Aprepitant pharmacokinetics

McCrea JB, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL, Hesney M, Lines CR, Petty KJ, Deutsch PJ, Murphy MG, Gottesdiener KM, Goldwater DR, Blum RA. Effects of the neurokininl receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther 2003 74 17-24. 

Depr M, Van Hecken A, Oeyen M, De Lepeleire I, Laethem T, Rothenberg P, Petty KJ, Ma-jumdar A, Crumley T, Panebianco D, Bergman A, de Hoon JN. Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. EurJ Clin Pharmacol (2005) 61, 341-6,... 

Aprepitant had no effect on the pharmacokinetics of a single dose of docetaxeL The activation of cyclophosphamide and thiotepa was slightly lower in patients receiving aprepitant, but this was not clinically relevant. However, because of the possibility of increased toxicity the manufacturer recommends caution with antineoplastics principally metabolised by the cytochrome P450 isoenzyme CYP3A4, particularly irinotecan, and also etoposide, vinorelbine, paclitaxel, ifosfamide, imatinib, vinblastine and vincristine, although there appears to be some limited evidence of safe concurrent use. 

Aprepitant 125 mg given one hour before docetaxel on day one, then 80 mg daily on days 2 and 3 had no effect on the pharmacokinetics of a single 60- to 100-mg/m infusion of docetaxel in 10 cancer patients, and did not alter the toxicity profile. Each subject acted as their own control. ... 

The UK manufacturer of aprepitant recommends caution when it is used with antineoplastics that are metabolised by CYP3A4, particularly irinotecan, because of the possibility of increased toxicity with this drug. They also mention that etoposide, vinoreibine, docetaxel, paclitaxel, ifosfamide, imatinib, vinblastine and vincristine, were given without dosage adjustment for potential interactions, but as this was not a formal interaction study they recommend caution. However, with intravenous docetaxel, it appears that no important changes in pharmacokinetics occur, and therefore dosage adjustments are unlikely to be needed for this drug,... 

In a randomised study 16 healthy subjeets took either aprepitant 125 mg on day 1 followed by 80 mg daily for 4 days, or 40 mg on day 1 followed by 25 mg daily for 4 days, with a single 2-mg oral dose of midazolam on days 1 and 5. The aprepitant 40/25 mg dosing sehedule had no significant effect on the pharmacokinetics of midazolam. However, the aprepitant 125/80 mg dosing schedule increased the AUC of oral midazolam by 126% and 229% on days 1 and 5, respectively, and increased the maximum plasma levels of midazolam by 46% and 94% on days 1 and 5, respectively. ... 

Aprepitant inhibits the cytochrome P450 isoenzyme CYP3A4 by which midazolam is metabolised, resulting in increased midazolam levels. The pharmacokinetic effect on intravenous midazolam indicate the effects of aprepitant on systemic rather than on intestinal CYP3A4 activity. Aprepitant is also a mild inducer of CYP3A4, however the induction is transient, with maximal effect 3 to 5 days after the end of treatment. 

Feuring M, Lee Y, Orlowski LH, Michiels N, De Smet M, Majumdar AK, Petty KJ, Goldberg MR, Murphy MG, Gottesdiener KM, Hesney M, Brackett LE, Wehling M. Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects. J Clin Pharmacol (2003) 43, 912-17. 

Effects of die neurokininl receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol 7 ier(2003) 74,17-24. 

Aprepitant had no clinically relevant effect on the pharmacokinetics of dolasetron, granisetron, ondansetron or palonosetron. 

No important pharmacokinetic interactions occur, therefore no dosage adjustment is required when aprepitant is given with dolasetron, ondansetron, granisetron or palonosetron. 

Li SX, PequignotE, Panebianco D, Lupinacci P, MajumdarA, RosenL, Ahmed T, Royalty JE, Rushmore TH, Murphy MG, Petty KJ. Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers. J Clin Pharmacol (2006) 46, 792-... 

Shah AK, Hunt TL, Gallagher SC, Cullen MT. Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers. CurrMedRes Opin (2005) 21, 595-601. 

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