Pharmacokinetic-pharmacodynamic determinants of oseltamivir efficacy using data from phase 2 inoculation studies

Craig Robert Rayner, Catherine Bulik, Mohamed A Kamal, Daniel K Reynolds, Stephen Toovey, Jeffrey P Hammel, Patrick F Smith, Sujata Bhavnani, Scott A Van Wart, Paul Ambrose, Alan Forrest

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Abstract

Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50 [IC50]0.18 nM) or B/Yamagata (IC5016.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC0-24), minimum concentration of OC in plasma (Cmin), and maximum concentration of OC in plasma (Cmax). Exposureresponse relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC0-24 evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC0-24 threshold (14,000 ng h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.
Original languageEnglish
Pages (from-to)3478 - 3487
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume57
Issue number8
DOIs
Publication statusPublished - 2013

Cite this

Rayner, C. R., Bulik, C., Kamal, M. A., Reynolds, D. K., Toovey, S., Hammel, J. P., Smith, P. F., Bhavnani, S., Van Wart, S. A., Ambrose, P., & Forrest, A. (2013). Pharmacokinetic-pharmacodynamic determinants of oseltamivir efficacy using data from phase 2 inoculation studies. Antimicrobial Agents and Chemotherapy, 57(8), 3478 - 3487. https://doi.org/10.1128/AAC.02440-12