antineoplastic therapy may open patients to uncontrolled CINV.

There is, however, no comprehensive, systematic assessment of the literature describing the extent of interaction between aprepitant or fosaprepitant and other drugs. The primary objective of this systematic review was to describe the pharmacokinetic disposition of drugs co‐administered with aprepitant or fosaprepitant using a standard definition of clinical significance. Our secondary objective was to describe adverse events ascribed to a drug interaction with aprepitant or fosaprepitant. The results of this systematic review will facilitate informed decision making regarding the selection of CINV prophylaxis.

Methods

The Preferred Reporting Items in Systematic Reviews and Meta‐Analyses Protocols 15 and the Preferred Reporting Items in Systematic Reviews and Meta‐Analyses guidelines 16 were followed in conducting this systematic review. Details on the search methods can be found in Supporting Information Appendix S1 (Tables S1 and S2). The publication selection, data extraction and quality assessment procedures are presented in Supporting Information Appendix S2.

We defined pharmacokinetic drug interactions as clinically significant according to the United States Food and Drug Administration (FDA) guidance document on drug interaction studies 17. That is, an interaction was clinically significant when: (1) the geometric mean ratio (GMR) for the comparison of a victim drug's maximum concentration (C _max) in the presence vs. in the absence of aprepitant or fosaprepitant was greater than 1.25 or less than 0.80 or (2) the GMR for the comparison of the AUC of a victim drug in the presence vs. in the absence of aprepitant or fosaprepitant was greater than 1.25 or less than 0.80. This definition was based on the GMR for C _max or AUC of the victim drug irrespective of the associated confidence interval (CI).

A significant adverse event was defined as an event where a patient experienced discomfort, harm or changes in a laboratory parameter that was indicative of an increased risk for harm that was highly suspected to have occurred due to co‐administration of aprepitant or fosaprepitant with the patient's other medications. In the case of comparative studies, a high suspicion of interaction was defined as a statistically significant difference in the rate of the adverse event in the presence of aprepitant or fosaprepitant vs. the absence of aprepitant or fosaprepitant. The probability that the findings of case reports were a result of a drug interaction with aprepitant or fosaprepitant was determined using the Drug Interaction Probability Scale (DIPS) 18. DIPS scores of 5 or greater indicate that a causal relationship between the adverse event and the drug interaction is probable or highly probable.

Results

Publication selection

Our literature search identified 4377 publications. Of these, 122 were brought to full text screening and 65 met criteria to be included in the qualitative synthesis. One publication 19 was excluded because it used methods that would affect the validity and generalizability of study findings. Hence, a total of 64 publications were included in the final synthesis (see Figure 1). Inter‐screener agreement was substantial with a calculated kappa of 0.77 (95% CI: 0.65–0.88) 20. The quality assessment of all included publications (case reports excluded) is reported in Supporting Information Appendix S3 (Tables S3–S5). The DIPS scores of included case reports are presented in Supporting Information Appendix S3 (Table S10).

Figure 1.

Study identification flow diagram

Publication characteristics

Of the 64 included publications, 34 evaluated pharmacokinetic interactions in adults (aprepitant/fosaprepitant and antineoplastic drug: 14 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34; aprepitant/fosaprepitant and non‐antineoplastic drug: 20 9, 11, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52). Thirty‐eight described adverse events in adults potentially resulting from drug interactions with aprepitant or fosaprepitant, eight of which also evaluated for a pharmacokinetic aprepitant/fosaprepitant drug interaction (aprepitant/fosaprepitant and antineoplastic drug: 24 23, 25, 33, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73; aprepitant and non‐antineoplastic drug: 14 35, 43, 46, 51, 52, 74, 75, 76, 77, 78, 79, 80, 81, 82). In all, 27 victim drugs were evaluated for pharmacokinetic interaction with aprepitant or fosaprepitant and an adverse event was ascribed by study authors to an interaction with aprepitant or fosaprepitant for 15 victim drugs. Table 1 summarizes the characteristics of included publications. Complete data summary tables are provided in Supporting Information Appendix S3 (Tables S6–S9). A summary of findings are presented in Table 2.

Table 1.

