gs-4071 and Body-Weight

Oseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, 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 were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CL(m)/F) and central volume of distribution (Vc(m)/F). Creatinine clearance was a significant predictor of CL(m)/F, while Vc(m)/F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individual post hoc predictions of maximum concentration of drug at steady state (C(max)) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC(0-24)) was high (r(2) = 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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Area Under Curve; Body Weight; Child; Child, Preschool; Clinical Trials as Topic; Creatinine; Dose-Response Relationship, Drug; Female; Humans; Infant; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Models, Theoretical; Oseltamivir; Predictive Value of Tests; Young Adult

Obesity is an independent risk factor for mortality in patients infected with pandemic influenza A virus (H1N1). Given the poor outcomes observed among adult obese patients with H1N1, the dosing of antiviral agents in this population has been questioned, and use of twice the standard oseltamivir dose has been suggested. However, studies evaluating the disposition of oseltamivir and oseltamivir carboxylate (the active metabolite) in the obese population are scant. We evaluated the single-dose and steady-state pharmacokinetics of oseltamivir (75 mg by mouth twice daily) in a cohort of 21 healthy adult volunteers with class III obesity (body mass index [BMI], ≥ 40 kg/m(2)). The median (minimum, maximum) age, weight, and BMI were 36 (19, 50) years, 122 (106, 159) kg, and 43.7 (40.0, 54.4) kg/m(2), respectively. The population pharmacokinetic exposure profiles of oseltamivir carboxylate (the active metabolite) were comparable between class III obese subjects and nonobese adults (healthy and infected). Similar to previous pharmacokinetic analyses in nonobese subjects, the mean (percent covariance [CV]) area under the concentration-time curve for the dosing interval (AUC(0-τ)) was 2,621 ng · h/ml (17) for oseltamivir carboxylate. Body size was significantly (P < 0.05) associated with oseltamivir and oseltamivir carboxylate apparent clearance, but the correlation coefficient was poor (R(2) ≤ 0.3). Creatinine clearance estimated by the Cockcroft-Gault method and lean body weight were also significantly (P < 0.05) but poorly (R(2) = 0.17) correlated with oseltamivir carboxylate apparent clearance. Since the systemic exposure of oseltamivir carboxylate is not reduced in class III obese adults with standard doses, a dose increment of oseltamivir is likely to be unnecessary.

Topics: Adult; Antiviral Agents; Body Mass Index; Body Weight; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Obesity; Oseltamivir; Treatment Outcome; Young Adult

A mechanistic population-pharmacokinetic model was developed to predict oseltamivir exposures in neonates and infants accounting for physiological changes during the first 2 years of life. The model included data from 13 studies, comprising 436 subjects with normal renal function (317 pediatric subjects (≥ 38 weeks postmenstrual age (PMA), ≥ 13 days old) and 119 adult subjects < 40 years). Concentration-time profiles of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were characterized by a four-compartment model, with absorption described by three additional compartments. Renal maturational changes were implemented by description of OC clearance with allometric function of weight and Hill function of PMA. Clearance of OC increased with weight up to 43 kg (allometric coefficient 0.75). Half the adult OC clearance was reached at a PMA of 45.6 weeks (95% confidence interval (CI) 41.6-49.6) with a Hill coefficient of 2.35 (95% CI 1.67-3.04). The model supports the European Union/United States-approved 3 mg/kg twice-daily oseltamivir dose for infants < 1 year (PMA ≥ 38 weeks) and allows prediction of exposures in preterm neonates.

Topics: Adult; Age Factors; Antiviral Agents; Body Weight; Dose-Response Relationship, Drug; Female; Humans; Infant; Infant, Newborn; Kidney; Male; Models, Biological; Oseltamivir

Oseltamivir is widely used for the treatment and prophylaxis of influenza. Renewed interest in the central nervous system (CNS) tolerability profile of oseltamivir has been triggered by the reports of neuropsychiatric adverse events in patients with influenza. In addition, a recent pre-clinical study in rodents suggested a hypothermic effect of oseltamivir. The current studies investigated the CNS effects, body temperature effect and toxicokinetic profile of oseltamivir in rats. The CNS/temperature study included three groups receiving oseltamivir (500, 763 and 1000 mg/kg free base by oral gavage), one vehicle/control group and one reference group (D-amphetamine, 10 mg/kg). CNS parameters (behaviour, motor activity and co-ordination and sensory/motor reflex responses) and rectal temperature were measured at baseline and at five intervals until 8 hr after dosing. In the toxicokinetic study, rats received oseltamivir by oral gavage at 763 or 1000 mg/kg free base. Plasma, cerebrospinal fluid (CSF) and perfused brain concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured until 8 hr after dosing. Median scores for CNS parameters were similar in controls and animals receiving oseltamivir at all time points. Oseltamivir had no physiologically relevant effect on body temperature, but induced a short-lived and small dose-independent decrease in temperature in all active treatment groups at 1 hr after dosing only. Plasma concentrations of OC were higher than of oseltamivir, but the reverse was true in CSF and brain. CNS penetration was low for both moieties. In rats, oseltamivir at supratherapeutic doses up to 1000 mg/kg free base did not exert any effects on CNS function or hypothermic effects and led to limited CNS exposure, resulting in large safety margins.

Topics: Administration, Oral; Animals; Antiviral Agents; Body Temperature; Body Weight; Brain; Central Nervous System; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Hypothermia; Male; Oseltamivir; Rats; Rats, Sprague-Dawley