Pharmacokinetics and safety of oseltamivir in patients with end-stage renal disease treated with automated peritoneal dialysis

Abstract

Aims: Patients with end-stage renal disease (ESRD) are at increased risk of developing complications associated with influenza infection. Oseltamivir is indicated for influenza treatment in ESRD patients, but the disposition is poorly understood in this patient population. This study aimed to characterize the pharmacokinetics and tolerability of oseltamivir in automated peritoneal dialysis (APD) and construct a pharmacokinetic model to assist with optimized dosing.

Methods: Ten adults with ESRD were prescribed an aggressive APD regimen consisting of three continuous cycler-assisted peritoneal dialysis (CCPD) sessions during the day and two continuous ambulatory (CAPD) sessions overnight. Oseltamivir was administered as a single 75 mg dose, immediately before APD treatment.

Results: Oseltamivir was rapidly eliminated via first-pass metabolism, with most of the dose (Fraction metabolized = 0.964) reaching the circulation as the active metabolite, oseltamivir carboxylate. This metabolite was cleared slowly and was quantifiable throughout the sampling interval. The disposition of oseltamivir and oseltamivir carboxylate was described by a two- and a one-compartment model, respectively. Metabolite clearance by CCPD [0.32 l h(-1) (70 kg)(-1) ] was 1.9-fold faster than via CAPD [0.17 l h(-1) (70 kg)(-1) ], with renal elimination being dominant in patients with residual urine production. Model simulations showed that a single 75 mg dose attained target exposures in patients with negligible or low urine clearance. However, higher doses are recommended for further investigation in patients with high residual renal function. In all patients, oseltamivir was well tolerated.

Conclusions: In APD patients with anuria or low residual renal elimination, a single 75 mg dose of oseltamivir produced exposures at the upper end of the safety margin.

Trial registration: ClinicalTrials.gov NCT01556633.

Keywords: end-stage renal disease; influenza; oseltamivir; peritoneal dialysis; pharmacokinetics; safety.

© 2014 The British Pharmacological Society.

Figures

Figure 1

Structure of the model describing the pharmacokinetics of oseltamivir and oseltamivir carboxylate in patients receiving oral oseltamivir and automated peritoneal dialysis. See Table 2 for parameter definitions

Figure 2

Arithmetic mean (±SD) plasma concentrations of oseltamivir (A) and oseltamivir carboxylate (B) on a logarithmic scale vs. time after a single 75 mg oral dose in patients with end-stage renal disease undergoing dialysis. Spaghetti plots of individual patient traces for oseltamivir (C) and oseltamivir carboxylate (D) are also provided. , Subject 10001; , Subject 10003; , Subject 10004; , Subject 10005; , Subject 10006; , Subject 10007; , Subject 10008; , Subject 10009; , Subject 10010

Figure 3

Visual predictive check for oseltamivir (OP) in plasma (A), oseltamivir carboxylate (OC) in plasma (B), oseltamivir carboxylate in dialysate (C) and oseltamivir carboxylate in urine (D). The model showed good predictive performance and identified two patients with a relatively high clearance of oseltamivir carboxylate (indicated by the mismatch between the 5% observed and predicted percentiles in B). Corresponding plots in urine (D) differentiated these two (high urine-producing) patients from the other two urine-producing patients, who had lower estimated urinary clearance. , observed data; , predicated 50th percentile (shaded, 95% confidence interval); , observed 50th percentile; , predicated 5th and 95th percentiles (shaded, 95% confidence interval); , observed 5th and 95th percentile