Study characteristics of included studies

Article (First author, year)	Study design	N	Population	Median age (range), years	Aprepitant (A) or Fosaprepitant (F)	Victim drug
Pharmacokinetic drug interaction publications
Antineoplastic drugs
Hsyu (2015) 34	Crossover RCT	18	Healthy	NR	A	Bosutinib PO
Sarantopoulos (2014) 30	Crossover study	12	Solid malignancy	56 (32–71)	A	Cabazitaxel IV
Walko (2012) 32	Crossover RCT	18	Breast cancer	55 (38–77)	A	Cyclophosphamide IV
Bubalo (2012) 21	Parallel RCT	22	Patients scheduled for HSCT	46 (19–63)a	A	Cyclophosphamide IV
De Jonge (2005) 22	PK study with historical control	8	Breast cancer or germ cell cancer	NR	A	Cyclophosphamide IV Thiotepa IV
Zhang (2012) 33	Crossover RCT	12	Advanced malignancy	52 (35–70)	A	Dinaciclib IV
Kaneta (2014) 26	Crossover study	16	Solid tumour	67.5 (56–76)	A	Docetaxel IV
Nygren (2005) 29	Crossover RCT	10	Solid malignancy	NR (50–68)	A	Docetaxel IV
Mir (2011) 28	Case report	1	Adenocarcinoma	54	A	Erlotinib (route NR)
Durand (2007) 23	Case report	1	Metastatic osteosarcoma	57	A	Ifosfamide IV
Vadhan‐Raj (2015) 31	Crossover RCT	47	Malignancy	NR	F	Ifosfamide (route NR)
Imbs (2016) 25	Crossover study	32	Solid malignancy	56 (24–72)	A	Pazopanib PO
Loos (2007) 27	Crossover study	12	Advanced solid malignancy	56 (NR)	A	Vinorelbine IV
Egerer (2010) 24	PK sub‐study of parallel RCT	30	Multiple myeloma	Aprepitant arm: 57.4 (40–69)a	A	Melphalan IV
				Placebo arm: 62.1 (39–71)a
Non‐antineoplastic drugs
McCrea (2003) 44	Crossover RCT	G1: 20	Healthy	G1: 34 (20–46)a	A	G1: Dexamethasone PO
		G2: 10		G2: 31 (20–44)a		G2: Methylprednisolone IV
Marbury (2011) 11	Crossover RCT	G1: 13	Healthy	Dexamethasone arm: 29.7 (18–45)a	F	G1: Dexamethasone PO
		G2: 10		Midazolam: 30.1 (18–44)a		G2: Midazolam PO
Nakade (2008) 45	PK modelling study	755	Japanese healthy patients and patients with solid malignancy	No dexamethasone: 62 (20–80)	A	Dexamethasone IV
				Dexamethasone arm: 63 (23–80)
Takahashi (2011) 50	Parallel RCT	20	Japanese cancer patients receiving chemotherapy	Aprepitant 125/80/80: 59.7 (47–71)a	A	Dexamethasone IV
				Aprepitant 40/25/25: 63.6 (55–72)a
Blum (2003) 36	Crossover RCT	G1: 17	Healthy	G1: 27.9 (18–44)a	A	G1: Granisetron PO
		G2: 15		G2: 34.4 (19–46)a		G2: Ondansetron IV
Li (2006) 41	Crossover RCT	12	Healthy	NR (19–52)	A	Dolasetron PO
Majumdar (2003) 9	Crossover RCT	16	Healthy	30 (20–43)a	A	Midazolam PO
Shadle (2004) 47	Parallel RCT	24	Healthy	Aprepitant: 29 (18–40)a	A	Midazolam IV
				Placebo: 29 (21–44)a		Tolbutamide PO
Majumdar (2007) 43	Crossover RCT	12	Healthy	NR (20–36)	A	Midazolam IV
Stoch (2011) 49	Crossover study	12	Healthy	34 (22–44)a	A	Midazolam PO and IV
Fujiwara (2014) 39	Crossover study	20	Stage IV cancer	66.5 (44–77)	A	Oxycodone PO
Shah (2005) 48	Crossover RCT	12	Healthy	29.9 (NR)a	A	Palonosetron IV
Maie (2014) 42	Crossover study	8	Lymphoma	NR	A	Prednisolone PO
Verwimp‐Hoeks (2012) 52	Case report	1	Laryngeal carcinoma + depression + anxiety	44	A	Quetiapine PO
Ibrahim (2008) 40	Retrospective review	26	Reduced intensity HSCT patients	52.5 (18–68)	A	Tacrolimus IV
Ngo (2009) 46	Parallel RCT	22	Healthy	Aprepitant: 27 (19–37)	A	Tolbutamide PO
				Placebo: 26 (19–39)
Depre (2005) 37	Parallel RCT	22	Healthy	29 (21–45)a	A	Warfarin PO
Feuring (2003) 38	Crossover RCT	11	Healthy	29.6 (22–45)a	A	Digoxin PO
Ball (2014) 35	Parallel RCT	236	Major depressive disorder	38.9 (18–65)	A	Paroxetine PO
te Beek (2013) 51	Crossover RCT	17	Healthy	27 (18–53)a	A	Alcohol IV

