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

Abstract

AIMSPatients 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. METHODSTen 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. RESULTSOseltamivir 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)] 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. CONCLUSIONSIn 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.

Optimization of anti-infective dosing regimens during online haemodiafiltration

“…Residual kidney function can be an important contributor to drug clearance [14]. The presence of residual kidney function may especially affect drugs that are actively secreted or reabsorbed by the tubule.…”

Identification of new oral dosing regimens for the neuraminidase inhibitor oseltamivir in patients with moderate and severe renal impairment

“…Study designs and PK sampling schemes for each of the 8 studies are summarized in Table . WP15648 was a dedicated renal impairment study (n = 5 per renal subgroup), whereas NV25655 was a small study investigating the disposition of oseltamivir in severe renal impairment (n = 6) and patients on automated peritoneal dialysis (data not shown). Studies PV15616, WP15647, WV15670, and NP15717 contributed data for patients with mild and moderate renal impairment, whereas studies WP15517 and WP15525 were single‐ and multiple‐dose PK studies in healthy volunteers.…”

How to use COVID-19 antiviral drugs in patients with chronic kidney disease

“…After oral administration, oseltamivir is rapidly converted into active metabolite i.e., oseltamivir carboxylate by hepatic esterase in GIT ( Patel et al, 2015 ). This carboxylate form binds and inhibits active sites of neuraminidase enzyme in influenza.…”

“…With a volume distribution of nearly 26 L, oseltamivir carboxylate can be available at the infected site with the same concentration as in plasma. The primary route of elimination for oseltamivir metabolites is urinary excretion, while a small amount of both metabolites (oseltamivir carboxylate and phosphate) can be found in faeces ( Patel et al, 2015 ).…”

“…Oseltamivir is safe in patients with hepatic and kidney dysfunction. Patients with a creatinine clearance <10 ml/min show high exposure to oseltamivir carboxylate; thus, a low dose of oseltamivir (75 mg/kg) is recommended in this group ( Table 1 ) ( Patel et al, 2015 ). However, the efficacy of low-dose oseltamivir on COVID-19 in patients with CKD is still unknown.…”