| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Sign In to gain access to subscriptions and/or personal tools.
|
|
|
|||||||
Sign In to gain access to subscriptions and/or personal tools. |
|||||||||
DRUG METABOLISM |
From Merck Research Laboratories, West Point, Pennsylvania (Mr. Shadle, Dr. Lee, Dr. Majumdar, Dr. Petty, Ms. Gargano, Dr. Bradstreet, Dr. Evans) and Buffalo Clinical Research Center, Buffalo, New York (Dr. Blum).
The NK1 receptor antagonist aprepitant (EMEND®), developed for use in combination with a 5HT3 receptor antagonist and a corticosteroid to prevent highly emetogenic chemotherapy-induced nausea and vomiting (CINV), has been shown to have a moderate inhibitory effect as well as a possible inductive effect on cytochrome P450 (CYP) 3A4. Aprepitant has been noted to produce modest decreases in plasma S(-)-warfarin concentrations, suggesting potential induction of CYP2C9. Because metabolism of some chemotherapeutic agents may involve CYP3A4, the potential inductive effect of the CINV dosing regimen of aprepitant on this metabolic pathway was evaluated using intravenous midazolam, a sensitive probe substrate of CYP3A4. The time course of induction of CYP2C9 by aprepitant was also evaluated using oral tolbutamide, a probe substrate of CYP2C9. In this double-blind, randomized, placebo-controlled, single-center study, 24 healthy subjects were randomized (12 subjects per group) to receive either an aprepitant 3-day regimen (aprepitant 125 mg p.o. on day 1 and aprepitant 80 mg p.o. on days 2 and 3) or matching placebo. All subjects also received probe drugs (midazolam 2 mg i.v. and tolbutamide 500 mg p.o.) once prior to aprepitant dosing (baseline) and again on days 4, 8, and 15. The ratio (aprepitant/placebo) of the geometric mean area under the plasma concentration curve (AUC) fold-change from baseline for midazolam was 1.25 on day 4 (p < 0.01), 0.81 on day 8 (p < 0.01), and 0.96 on day 15 (p = 0.646). The ratio (aprepitant/placebo) of the geometric mean AUC fold-change from baseline for tolbutamide was 0.77 on day 4 (p < 0.01), 0.72 on day 8 (p < 0.001), and 0.85 on day 15 (p = 0.05). Assessed using intravenous midazolam as a probe, aprepitant 125/80 mg p.o. administered over days 1 to 3 produced clinically insignificant weak inhibition (day 4) and induction (day 8) of CYP3A4 activity and no effect on CYP3A4 activity on day 15. Assessed using oral tolbutamide as a probe, the aprepitant regimen also produced modest induction of CYP2C9 activity on days 4 and 8, which resolved nearly to baseline by day 15. Thus, the aprepitant regimen for CINV results in modest, transient induction of CYPs 3A4 and 2C9 in the 2 weeks following administration.
Key Words: Aprepitant • midazolam • tolbutamide • CYP3A4 • CYP2C9 • pharmacokinetics
Address for reprints: Craig Shadle, Clinical Pharmacology, Merck Research Laboratories, BLB-33, 5 Sentry Parkway West, Blue Bell, PA 19422.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  X.-H. Zhu, J.-J. Jiao, C.-L. Zhang, J.-S. Lou, and C.-X. Liu Limited sampling strategy in rats to predict the inhibited activities of hepatic CYP3A Lab Anim, July 1, 2009; 43(3): 284 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jarkowski III Possible contribution of aprepitant to ifosfamide-induced neurotoxicity Am. J. Health Syst. Pharm., December 1, 2008; 65(23): 2229 - 2231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B Ibrahim, M. H Abidi, L. J Ayash, S. M Cronin, C. Cadotte, J. Mulawa, P. A Jacobson, D. W Smith, J. P Uberti, and D. J Edwards Effect of aprepitant on intravenous tacrolimus disposition in reduced intensity hematopoietic stem cell transplantation Journal of Oncology Pharmacy Practice, September 1, 2008; 14(3): 113 - 121. [Abstract] [PDF]
|
|
|
|
 |
|
 J-P Durand, B Gourmel, O Mir, and F Goldwasser Antiemetic neurokinin-1 antagonist aprepitant and ifosfamide-induced encephalopathy Ann. Onc., April 1, 2007; 18(4): 808 - 809. [Full Text] [PDF]
|
|
|
|
 |
|
 G. H. Wynn, N. B. Sandson, and K. L. Cozza Gastrointestinal Medications Psychosomatics, February 1, 2007; 48(1): 79 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Shelepova, A. N. Nafziger, J. Victory, A. D. M. Kashuba, E. Rowland, Y. Zhang, E. Sellers, G. Kearns, J. S. Leeder, A. Gaedigk, et al. Effect of a Triphasic Oral Contraceptive on Drug-Metabolizing Enzyme Activity as Measured by the Validated Cooperstown 5+1 Cocktail J. Clin. Pharmacol., December 1, 2005; 45(12): 1413 - 1421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Wilke, R. L. Berg, H. J. Vidaillet, M. D. Caldwell, J. K. Burmester, and M. A. Hillman Impact of Age, CYP2C9 Genotype and Concomitant Medication on the Rate of Rise for Prothrombin Time During the First 30 Days of Warfarin Therapy Clin. Med. Res., November 1, 2005; 3(4): 207 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M Massaro and K. L Lenz Aprepitant: A Novel Antiemetic for Chemotherapy-Induced Nausea and Vomiting Ann. Pharmacother., January 1, 2005; 39(1): 77 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. I. Sanchez, R. W. Wang, D. J. Newton, R. Bakhtiar, P. Lu, S.-H. L. Chiu, D. C. Evans, and S.-E. W. Huskey CYTOCHROME P450 3A4 IS THE MAJOR ENZYME INVOLVED IN THE METABOLISM OF THE SUBSTANCE P RECEPTOR ANTAGONIST APREPITANT Drug Metab. Dispos., November 1, 2004; 32(11): 1287 - 1292. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