Clinical drug interaction publications (i.e. publications that did not report pharmacokinetic data)
Antineoplastic drugs
Kameda (2014) 60	Prospective observational cohort study	20	Japanese, breast cancer	48.5 (23–67)b	F	Anthracycline IV
Sato (2014) 64	Retrospective review	56	Receiving fosaprepitant through peripheral IV line	50 (31–85)	F	Anthracycline IV
Lundberg (2014) 61	Retrospective review	150	Patients administered fosaprepitant IV through a peripheral vein	Reaction group: 54 (IQR: 49–62)	F	Anthracycline IV
				No reaction group: 59 (IQR: 51–67)
Mogi (2014) 62	Retrospective review	80	Colorectal cancer	NR	F	Anthracycline IV
Fujii (2015) 55	Retrospective study	267	Patients administered anthracycline or cisplatin based regimen not through a central line	54.3 (NR)a	A/F	Anthracycline/ Platinum IV
Hegerova (2015) 56	Retrospective review	180	Patients administered platinum‐based therapy not containing anthracycline or patients administered anthracycline‐cyclophosphamide hemotherapy	Platinum‐based chemotherapy: 46.4 (22–77)a	F	Anthracycline/ Platinum IV
				Anthracycline‐based chemotherapy: 53.3 (31–74)a
Tsuda (2016) 73	Retrospective review	100	Chemo‐naïve breast cancer patients receiving anthracycline‐containing chemotherapy	Aprepitant: 52 (30–75)	A/F	Anthracycline IV
				Fosaprepitant: 47 (31–66)
Ruellan (2012) 63	Case report	1	Erthyrodermic Sezary syndrome	65	A	Bexarotene PO
Sassier (2016) 71	Case report	1	Non‐small cell lung cancer and brain metastases	56	A	Erlotinib (route NR)
Howell (2008) 58	Retrospective cohort study	45	Sarcoma	Aprepitant: 53 (NR)a	A	Ifosfamide IV
				No aprepitant: 48 (NR)a
Ho (2010) 57	Retrospective case–control	54	Sarcoma	Cases: 48 (NR)a	A	Ifosfamide IV
				Controls: 44.8 (NR)a
Stern (2015) 67	Retrospective study	187	Treated with ifosfamide	27 (0–78)	A	Ifosfamide IV
Chenaf (2015) 54	Retrospective review of pharmacovigilance database	178	Treated with ifosfamide and experiencing neurotoxicity	Brand name: 49 (NR)	A	Ifosfamide (route NR)
				Generic: 14 (NR)
Gupta (2016) 69	Retrospective chart review	81	Treated with ifosfamide	NR	F	Ifosfamide IV
Mahe (2016) 70	Retrospective study	213	Treated with ifosfamide	13 (1–20)c	A	Ifosfamide (route NR)
Jarkowski (2008) 59	Case report	1	Malignant peripheral nerve sheath tumour	24	A	Ifosfamide IV
McDonnell (2012) 68	Case report	1	Non‐Hodgkin lymphoma	66	A	Ifosfamide (route NR)
Shindorf (2013) 66	Case reports	2	C1: Ovarian malignant mixed mesodermal tumour (MMMT), C2: uterine MMMT	C1:	A	Ifosfamide IV
				67C2: 41
Sejourne (2014) 65	Case reports	2	C1: uterine leiomyosarcoma	C1: 39	A	Ifosfamide IV
			C2: pleiomorphic rhabdomyosarcoma	C2: 75
Barthelemi (2015) 53	Case series	10	Ifosfamide‐induced encephalopathy	NR (8 children: 2–15; 2 adults: 51 and 80)	A	Ifosfamide (route NR)
Sunela (2016) 72	Case reports	2	C1: osteosarcoma with previous history of breast cancer	C1: 59	A	Ifosfamide IV
			C2: metastatic sarcoma	C2: 65
Non‐antineoplastic drugs
Walsh (2013) 78	Crossover RCT	8	Illicit opioid users	32.3 (NR)a	A	Oxycodone intranasal and PO
Jones (2013) 74	Parallel RCT	15	Methadone‐maintained patients with opioid abuse and dependence	47.3 (31–59)a	A	Methadone PO
Mir (2012) 75	Retrospective case–control study	44	Chemotherapy naïve patients receiving SSRI or SNRI	59 (34–78)	A	SSRI (route NR)
Takaki (2016) 82	Retrospective study	14	Patients receiving anticancer therapy	59 (33–78)a	A	Warfarin PO
Yano (2011) 79	Case reports	2	C1: ovarian malignancy + disseminated intravascular coagulation	C1: 50	A	Warfarin PO
			C2: peritoneal recurrence and liver metastasis of uterine cervical adenocarcinoma	C2: 43
Ohno (2014) 77	Case reports	2	C1: small cell lung cancer + atrial fibrillation, Japanese	C1: 60	A	Warfarin PO
			C2: endometrial carcinoma + pulmonary thrombosis and deep vein thrombosis, Japanese	C2: 47
Nakano (2015) 76	Case report	1	Squamous cell carcinoma including urothelial carcinoma + deep vein thrombosis	64	A	Warfarin PO
Inagaki (2015) 80	Case report	1	Clear cell carcinoma + pulmonary embolism	63	A	Warfarin (route NR)
Okada (2016) 81	Case report	1	Rhabdomyosarcoma and occlusion of left middle cerebral artery, Japanese	15	A	Warfarin PO

