title: Population pharmacokinetic analysis of oseltamivir and oseltamivir carboxylate following intravenous and oral administration to patients with and without renal impairment.
abstract: This work characterizes the pharmacokinetics (PK) of oseltamivir phosphate (OP) and its active metabolite, oseltamivir carboxylate (OC), and investigates oseltamivir i.v. dosing regimens for treatment of influenza in patients with normal renal function and with various degrees of renal impairment. Initially, data collected from 149 subjects with normal renal function and mild to severe renal impairment who were administered 40-200 mg oseltamivir i.v. were described by a four-compartment model. Two compartments described OP, one compartment described OC and one compartment described OP to OC metabolism. Then, data of 128 subjects administered 20-1,000 mg oseltamivir orally were added. The absorption model included three first-order processes with direct (via first-pass) input in the OC compartment and two (direct and delayed) inputs in the OP compartment. Simulations and PK bridging were used to recommend i.v. dosing regimens. The analysis demonstrated that renal function had a major effect on OC clearance (CL M ) and exposure. CL M for subjects with mild, moderate and severe renal impairment was 18, 50, and 84 % lower than for subjects with normal renal function. Simulations were used to select i.v. dosing regimens that provide OC Cmin coverage and exposures comparable to those achieved in subjects with normal renal function administered 75 mg b.i.d. orally. The oseltamivir dose depended on the degree of renal impairment and was independent of route of administration. Specifically, 75 mg b.i.d. is recommended for subjects with normal renal function or mild renal impairment, 30 mg b.i.d. for subjects with moderate renal impairment, and 30 mg q.d. for subjects with severe renal impairment. Recommended i.v. doses were the same as those recommended for oral administration in corresponding renal impairment groups.
authors.affiliation: QuantPharm LLC, 49 Flints Grove Drive, North Potomac, MD, 20878, USA, lgibiansky@quantpharm.com.
authors.forename: Leonid
authors.initials: L
authors.lastname: Gibiansky
authors.forename: Mylène
authors.initials: M
authors.lastname: Giraudon
authors.forename: Craig R
authors.initials: CR
authors.lastname: Rayner
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brennan
authors.forename: Vishak
authors.initials: V
authors.lastname: Subramoney
authors.forename: Richard
authors.initials: R
authors.lastname: Robson
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Kamal
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001682:Biological Availability; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D053139:Oseltamivir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D055815:Young Adult
chemical_list: D053139:Oseltamivir; C535162:oseltamivir carboxylate
references.citation: J Chromatogr B Biomed Sci Appl. 2000 Aug 18;745(2):373-88
references.pmid: 11043756
references.citation: Am J Health Syst Pharm. 2009 Apr 1;66(7):642-8
references.pmid: 19299371
references.citation: J Antimicrob Chemother. 2011 Sep;66(9):2083-91
references.pmid: 21700623
references.citation: Clin Pharmacokinet. 2005;44(10):1051-65
references.pmid: 16176118
references.citation: Clin Pharmacokinet. 2011 Sep;50(9):613-23
references.pmid: 21827216
references.citation: Antimicrob Agents Chemother. 2013 Aug;57(8):3470-7
references.pmid: 23669384
references.citation: Nephron. 1976;16(1):31-41
references.pmid: 1244564
references.citation: Ann Pharmacother. 2000 Sep;34(9):1066-9
references.pmid: 10981254
references.citation: J Clin Pharmacol. 2008 Aug;48(8):935-47
references.pmid: 18524996
references.citation: J Pharmacokinet Pharmacodyn. 2001 Apr;28(2):171-92
references.pmid: 11381569
references.citation: Antimicrob Agents Chemother. 2011 Dec;55(12):5640-5
references.pmid: 21930881
references.citation: Clin Pharmacokinet. 1999 Dec;37(6):471-84
references.pmid: 10628898
references.citation: J Antimicrob Chemother. 2010 Apr;65 Suppl 2:ii5-ii10
references.pmid: 20215135
references.citation: Antimicrob Agents Chemother. 2012 Sep;56(9):4729-37
references.pmid: 22733065