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Antimicrob Agents Chemother. Pharmacokinetic-Pharmacodynamic Determinants of Oseltamivir Efficacy Using Data from Phase 2 Inoculation Studies
[Source: Antimicrobial Agents and Chemotherapy, full text: (LINK). Abstract, edited.]
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Pharmacokinetic-Pharmacodynamic Determinants of Oseltamivir Efficacy Using Data from Phase 2 Inoculation Studies
C.R. Rayner 1,2,3, C.C. Bulik 4, M.A Kamal 1, D.K. Reynolds 4, S. Toovey 1,3,5, J.P. Hammel 4, P.F. Smith 1,3, S.M. Bhavnani 4,6, S.A. Van Wart 4,6, P.G. Ambrose 4,6 and A. Forrest 4,6
Author Affiliations: <SUP>1</SUP>Hoffman-La Roche, Inc., Nutley, NJ; <SUP>2</SUP>Monash Institute of Pharmaceutical Sciences, Melbourne, Australia; <SUP>3</SUP>d3 Limited; <SUP>4</SUP>Institute for Clinical Pharmacodynamics, Latham, NY; <SUP>5</SUP>Royal Free and University College Medical School, London, UK; <SUP>6</SUP>University at Buffalo, Buffalo, NY.
ABSTRACT
Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two Phase 2 influenza inoculation studies were evaluated. Healthy volunteers in Studies 1 and 2 were experimentally infected with influenza A/Texas (IC<SUB>50</SUB>=0.18 nM) or B/Yamagata (IC<SUB>50</SUB>=16.76 nM), respectively. In Study 1, 80 subjects received oral oseltamivir 20, 100, or 200 mg twice daily (BID), 200 mg once daily, or placebo for 5 days. In Study 2, 60 subjects received oral oseltamivir 75 or 150 mg BID or placebo for 5 days. Oseltamivir carboxylate (active metabolite or OC) PK was evaluated using individual PK data and a population PK model to derive individual AUC<SUB>0-24</SUB>, C<SUB>min</SUB>, and C<SUB>max</SUB> values. Exposure-response 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 AUC<SUB>0-24</SUB> 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 AUC<SUB>0-24</SUB> threshold (∼14,000 ng?hr/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.
FOOTNOTES
Corresponding author: Dr. Craig Rayner, d3 Ltd, 8 Connaught Place, Central Hong Kong craig.rayner@d3medicine.com
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
-C.R. Rayner 1,2,3, C.C. Bulik 4, M.A Kamal 1, D.K. Reynolds 4, S. Toovey 1,3,5, J.P. Hammel 4, P.F. Smith 1,3, S.M. Bhavnani 4,6, S.A. Van Wart 4,6, P.G. Ambrose 4,6 and A. Forrest 4,6
Author Affiliations: <SUP>1</SUP>Hoffman-La Roche, Inc., Nutley, NJ; <SUP>2</SUP>Monash Institute of Pharmaceutical Sciences, Melbourne, Australia; <SUP>3</SUP>d3 Limited; <SUP>4</SUP>Institute for Clinical Pharmacodynamics, Latham, NY; <SUP>5</SUP>Royal Free and University College Medical School, London, UK; <SUP>6</SUP>University at Buffalo, Buffalo, NY.
ABSTRACT
Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two Phase 2 influenza inoculation studies were evaluated. Healthy volunteers in Studies 1 and 2 were experimentally infected with influenza A/Texas (IC<SUB>50</SUB>=0.18 nM) or B/Yamagata (IC<SUB>50</SUB>=16.76 nM), respectively. In Study 1, 80 subjects received oral oseltamivir 20, 100, or 200 mg twice daily (BID), 200 mg once daily, or placebo for 5 days. In Study 2, 60 subjects received oral oseltamivir 75 or 150 mg BID or placebo for 5 days. Oseltamivir carboxylate (active metabolite or OC) PK was evaluated using individual PK data and a population PK model to derive individual AUC<SUB>0-24</SUB>, C<SUB>min</SUB>, and C<SUB>max</SUB> values. Exposure-response 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 AUC<SUB>0-24</SUB> 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 AUC<SUB>0-24</SUB> threshold (∼14,000 ng?hr/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.
FOOTNOTES
Corresponding author: Dr. Craig Rayner, d3 Ltd, 8 Connaught Place, Central Hong Kong craig.rayner@d3medicine.com
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
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