RCT, randomized controlled trial; NR, not reported; PK, pharmacokinetic; IQR, interquartile range; C1: case 1, C2: case 2; G1: group 1; G2: group 2; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor

^aMean age and range reported

^bCharacteristics of 6 patients who experienced vascular‐pain only presented by study authors

^cPatients who experienced neurotoxicity

Table 2.

Summary of findings regarding pharmacokinetic interactions with aprepitant/fosaprepitant

Drugs evaluated for pharmacokinetic interactions with aprepitant
Clinically significant interaction a :	Antineoplastic agents:	bosutinib PO cabazitaxel IV cyclophosphamide IV
	Non‐antineoplastic agents:	dexamethasone PO methylprednisolone IV midazolam IV and PO oxycodone PO tolbutamide PO
Possibly significant interaction b :	Antineoplastic agents:	erlotinib (route not reported) ifosfamide IV pazopanib PO thiotepa IV
	Non‐antineoplastic agents:	dexamethasone IV paroxetine PO quetiapine PO tacrolimus IV
Possibly no clinically significant interaction c :	Antineoplastic agents:	melphalan IV
	Non‐antineoplastic agents:	alcohol IV prednisolone PO
No clinically significant interaction d :	Antineoplastic agents:	dinaciclib IV docetaxel IV vinorelbine IV
	Non‐antineoplastic agents:	digoxin PO dolasetron PO granisetron PO ondansetron IV palonosetron IV warfarin PO

Drugs evaluated for pharmacokinetic interactions with fosaprepitant
Clinically significant interaction a :	Antineoplastic agents:	none evaluated
	Non‐antineoplastic agents:	dexamethasone PO midazolam PO
No clinically significant interaction c :	Antineoplastic agents:	ifosfamide IV
	Non‐antineoplastic agents:	none evaluated

^aMet pre‐defined definition of clinical significance;

^bSignificant change in pharmacokinetic parameters observed; GMR of C _max or AUC not provided;

^cNo significant change in pharmacokinetic parameters observed; GMR of C _max or AUC not provided;

^dDid not meet pre‐defined definition of clinical significance

Pharmacokinetic interactions with aprepitant or fosaprepitant

Antineoplastic drugs

Thirteen included publications evaluated interactions between aprepitant and 10 individual antineoplastic drugs 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33, 34 and one publication evaluated an interaction between fosaprepitant and ifosfamide 31. Seven included publications reported a GMR for AUC or C _max with and without aprepitant or fosaprepitant, which allowed assessment of clinical significance 27, 29, 30, 31, 32, 33, 34. Of these, three interactions met criteria for clinical significance: bosutinib PO 34, cabazitaxel IV 30 and cyclophosphamide IV 32.

GMR for AUC and C _max with/without aprepitant were not reported in the publications describing erlotinib (route not reported) 28, ifosfamide IV 23, melphalan IV 24, pazopanib IV 25, and thiotepa IV disposition 22. However, significant differences in other pharmacokinetic parameters were reported for several of these drugs when co‐administered with aprepitant. Changes in parameters indicative of reduced clearance were reported for CYP3A4 substrates in the presence of aprepitant: erlotinib (two‐fold increase in the trough concentration) 28, pazopanib IV (reduction of mean oral clearance by 24–37%) 25 and thiotepa IV (20% lower tepa exposure) 22. In addition, ifosfamide clearance was increased by approximately 60% in the presence of aprepitant 23.

