Peramivir

Peramivir is an antiviral drug with activity against influenza virus.

Cardiac Electrophysiology

At twice the maximum recommended dose, RAPIVAB did not prolong the QTc interval to any clinically relevant extent.

The pharmacokinetics of peramivir was evaluated in Phase 1 trials in adults. The pharmacokinetic parameters following intravenous administration of peramivir (0.17 to 2 times the recommended dose) showed a linear relationship between dose and exposure parameters (C_max and AUC).

Following intravenous administration of a single dose of peramivir 600 mg over 30 minutes, a maximum serum concentration (C_max) of 46,800 ng/mL (46.8 μg/mL) was reached at the end of infusion. AUC_0-∞ values were 102,700 ng•hr/mL.

Distribution

In vitro binding of peramivir to human plasma proteins is less than 30%.

Based on a population pharmacokinetic analysis, the central volume of distribution was 12.56 L.

Metabolism and Elimination

Peramivir is not a substrate for CYP enzymes, does not affect glucuronidation, and is not a substrate or inhibitor of P-glycoprotein mediated transport.

Peramivir is not significantly metabolized in humans.

The elimination half-life of peramivir following IV administration to healthy subjects of 600 mg as a single dose is approximately 20 hours. The major route of elimination of peramivir is via the kidney. Renal clearance of unchanged peramivir accounts for approximately 90% of total clearance. Negligible accumulation was observed following multiple doses, either once or twice daily, for up to 10 days.

Specific Populations

Race

Pharmacokinetics of peramivir was evaluated primarily in Caucasians and Asians. Based on a population pharmacokinetic analysis including race as a covariate, volume of distribution was dependent on weight and Asian race. No dose adjustment is required based on weight or Asian race.

Gender

Peramivir pharmacokinetics was similar in male and female subjects.

Pediatric Patients

The pharmacokinetics of peramivir has been evaluated in a study in pediatric subjects 2 to 17 years of age with acute uncomplicated influenza. Pharmacokinetic sampling in this study was limited to approximately 3 hours after administration of peramivir. Pharmacokinetics of peramivir in subjects 13 to 17 years of age was similar to those in adult subjects, with a C_max of 54,300 ng/mL and AUC_0-last of 72,400 ng•h/mL after administration of a single 600 mg dose. Pharmacokinetics of peramivir in subjects 2 to 12 years of age (C_max of 61,300 ng/mL and AUC_0-last of 81,700 ng•h/mL) administered a single 12 mg/kg dose was also similar to that in adult subjects administered a single 600 mg dose.

Geriatric Patients

Peramivir pharmacokinetics in elderly subjects was similar to non-elderly subjects. Peak concentrations of peramivir after a single 4 mg/kg IV dose were approximately 10% higher in elderly subjects when compared to young adults (22,647 vs 20,490 ng/mL, respectively). Exposure (AUC_0-12) to peramivir at steady state was roughly 34% higher in elderly subjects compared to young adults (61,572 vs 46,000 ng•hr/mL, respectively). Dose adjustment is not required for elderly patients.

Patients with Impaired Renal Function

A trial was conducted in adult subjects with various degrees of renal impairment. When compared to a concurrent cohort with normal renal function, no change in mean C_max was observed (6 subjects per cohort). However, mean AUC_0-∞ after a single 2 mg/kg IV dose was increased by 28%, by 302%, and by 412% in subjects with creatinine clearance 50-79, 30-49, and 10-29 mL/min, respectively.

Hemodialysis was effective in reducing systemic exposure of peramivir by 73% to 81%.

A reduced dose of peramivir is recommended for patients with creatinine clearance below 50 mL/min.

The pharmacokinetics of peramivir has not been studied in pediatric subjects with renal impairment. Given that the pharmacokinetics in pediatric subjects is comparable to that observed in adults, the same proportional dose reduction in pediatric patients is recommended.

Patients with Hepatic Impairment

The pharmacokinetics of peramivir in subjects with hepatic impairment has not been studied. No clinically relevant alterations to peramivir pharmacokinetics are expected in patients with hepatic impairment based on the route of peramivir elimination.

Assessment of Drug Interactions

The potential for CYP mediated interactions involving peramivir with other drugs is low, based on the known elimination pathway of peramivir, and data from in vitro studies indicating peramivir does not induce or inhibit cytochrome P450.

There was no evidence of drug-drug interactions when peramivir was administered with oral rimantadine, oseltamivir, or oral contraceptives containing ethinyl estradiol and levonorgestrel; or when peramivir IM was administered with oral probenecid.

Peramivir is primarily cleared in the urine by glomerular filtration.

Peramivir caused renal tubular necrosis and abnormal renal function in rabbits. Toxicities included tubular dilatation and necrosis with protein casts in cortical areas, dilated tubules with mineralization in corticomedullary junction areas, and multifocal tubular regeneration. The rabbit appeared to be the sensitive species for peramivir renal toxicity, which was noted at exposures approximately 2- to 4-fold those in humans at the clinically recommended dose.