Oseltamivir dosing optimisation in patients treated with automated peritoneal dialysis

Background: Peritoneal Dialysis (PD) is a renal replacement therapy commonly used in patients with end-stage renal disease (ESRD). Automated PD (APD) is more convenient than traditional continuous ambulatory PD (CAPD) because the manual delivery and drainage of dialysate is not required. Oseltamivir is an oral prodrug widely indicated for the treatment of influenza infections. The active metabolite, oseltamivir carboxylate (OC), is primarily eliminated renally. However, the pharmacokinetics (PK) of OC is poorly understood in patients receiving APD, which may produce faster drug clearances than CAPD due to the rapid replacement cycles.
Objectives: To develop a population PK model for oseltamivir and OC in adult ESRD subjects undergoing an aggressive APD regimen, and simulate the dosing schedules that provide adequate OC exposures.
Methods: Ten patients received three continuous cycler-assisted PD (CCPD) followed by two CAPD exchanges daily. A single oral dose of 75mg oseltamivir was administered immediately prior to APD commencement. Plasma, dialysate and urine were collected for the measurement of oseltamivir phosphate (OP) and OC concentrations. The data was analysed by nonlinear mixed-effects modelling (NONMEM version 7.2). Monte Carlo simulations were performed using different dosing and APD regimens to determine the attainment of target exposures
(AUC0-120 = 32 mg.h/L; C120 = 170 µg/L).
Results: Visual inspection of data identified a delay between the maximal plasma concentration of OP and the OC metabolite. To account for this, a transit compartment was incorporated, and represented the hepatic first-pass metabolism of OP to OC. A substantial fraction of the dose was estimated for first-pass conversion (Fmet = 0.964), with the remainder absorbed as unchanged OP. The disposition of OP and OC was described by two- and one-compartment models, respectively. The estimated OC clearance by CCPD (CLMCCPD = 0.319 L/h/70 kg) was ~ 2-fold faster than via CAPD (CLMCAPD = 0.170 L/h/70 kg). In urine-producing patients (n = 4), the major route of OC clearance was renal elimination (CLMU = 0.736 L/h/70kg). Individual post-hoc estimates clearly distinguished two sub-groups with low and high urinary clearance. In the latter, target exposures were only achieved with multiple oseltamivir doses.
Conclusions: In subjects undergoing APD, a single oral dose of 75mg oseltamivir is suitable only when residual urine clearance is low or negligible. However, in high urinary clearance patients, appropriate dosing schedules may include 75mg every 48 h or 30mg daily over five consecutive days.