Non‐antineoplastic drugs

Twenty publications evaluated aprepitant or fosaprepitant interactions with 16 non‐antineoplastic drugs 9, 11, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52. Interactions between fosaprepitant and dexamethasone PO 11 or midazolam PO 11 and between aprepitant and dexamethasone PO 44, methylprednisolone IV 44, midazolam PO/IV 9, 47, 49, oxycodone PO 39 and tolbutamide PO 46 met criteria for clinical significance.

Multiple included publications evaluated aprepitant drug interactions with CYP probe drugs: midazolam PO/IV 9, 43, 47, 49 and tolbutamide PO 46, 47, implying effects on CYP3A4 and CYP2C9, respectively. A significant interaction with a higher dose of aprepitant (125 mg on day 1) was consistently demonstrated 9, 43, 47, 49. When a lower dose of aprepitant of 40 mg PO day 1, followed by 25 mg PO on days 2 and 3 was administered with midazolam PO, the interaction did not meet criteria for clinical significance (GMR AUC_0–inf 1.22; 95% CI: 0.93–1.61 on day 1) 9. Similarly, when a lower aprepitant dose of 40 mg was administered with tolbutamide PO, the interaction did not meet criteria for significance (GMR AUC_0–inf 0.87, 90% CI: not reported on day 4) 46.

Study authors did not report a GMR for AUC or C _max when describing the co‐administration of the following drugs with aprepitant: alcohol IV 51, dexamethasone IV 45, 50, prednisolone PO 42, quetiapine PO 52, tacrolimus IV 40 and paroxetine PO 35. However, significant differences in other pharmacokinetic parameters were reported when aprepitant was co‐administered with several of these drugs. Reduced clearance or measures indicative of reduced clearance were observed for victim drugs which are CYP3A4 substrates: dexamethasone IV (reduction of dexamethasone clearance by approximately 25% and 50% in presence of aprepitant 40 mg or 125 mg, respectively 45, 50), quetiapine PO (11‐fold increase in plasma quetiapine concentration in presence of aprepitant 52) and tacrolimus IV (43% increase in mean dose‐normalized tacrolimus concentration in presence of aprepitant 40). In addition, the arithmetic mean AUC_0–24h and C _max of paroxetine, a CYP2D6 substrate, were reduced by approximately 25% and 20%, respectively, in the presence of aprepitant 35.

Adverse events ascribed to interactions with aprepitant or fosaprepitant

Most (76%; 26/34) publications reporting pharmacokinetic data did not report adverse events attributed to an aprepitant/fosaprepitant drug interaction. Eight publications did report that certain adverse events occurred more frequently with concomitant aprepitant administration. Of these, only one provided P‐values 51 and two were case reports 23, 52. The results of these three publications are presented with the other publications evaluating adverse events attributed to aprepitant or fosaprepitant below.

Antineoplastic drugs

Twenty‐four included publications reported adverse events attributed to co‐administration of aprepitant or fosaprepitant and an antineoplastic agent (anthracyclines, bexarotene PO, dinaciclib IV, erlotinib, ifosfamide IV, and pazopanib IV) 23, 25, 33, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 72. Of these, interactions between fosaprepitant and anthracyclines and aprepitant and ifosfamide IV were the suspected cause.

One prospective study 60 and six retrospective studies 55, 56, 61, 62, 64, 73 evaluated the incidence of phlebitis when fosaprepitant and anthracycline chemotherapy were administered via the same peripheral vein. Two of these studies compared the incidence of this adverse event in patients receiving anthracycline vs. non‐anthracycline chemotherapy 55, 56. In these studies, the reported odds ratios of having phlebitis with fosaprepitant and anthracycline therapy vs. fosaprepitant and platinum chemotherapy were 12.95 (95% CI: 5.74 to 29.2) 55 and 8.1 (95% CI: 2.0 to 31.9) 56. Other studies comparing phlebitis rates with/without fosaprepitant also noted statistically significant increases in phlebitis with fosaprepitant compared to aprepitant 62, 64, 73.

Thirteen publications (six retrospective studies, nine case reports and one case series) 23, 53, 54, 57, 58, 59, 65, 66, 67, 68, 69, 70, 72 evaluated neurotoxicity associated with the combination of ifosfamide and aprepitant/fosaprepitant. The interaction between aprepitant and ifosfamide was a probable cause of neurotoxicity in one of the nine case reports (DIPS: 6) 23. Neurotoxicity was unlikely to be due to an interaction between ifosfamide and aprepitant/fosaprepitant in the remaining case reports (DIPS: <5) 59, 65, 66, 68, 72. Results from the retrospective studies, four specifically evaluating the co‐administration of ifosfamide IV with aprepitant/fosaprepitant 57, 58, 69, 70 and two evaluating general risk factors for ifosfamide‐induced neurotoxicity 54, 67, did not demonstrate an increased likelihood of ifosfamide‐induced neurotoxicity or encephalopathy in the presence of aprepitant/fosaprepitant.

