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Antimicrob Agents Chemother. 2013 May 13. [Epub ahead of print]
Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics.
Kamal MA, Wart SA, Rayner CR, Subramoney V, Reynolds DK, Bulik CC, Smith PF, Bhavnani SM, Ambrose PG, Forrest A.
Source
Hoffmann La-Roche, Inc., Nutley, NJ;
Abstract
Oseltamivir is a potent inhibitor of influenza neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on PK variability of oseltamivir and its active metabolite oseltamivir carboxylate (OC). Dosing history, plasma concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1-78 years and given oseltamivir doses of 20-1000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated in NONMEM and subject covariates were assessed using stepwise forward selection (α=0.01) and backward elimination (α=0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC, and a one-compartment model with first-order elimination of OC was utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent clearance OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F while Vcm/F also decreased linearly with age. A visual predictive check indicated the final model described oseltamivir and OC plasma concentrations adequately across dose regimens and subject covariate ranges. Concordance of population mean and individual post-hoc predictions of Cmax and AUC0-24 was high (r2=0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.
PMID:
23669384
[PubMed - as supplied by publisher]
Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics.
Kamal MA, Wart SA, Rayner CR, Subramoney V, Reynolds DK, Bulik CC, Smith PF, Bhavnani SM, Ambrose PG, Forrest A.
Source
Hoffmann La-Roche, Inc., Nutley, NJ;
Abstract
Oseltamivir is a potent inhibitor of influenza neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on PK variability of oseltamivir and its active metabolite oseltamivir carboxylate (OC). Dosing history, plasma concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1-78 years and given oseltamivir doses of 20-1000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated in NONMEM and subject covariates were assessed using stepwise forward selection (α=0.01) and backward elimination (α=0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC, and a one-compartment model with first-order elimination of OC was utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent clearance OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F while Vcm/F also decreased linearly with age. A visual predictive check indicated the final model described oseltamivir and OC plasma concentrations adequately across dose regimens and subject covariate ranges. Concordance of population mean and individual post-hoc predictions of Cmax and AUC0-24 was high (r2=0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.
PMID:
23669384
[PubMed - as supplied by publisher]
