Population pharmacokinetic analysis of oseltamivir and oseltamivir carboxylate following intravenous and oral administration to patients with and without renal impairment

  • Leonid Gibiansky
  • Mylène Giraudon
  • Craig R. Rayner
  • Barbara J. Brennan
  • Vishak Subramoney
  • Richard Robson
  • Mohamed A. Kamal
Original Paper


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.


Intravenous Oseltamivir Oseltamivir carboxylate Pharmacokinetics Renal impairment 

Supplementary material

10928_2015_9411_MOESM1_ESM.pdf (411 kb)
Supplementary material 1 (PDF 405 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Leonid Gibiansky
    • 1
  • Mylène Giraudon
    • 2
  • Craig R. Rayner
    • 3
    • 4
  • Barbara J. Brennan
    • 5
  • Vishak Subramoney
    • 5
  • Richard Robson
    • 6
  • Mohamed A. Kamal
    • 5
  1. 1.QuantPharm LLCNorth PotomacUSA
  2. 2.Roche Pharmaceutical Research and Early DevelopmentRoche Innovation CenterBaselSwitzerland
  3. 3.d3 Medicine LLCHillsboroughUSA
  4. 4.Monash UniversityMelbourneAustralia
  5. 5.Roche Pharmaceutical Research and Early DevelopmentRoche Innovation CenterNew YorkUSA
  6. 6.Christchurch Clinical Studies TrustChristchurchNew Zealand

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