Non‐antineoplastic drugs

Fourteen included studies 35, 43, 46, 51, 52, 74, 75, 76, 77, 78, 79, 80, 81, 82 described potential drug interactions between aprepitant and alcohol IV, methadone PO, midazolam IV, oxycodone intranasal and PO, selective serotonin reuptake inhibitors/serotonin‐norepinephrine reuptake inhibitors PO (SSRIs/SNRIs), paroxetine PO, quetiapine PO, tolbutamide PO, and warfarin PO. A probable interaction was observed between aprepitant and alcohol IV 51, oxycodone 78, quetiapine PO 52, SSRIs/SNRIs 75 and warfarin 76, 77, 79, 82.

A randomized crossover study evaluating the pharmacokinetics of alcohol IV with/without aprepitant also conducted psychomotor and cognitive function tests on its subjects. A statistically significant decline in function was found for immediate pattern recognition (P = 0.043) and adaptive tracking at 7.5 h (P = 0.043) when aprepitant was given concomitantly with alcohol IV. However, study authors concluded that these differences were not clinically relevant 51.

A randomized crossover study examined the effects of aprepitant on the subjective and physiologic response to oxycodone in individuals with opioid abuse to identify whether neurokinin‐1 receptor antagonists diminish the effects of opioids related to their abuse potential 78. A statistically significant enhanced response to high oxycodone doses was noted in the presence of aprepitant with aprepitant increasing the ‘high’ that patients experienced (PO oxycodone: P = 0.39; intranasal oxycodone: P = 0.007) and the estimated street value of the oxycodone (PO oxycodone: P = 0.023; intranasal oxycodone: P = 0.004). A lower respiratory rate (PO oxycodone: P < 0.025; intranasal oxycodone: 0.005) and increased end tidal carbon dioxide (PO oxycodone: P = 0.028; intranasal oxycodone: P = 0.001) was also noted in the presence of aprepitant.

A case report suggested a probable interaction between quetiapine PO and aprepitant (DIPS: 6). Deep somnolence was reported when aprepitant was administered with quetiapine on days the patient was receiving chemotherapy 52.

In addition, a retrospective, case–control study found that patients receiving aprepitant together with SSRIs/SNRIs PO had higher rates of National Cancer Institute‐Common Toxicity Criteria version 3.0 (NCI‐CTC v3.0) grade 2 or greater vomiting than a patient not receiving a SSRI or SNRI (P = 0.04) 75.

One retrospective study and seven case reports described changes to International Normalized Ratio (INR) following the initiation of aprepitant administration in patients receiving chronic warfarin therapy 76, 77, 79, 80, 81, 82. The retrospective study reported statistically significant increases in INR during the first week after aprepitant administration (P = 0.0000149) and significant decreases 2 weeks after aprepitant administration (P = 0.00069) vs. the week prior to aprepitant administration. The DIPS scores for four of these case reports indicated that an interaction between aprepitant and warfarin PO was probable 76, 77, 79.

Discussion

Interactions between aprepitant/fosaprepitant and bosutinib PO 34, cabazitaxel IV 30, cyclophosphamide IV 32, dexamethasone PO 11, 44, methylprednisolone IV 44, midazolam PO/IV 9, 43, 47, 49, oxycodone PO 39 and tolbutamide PO 47 were clinically significant as defined by the FDA 17. In addition, clinical descriptions of adverse events probably or highly probably caused by co‐administration of aprepitant or fosaprepitant with alcohol IV 51, anthracyclines IV 55, 56, 60, 61, 62, 64, 73, ifosfamide IV 23, midazolam IV 43, oxycodone intranasal and PO 78, quetiapine PO 52, SSRIs/SNRIs 75 and warfarin PO 76, 77, 79, 82 were identified.

Midazolam and tolbutamide are commonly used as probes in drug interaction studies to determine whether the investigated drug is an inhibitor or inducer of CYP3A4 or CYP2C9, respectively 17. Included publications using midazolam PO support the classification of fosaprepitant as a weak CYP3A4 inhibitor 11 and aprepitant as a moderate CYP3A4 inhibitor 9 after the administration of the usual adult doses for CINV prevention. Delayed effects of aprepitant as a weak CYP3A4 inducer 47, 49 and a weak CYP2C9 inducer have also been noted several days after the administration of aprepitant 47.

