title: Effect of impaired renal function and haemodialysis on the pharmacokinetics of aprepitant.
abstract: BACKGROUND
  The neurokinin NK(1)-receptor antagonist aprepitant has demonstrated efficacy in preventing highly emetogenic chemotherapy-induced nausea and vomiting.
  
  
  OBJECTIVE
  The objective of the present study was to investigate the effects of impaired renal function on the pharmacokinetics and safety of aprepitant.
  
  
  METHODS
  A total of 32 patients and healthy subjects were evaluated in this open-label, two-part study. Pharmacokinetic parameters after a single oral dose of aprepitant 240 mg were measured in eight patients with end-stage renal disease (ESRD) requiring haemodialysis, eight patients with severe renal insufficiency (SRI [24-hour creatinine clearance <30 mL/min/1.73 m(2)]) and 16 healthy and age-, sex- and weight-matched subjects (controls).
  
  
  RESULTS
  In ESRD patients, the area under the plasma concentration-time curve (AUC) from 0 to 48 hours (AUC(48)) for aprepitant was on average approximately 36% lower than that observed in control subjects (ratio [ESRD patients/healthy controls] of geometric means = 0.64), but the 90% confidence interval 0.52, 0.78 for the ratio of true mean AUC(48) fell within the predefined target interval of 0.5, 2.0. Also in ESRD patients, there was no statistically or clinically significant difference in unbound aprepitant AUC (which may be more clinically relevant than total aprepitant AUC) when compared with healthy control subjects. Aprepitant pharmacokinetic parameters in ESRD patients were clinically similar when haemodialysis was initiated at 4 hours or 48 hours after aprepitant administration. In SRI patients, the ratio (SRI patients/healthy controls) of aprepitant AUC from zero to infinity (AUC(infinity)) geometric mean value was 0.79 with a 90% confidence interval of 0.56, 1.10. On average, in SRI patients the principal aprepitant pharmacokinetic parameters (AUC(infinity), initial maximum plasma concentration [C(max)], time to initial C(max), and apparent elimination half-life) were not statistically different from those obtained in healthy control subjects. Aprepitant was generally well tolerated in both ESRD and SRI patients.
  
  
  CONCLUSIONS
  The results of this study demonstrate that ESRD, haemodialysis and SRI have no clinically meaningful effect on aprepitant pharmacokinetics. Therefore, no dosage adjustment of aprepitant is warranted in SRI or ESRD patients.
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Bergman
authors.forename: Thomas
authors.initials: T
authors.lastname: Marbury
authors.forename: Trisha
authors.initials: T
authors.lastname: Fosbinder
authors.forename: Suzanne
authors.initials: S
authors.lastname: Swan
authors.forename: Lisa
authors.initials: L
authors.lastname: Hickey
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Bradstreet
authors.forename: John
authors.initials: J
authors.lastname: Busillo
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Petty
authors.forename: Kala-Jyoti Viswanathan
authors.initials: KJ
authors.lastname: Aiyer
authors.forename: Marvin
authors.initials: M
authors.lastname: Constanzer
authors.forename: Su-Er W
authors.initials: SE
authors.lastname: Huskey
authors.forename: Anup
authors.initials: A
authors.lastname: Majumdar
mesh_terms: D000328:Adult; D000932:Antiemetics / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000077608:Aprepitant; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000378:metabolism*; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D064729:Neurokinin-1 Receptor Antagonists; D011446:Prospective Studies; D011485:Protein Binding; D006435:Renal Dialysis
chemical_list: D000932:Antiemetics; D001798:Blood Proteins; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D000077608:Aprepitant