Population pharmacokinetics of peramivir in healthy volunteers and influenza patients.

UNLABELLED: Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. SUBJECTS: Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.

Pharmacokinetic assessment of peramivir in a hospitalized adult undergoing continuous venovenous hemofiltration.

OBJECTIVE: To report a sieving coefficient for peramivir in a patient receiving continuous venovenous hemofiltration (CVVH). CASE SUMMARY: An 18-year-old male presented with chills, myalgias, and dyspnea and was hospitalized. Nasal secretions were positive for influenza by rapid antigen test at an outside facility and oseltamivir was commenced. Oral absorption was predicted to be unreliable, and intravenous peramivir was accessed as an emergency investigational new drug applicaiton (eIND). CVVH was initiated after the development of acute renal failure, with blood samples collected to determine peramivir concentrations. DISCUSSION: Peramivir, an intravenous investigational neuraminidase inhibitor with activity against influenza viruses, has limited data for dosing in the setting of CVVH. A single patient received 600 mg of peramivir intravenously and had blood and ultrafiltrate concentrations measured serially. A sieving coefficient of approximately 0.9 was identified. CONCLUSIONS: Peramivir is well cleared by CVVH, and drug exposure is potentially predictable based on flow rates. Further study is necessary.

Clinical experience in adults and children treated with intravenous peramivir for 2009 influenza A (H1N1) under an Emergency IND program in the United States.

BACKGROUND: Peramivir, an investigational intravenous neuraminidase inhibitor in Phase 3 trials for hospitalized patients, was made available during the 2009 H1N1 influenza pandemic under the Emergency Investigational New Drug (eIND) regulations. We describe the clinical characteristics and outcomes of all patients for whom peramivir was requested under the eIND. METHODS: After obtaining eIND approval from the Food and Drug Administration and local institutional review board approval, clinicians caring for hospitalized patients with influenza administered intravenous peramivir and collected information on demographic characteristics, clinical characteristics, and outcomes. RESULTS: From April through October 2009, peramivir was requested for 42 patients and administered to 20 adults and 11 children. At hospitalization, all patients had rapidly progressing, radiographically confirmed viral pneumonia with respiratory failure, and all but 1 patient required mechanical ventilation. In most patients, including 1 person with documented oseltamivir-resistant infection, the illness had progressed despite oseltamivir treatment. Peramivir was administered for 1-14 days (median duration, 10 days). The 14-day, 28-day, and 56-day survival rates were 76.7%, 66.7%, and 59.0%, respectively. Peramivir was generally well tolerated. CONCLUSIONS: Intravenous peramivir was well tolerated and was associated with recovery in most patients hospitalized with severe 2009 H1N1 influenza viral pneumonia and treated under an eIND.

Peramivir pharmacokinetics in two critically ill adults with 2009 H1N1 influenza A concurrently receiving continuous renal replacement therapy.

STUDY OBJECTIVE: To determine the pharmacokinetics of intravenous peramivir-an investigational neuraminidase inhibitor for the treatment of 2009 H1N1 infection or nonsubtypable influenza A thought to be the 2009 H1N1 virus-in patients concurrently receiving continuous renal replacement therapy (CRRT). DESIGN: Pharmacokinetic analysis. SETTING: Critical care unit at a university-affiliated hospital. PATIENTS: Two critically ill women with 2009 H1N1 influenza A treated with compassionate-use intravenous peramivir administered as a daily infusion of 600 mg over 30 minutes while receiving continuous venovenous hemodiafiltration (CVVHDF), a form of CRRT. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected from the two patients before and 30 minutes after the fourth (first patient) and ninth (second patient) peramivir infusion to estimate minimum (C(min)) and maximum (C(max)) plasma concentrations, respectively. Two additional postinfusion concentrations were measured from each patient to estimate noncompartmental pharmacokinetic parameters of peramivir while receiving CVVHDF. In the two patients, respectively, C(min) was 2170 and 251 ng/ml, C(max) was 18,400 and 20,300 ng/ml, area under the plasma concentration-time curve from 0-24 hours (AUC(0-24)) was 178,000 and 94,400 ng·hour/ml, drug clearance was 56 and 106 ml/minutes, and plasma half-life was 7.6 and 3.7 hours. The volume of distribution adjusted for ideal body weight at steady state was 0.51 and 0.54 L/kg, respectively. CONCLUSION: The first patient had a slower peramivir plasma clearance compared with the second patient, but both patients had higher peramivir clearances as calculated from AUC(0-24) than those predicted by CRRT. Thus, the dosage of intravenous peramivir was appropriate in these patients. Additional pharmacokinetic data are needed to confirm these results and help guide dosing in patients receiving various forms of CRRT.