Interestingly, the information required to apply the FDA definition of a significant interaction was not provided in 40% (14/35) of included pharmacokinetic studies. However, in 10 of these 14 publications, significant differences in pharmacokinetic parameters other than GMR for C _max or AUC were reported for the following victim drugs: dexamethasone IV, erlotinib (route not reported), ifosfamide IV, quetiapine PO, pazopanib PO, paroxetine PO, tacrolimus IV and thiotepa IV 22, 23, 25, 28, 35, 40, 45, 50, 52. Hence, there is a possibility that these interactions may be clinically significant and caution is advisable when these drugs are administered with aprepitant.

In several instances (e.g. dinaciclib IV, ifosfamide, vinorelbine IV, dolasetron PO (poor metabolizers), granisetron PO, ondansetron IV and palonosetron IV), considerable variability in the GMR was observed and the upper or lower limit of the 90% CI exceeded the GMR threshold for clinical significance 27, 31, 33. The FDA guidance document states that a drug interaction can be considered not to be clinically significant if the 90% CI for the systemic exposure ratios fall completely within 80 to 125% 17. Thus, cases where the 90% CIs for the GMR for AUC or C _max fall outside this range may be a cause for concern.

Cyclophosphamide IV merits discussion since pharmacokinetic data were not reported consistently across the three included publications that describe the co‐administration of aprepitant and cyclophosphamide 21, 22, 32. One of these three publications reported GMRs for AUC and C _max with/without aprepitant and a designation of a clinically significant interaction was made based on this information 32. Study authors for the other two publications did not report a clinically significant interaction. However, specific AUC and C _max values were not reported in either of these publications and we were unable to draw conclusions based on our predefined definition 21, 22.

Reports of the interaction between ifosfamide and aprepitant/fosaprepitant were also conflicting. While case reports 23, 59, 65, 66, 72 attributed ifosfamide‐induced neurotoxicity to an aprepitant‐ifosfamide drug interaction, only one case report had a DIPS score that would suggest that the interaction was the probable cause (DIPS score: 6) 23. The included retrospective studies did not report P‐values or demonstrate a statistically significant difference in ifosfamide‐induced neurotoxicity rates in the presence of aprepitant 54, 57, 58, 67, 69, 70. Furthermore, results from a randomized crossover trial reported GMRs for C _max and AUC with/without fosaprepitant that did not meet our definition of a clinically significant interaction 31. Large, prospective studies are required to determine risk factors, including the co‐administration of aprepitant or fosaprepitant, for ifosfamide‐induced neurotoxicity.

All of the victim drugs that were found to have a clinically significant pharmacokinetic interaction with aprepitant or fosaprepitant were CYP3A4 or CYP2C9 substrates, consistent with what is known about the pharmacology of aprepitant and fosaprepitant. However, several CYP3A4 or CYP2C9 substrates were found not to interact to a clinically significant extent with aprepitant or fosaprepitant. Co‐administration of aprepitant and CYP3A4 substrates which were also substrates of p‐glycoprotein or other efflux transporters (Supporting Information Appendix S4) often did not lead to significant changes in pharmacokinetic disposition. We speculate that, for these drugs, elimination via alternative pathways compensates for inhibition of CYP3A4 by aprepitant/fosaprepitant and mitigates the magnitude of the interaction.

Patient‐related factors may also influence the magnitude of a CYP3A4‐mediated drug interaction. Patients with increased sensitivity to CYP3A4 inhibition or with reduced capacity to compensate for CYP3A4 inhibition may be at higher risk of clinically significant interactions with aprepitant or fosaprepitant. For example, patients may have reduced CYP3A4 and hepatic drug transporter activity by virtue of their age, disease states, genotype or concurrent drug therapy. Patients with inflammatory conditions or cancer may also have reduced CYP3A4 capacity 83. Young children may be particularly vulnerable since CYP3A4 concentrations steadily increase after birth and reach 30–40% of adult levels during the first year of life 84. Similarly, the activities of potentially compensatory pathways such as hepatic drug transporters p‐glycoprotein and organic anion‐transporting polypeptide transporters increase with age 85.

The strength of this systematic review is its rigorous approach to identify drug interaction publications, its application of a well‐recognized definition of clinical significance of drug interactions and its use of a validated tool to assess the probability of adverse events described in case reports.

