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Clinical Trial
. 2015 Nov;80(5):1042-50.
doi: 10.1111/bcp.12691. Epub 2015 Aug 18.

Population pharmacokinetics of oseltamivir in non-pregnant and pregnant women

Venkateswaran C Pillai  1 , Kelong Han  2 , Richard H Beigi  3 , Gary D Hankins  4 , Shannon Clark  4 , Mary F Hebert  5 , Thomas R Easterling  5 , Anne Zajicek  6 , Zhaoxia Ren  6 , Steve N Caritis  3 , Raman Venkataramanan  1
Affiliations
Clinical Trial

Population pharmacokinetics of oseltamivir in non-pregnant and pregnant women

Venkateswaran C Pillai et al. Br J Clin Pharmacol. 2015 Nov.

Abstract

Aims: Physiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to evaluate systematically the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy.

Methods: A multicentre steady-state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration-time profiles were analyzed using both non-compartmental and population pharmacokinetic modelling (pop PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS.

Results: The systemic exposure of oseltamivir carboxylate (OC, active metabolite of OS) was reduced approximately 30 (19-36)% (P < 0.001) in pregnant women. Pregnancy significantly (P < 0.001) influenced the clearance (CL/F) and volume of distribution (V/F) of OC. Both non-compartmental and population pharmacokinetic approaches documented approximately 45 (23-62)% increase in clearance (CL/F) of OC during pregnancy.

Conclusion: Based on the decrease in exposure of the active metabolite, the currently recommended doses of OS may need to be increased modestly in pregnant women in order to achieve comparable exposure with that of non-pregnant women.

Keywords: oseltamivir; population pharmacokinetics; pregnancy.

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Figures

Figure 1
Figure 1
Mean plasma concentration–time profiles of oseltamivir (A and B) and oseltamivir carboxylate (C and D) in non-pregnant and pregnant women. A and C formula image non-pregnant, formula image pregnant. B and D formula image non-pregnant, formula image trimester 1, formula image trimester 2,  formula image trimester 3
Figure 2
Figure 2
Structure of oseltamivir carboxylate population pharmacokinetic model. ka, absorption rate constant; k1, conversion rate constant of oseltamivir to oseltamivir carboxylate; k2 and k3, elimination rate constant of oseltamivir and oseltamivir carboxylate, respectively
Figure 3
Figure 3
Goodness of fit diagnostic plots for oseltamivir carboxylate concentrations fitted using one compartment model with first order absorption and elimination. Observed plasma concentrations vs. population predicted concentrations (A), observed concentrations vs. individual predicted concentrations (B), population weighted residuals vs. time after dose (C) and individual weighted residuals vs. time after dose (D). The solid line indicates the line of identity
Figure 4
Figure 4
% oral clearance (CL/F) of oseltamivir and oseltamivir carboxylate in non-pregnant and first (TRI1), second (TRI2) and third (TRI3) trimester of pregnancy. Open bar indicates CL/F of oseltamivir whereas the filled bar represents CL/F of oseltamivir carboxylate. The results are expressed as mean ± SD. *P < 0.05 and **P < 0.01 vs. non-pregnant oseltamivir carboxylate, one way anova followed by Tukey's multiple comparison post hoc test
Figure 5
Figure 5
Frequency distribution of oseltamivir carboxylate area under the concentration–time (AUC) curve between non-pregnant and pregnant women. The frequency distribution of AUC of non-pregnant and pregnant women is shown as the open and dotted bar, respectively
Figure 6
Figure 6
Predictive performance of the final model was analyzed using visual predictive check plots. The model predicted concentrations of oseltamivir (top) and oseltamivir carboxylate (bottom) were shown as 5, 50 and 95 percentiles lines and were plotted against observed concentrations at each time after dose. formula image 5th and 95th percentile,  formula image 50 percentile (median), formula image Observants.
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References

    1. Freeman DW, Barno A. Deaths from Asian influenza associated with pregnancy. Am J Obstet Gynecol. 1959;78:1172–5. - PubMed
    1. Mosby LG, Rasmussen SA, Jamieson DJ. 2009 pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol. 2011;205:10–8. - PubMed
    1. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/flu/protect/vaccine/pregnant.htm (last accessed 2014). In, Atlanta, GA, 2014.
    1. Cervantes-Gonzalez M, Launay O. Pandemic influenza A (H1N1) in pregnant women: impact of early diagnosis and antiviral treatment. Expert Rev Anti Infect Ther. 2010;8:981–4. - PubMed
    1. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM. Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recommendations and reports: morbidity and mortality weekly report and reports / Centers for Disease Control. 2011;60:1–24. - PubMed

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