Population Pharmacokinetics of Oseltamivir When Coadministered With Probenecid

Abstract

Oseltamivir is a potent, selective, oral neuraminidase inhibitor for the treatment and prophylaxis of influenza. Plasma concentrations of the active metabolite, oseltamivir carboxylate, are increased in the presence of probenecid, suggesting that the combination could allow for the use of reduced doses of oseltamivir. To investigate this proposal, we developed a population pharmacokinetic model and simulated the pharmacokinetics of candidate combination regimens of oral oseltamivir (45 mg and 30 mg twice a day) plus oral probenecid (500 mg/6 hourly). Probenecid plus oseltamivir 45 mg achieved all the pharmacokinetic parameters expected of oseltamivir alone, but combination with oseltamivir 30 mg and dose interval extension approaches did not. An oseltamivir-probenecid combination may compromise tolerability and enhance the potential for drug interactions. In addition, increased dosing requirements may affect compliance and attainment of optimal oseltamivir exposure, potentially facilitating the emergence of viral strains with reduced susceptibility to oseltamivir. These factors, set alongside increased capacity for oseltamivir production, should be carefully considered before an oseltamivir-probenecid combination is used.

Oseltamivir and Oseltamivir Carboxylate Pharmacokinetics in Obese Adults: Dose Modification for Weight Is Not Necessary

“…These comparisons from multiple sources indicate that the exposure of oseltamivir carboxylate is not lower in obese compared to nonobese adults administered standard oseltamivir phosphate doses. Lastly, our findings are consistent with results generated through a POP-PK analysis of 115 nonobese male subjects by Rayner and colleagues (14). In that study of non-class III obese subjects, the population-simulated median (5th, 95th percentile) AUC 0-24 , C max , and C min values for oseltamivir carboxylate were 12,098 (8,236, 18,207) (17).…”

“…Despite this relative difference in model fit, use of the population model to simulate concentration-time profiles of 5,000 patients yielded comparable AUC 0-, C max , and C min values to those generated by our noncompartmental analysis approach (Table 4 and Table 2). The data distribution around the central tendency estimates were also comparable to previously published data and are described with more detail in the Discussion (14,22).…”

“…The final mean POP-PK parameter and covariance matrix estimates were used through the population simulation option within ADAPT 5. The central tendency and distributions generated by our simulations were compared with those generated by our noncompartmental analysis and previous studies (14,22).…”

Investigating Clinically Adequate Concentrations of Oseltamivir Carboxylate in End-Stage Renal Disease Patients Undergoing Hemodialysis Using a Population Pharmacokinetic Approach

“…Samples were analyzed using a previously validated high-performance liquid chromatography-double mass spectrometry method (9). The lower limits of quantification (LOQs) for OP and OC were 1.0 and 10 ng/ml, respectively.…”

“…The first-order conditional estimation method was employed for all model runs, with the INTERACTION option. The base model was adapted from that described by Rayner et al (9): this described the pharmacokinetics of oseltamivir with a multicompartment linear model, where OP kinetics were described by a two-compartment model with first-order absorption, OC kinetics were described by a two-compartment model, and metabolism was described by an intermediate compartment placed between the OP and OC central compartments. Complete (100%) metabolism was assumed, and the OC central volume was estimated.…”