It is limited by the small sample size of many of the included studies and lack of power to detect differences in adverse events, as well as, at least for the non‐antineoplastic victim medications, the conduct of many studies in healthy subjects. This limits the external generalizability of study results and was reflected in the quality assessment of included studies. Our ability to assess the clinical significance of pharmacokinetic interactions was also limited by the proportion of reports which did not present values for GMR for AUC or C _max. With respect to the drug interaction studies reporting adverse events, an association between the reported adverse event and co‐administration of aprepitant and a victim drug could not always be confirmed as a result of multiple confounding factors. For example, many of the studies evaluating ifosfamide‐induced neurotoxicity were confounded by the presence of other potential risk factors, such as plasma albumin concentrations and co‐administration of central nervous system acting agents. This ambiguity is reflected in the DIPS scores. Furthermore, the evaluation of adverse events related to drug interactions was limited to the timeframe of the studies. It is possible that changes in exposure to chemotherapy may have long‐term consequences. No publication was identified that evaluated the long‐term effects of an aprepitant/fosaprepitant drug interaction. This is an evidence gap that requires further investigation.

Despite these limitations, the findings of this systematic review are generalizable to adults with cancer since most studies (27/34) evaluated drug interactions after a single 125 mg dose of aprepitant or when given at the FDA‐approved adult dose (Supplemental Tables S6–S9). The findings are also generalizable to most children since CYP3A4 activity approaches adult levels by early childhood.

Conclusion

Using systematic methods, we identified clinically significant interactions between aprepitant and fosaprepitant and 14 drugs. Administration of fosaprepitant and anthracycline antineoplastic agents via the same peripheral vein should be avoided. Dose adjustment of the victim drug or use of antiemetic agents other than aprepitant or fosaprepitant should be considered for patients receiving dexamethasone PO, methylprednisolone IV, midazolam PO/IV, oxycodone PO, or tolbutamide PO. We suggest that neurokinin‐1 receptor antagonists without CYP3A4 activity be considered for patients receiving bosutinib PO, cabazitaxel IV or cyclophosphamide IV. Although less clear, the use of antiemetics other than aprepitant/fosaprepitant may be appropriate in patients receiving erlotinib, pazopanib IV or thiotepa IV. Our findings are summarized in Table 2. Individuals with reduced capacity to metabolize drugs via CYP3A4 or other pathways, including neonates and young children, may be at higher risk of experiencing clinically significant interactions due to aprepitant/fosaprepitant drug co‐administration.

Competing Interests

There are no competing interests to declare.

We thank Ms. Alanna Marson and Ms. Joanna Bielecki for guidance with the search strategy for the systematic review. We would also like to thank Dr. Lusine Abrahamyan and Dr. Petros Pechlivanoglou for support and guidance. We are grateful to Dr. Masanobu Takeuchi and Dr. Hitomi Hino for their help with article translation.

Supporting information

Appendix S1 Literature search

Table S1 Search strategy

Table S2 List of grey literature sources searched

Appendix S2 Publication selection, data extraction and quality assessment procedures

Appendix S3 Study results

Table S3 Downs and Black quality assessment for publications evaluating pharmacokinetic drug interactions between aprepitant or fosaprepitant and antineoplastic drugs

Table S4 Downs and Black quality assessment for publications evaluating pharmacokinetic drug interactions between aprepitant or fosaprepitant and non‐antineoplastic drugs

Table S5 Downs and Black quality assessment for publications evaluating clinical drug interactions between aprepitant or fosaprepitant and antineoplastic and non‐antineoplastic drugs

Table S6 Studies evaluating pharmacokinetic drug interactions between aprepitant or fosaprepitant and antineoplastic agents

Table S7 Studies evaluating pharmacokinetic drug interactions between aprepitant or fosaprepitant and non‐antineoplastic agents

Table S8 Drug interaction studies evaluating potential adverse events resulting from potential drug interactions between aprepitant or fosaprepitant and an antineoplastic agent

Table S9 Drug interaction studies evaluating potential adverse events resulting from potential drug interactions between aprepitant or fosaprepitant and a non‐antineoplastic agent

Table S10 Drug interaction probability scale evaluation for case reports

Appendix S4 Victim drug routes of metabolism, transporters where victim drugs are substrates and renal elimination

Patel, P. , Leeder, J. S. , Piquette‐Miller, M. , and Dupuis, L. L. (2017) Aprepitant and fosaprepitant drug interactions: a systematic review. Br J Clin Pharmacol, 83: 2148–2162. doi: 10.1111/bcp.13322.