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

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 (CLM) and exposure. CLM 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.

Keywords

Intravenous Oseltamivir Oseltamivir carboxylate Pharmacokinetics Renal impairment 

Supplementary material

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

References

  1. 1.
    FDA Oseltamivir Package Insert http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM183850.pdf. Accessed 26 November 2014
  2. 2.
    Parrott N, Davies B, Hoffmann G, Koerner A, Lave T, Prinssen E, Theogaraj E, Singer T (2011) Development of a physiologically based model for oseltamivir and simulation of pharmacokinetics in neonates and infants. Clin Pharmacokinet 50(9):613–623CrossRefPubMedGoogle Scholar
  3. 3.
    Kamal MA, Van Wart SA, Rayner CR, Subramoney V, Reynolds DK, Bulik CC, Smith PF, Bhavnani SM, Ambrose PG, Forrest A (2013) Population pharmacokinetics of oseltamivir: pediatrics through geriatrics. Antimicrob Agents Chemother 57(8):3470–3477CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    New Zealand Tamiflu® Data Sheet. www.medsafe.govt.nz/profs/datasheet/t/Tamiflucapsusp.pdf. Accessed 11 January 2013
  5. 5.
    Brennan BJ, Davies B, Cirrincione-Dall G, Morcos PN, Beryozkina A, Chappey C, Aceves Baldó P, Lennon-Chrimes S, Rayner CR (2012) Safety, tolerability, and pharmacokinetics of intravenous oseltamivir: single- and multiple-dose phase I studies with healthy volunteers. Antimicrob Agents Chemother 56(9):4729–4737CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Wiltshire H, Wiltshire B, Citron A, Clarke T, Serpe C, Gray D, Herron W (2000) Development of a high performance liquid chromatographic-mass spectrometric assay for the specific and sensitive quantification of Ro 64-0802, an anti-influenza drug, and its pro-drug, oseltamivir, in human and animal plasma andurine. J Chromatogr B Biomed Sci Appl 745:373–388CrossRefPubMedGoogle Scholar
  7. 7.
    Beal S, Sheiner LB, Boeckmann A, Bauer RJ (2014) NONMEM user’s guides (1989–2014). Icon Development Solutions, Ellicott CityGoogle Scholar
  8. 8.
    Rayner CR, Chanu P, Gieschke R, Boak LM, Jonsson EN (2008) Population pharmacokinetics of oseltamivir when coadministered with probenecid. J Clin Pharmacol 48(8):935–947CrossRefPubMedGoogle Scholar
  9. 9.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41CrossRefPubMedGoogle Scholar
  10. 10.
    Pai MP, Paloucek FP (2000) The origin of the “ideal” body weight equations. Ann Pharmacother 34(9):1066–1069CrossRefPubMedGoogle Scholar
  11. 11.
    Demirovic JA, Pai AB, Pai MP (2009) Estimation of creatinine clearance in morbidly obese patients. Am J Health Syst Pharm 66(7):642–648CrossRefPubMedGoogle Scholar
  12. 12.
    Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B (2005) Quantification of lean body weight. Clin Pharmacokinet 44(10):1051–1065CrossRefPubMedGoogle Scholar
  13. 13.
    He G, Massarella J, Ward P (1999) Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 37:471–484CrossRefPubMedGoogle Scholar
  14. 14.
    Yano Y, Beal SL, Sheiner LB (2001) Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn 28:171–192CrossRefPubMedGoogle Scholar
  15. 15.
    Kamal MA, Brennan B, Subramoney V, Morcos PA, Frey C, Rayner C (2011) Identification of New Oral Dosing Regimens for the Neuraminidase Inhibitor Oseltamivir (Tamiflu®) in Patients with Moderate and Severe Renal Impairment Supported by Population Pharmacokinetics. ACoP Abstract. www.go-acop.org/sites/default/files/webform/posters/ACOP_2011.ppt. Accessed 11 January 2013
  16. 16.
  17. 17.
    Davies BE (2010) Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. J Antimicrob Chemother 65(Suppl 2):ii5-10Google Scholar
  18. 18.
    Pai MP, Lodise TP Jr (2011) Oseltamivir and oseltamivir carboxylate pharmacokinetics in obese adults: dose modification for weight is not necessary. Antimicrob Agents Chemother 55:5640–5645CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Thorne-Humphrey LM, Goralski KB, Slayter KL, Hatchette TF, Johnston BL, McNeil SA, and (The 2009 OPTIMO Study Group) (2011) Oseltamivir pharmacokinetics in morbid obesity (OPTIMO trial). J Antimicrob Chemother 66(9):2083–2091Google Scholar

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

Personalised recommendations