tetano
Editor, Senior Moderator
Antimicrob Agents Chemother. 2013 May 13. [Epub ahead of print]
Pharmacokinetic-Pharmacodynamic Determinants of Oseltamivir Efficacy Using Data from Phase 2 Inoculation Studies.
Rayner CR, Bulik CC, Kamal MA, Reynolds DK, Toovey S, Hammel JP, Smith PF, Bhavnani SM, Van Wart SA, Ambrose PG, Forrest A.
Source
Hoffman-La Roche, Inc., Nutley, NJ;
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 (IC50=0.18 nM) or B/Yamagata (IC50=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 AUC0-24, Cmin, and Cmax 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 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?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.
PMID:
23669386
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23669386
Pharmacokinetic-Pharmacodynamic Determinants of Oseltamivir Efficacy Using Data from Phase 2 Inoculation Studies.
Rayner CR, Bulik CC, Kamal MA, Reynolds DK, Toovey S, Hammel JP, Smith PF, Bhavnani SM, Van Wart SA, Ambrose PG, Forrest A.
Source
Hoffman-La Roche, Inc., Nutley, NJ;
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 (IC50=0.18 nM) or B/Yamagata (IC50=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 AUC0-24, Cmin, and Cmax 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 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?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.
PMID:
23669386
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23669386