Aprepitant inhibits metabolism of oral midazolam resulting inincreased plasma levels
In a randomised study 16 healthy subjects took either aprepitant 125mg on day 1 followed by 80mg daily for 4 days,or 40mg on day 1 followed by 25mg daily for 4 days, with a single 2mg oral dose of midazolam on days 1 and 5. The aprepitant 40/25 mg dosing schedule had no significant effect on pharmacokinetics of midazolam. However, aprepitant 125/80 mg dosing schedule increased AUC of oral midazolam by 126 % and 229 % on days 1 and 5, respectively, and increased maximum plasma levels of midazolam by 46 % and 94 % on days 1 and 5, respectively (See reference number 1).
In a randomised,placebo-controlled study, 24 healthy subjects were given aprepitant 125mg on day one then 80mg daily for a further 2 days. A single 2mg intravenous dose of midazolam was given on days 4,8 and 15. The 3-day aprepitant regimen increased midazolam levels slightly on day 4 (AUC increased by 25 % and clearance reduced by 20%),decreased midazolam levels slightly on day 8 (AUC decreased by 19 % and clearance increased by 24%) and had almost no effect by day 15, when compared to placebo (See reference number 2).
Aprepitant inhibits cytochrome P450 isoenzyme CYP3A4 by which midazolam is metabolised, resulting in increased midazolam levels. The pharmacokinetic effect on intravenous midazolam indicate effects of aprepitant on systemic rather than on intestinal CYP3A4 activity. Aprepitant is also a mild inducer of CYP3A4,(See reference number 2,3) however induction is transient, with maximal effect 3 to 5 days after end of treatment.
Based on way midazolam interacts with similarly potent inhibitors of CYP3A4, aprepitant may be expected to increased drowsiness and length of sedation and amnesia in patients given midazolam. Consider reducing midazolam dose in patients given aprepitant and monitor outcome of concurrent use carefully. The manufacturer notes that potential effects of increased levels of other benzodiazepines metabolised via CYP3A4, such as alprazolam and triazolam, should be considered if
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They also state that effects of aprepitant on plasma levels of intravenously administered CYP3A4 substrates are expected to be less than effects on orally administered substrates (See reference number 3)
1. Majumdar AK,McCrea JB, Panebianco DL, Hesney M, Dru J, Constanzer M, Goldberg MR,Murphy G, Gottesdiener KM, Lines CR, Petty KJ, Blum RA. Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther (2003) 74, 150–
6.
Shadle CR,Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, Evans JK, Blum RA.Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol (2004) 44, 215–23.
Emend (Aprepitant). Merck Sharp & Dohme Ltd. UK Summary of product characteristics,February 2007.