Rapivab (Page 4 of 5)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Peramivir is an antiviral drug with activity against influenza virus [see Microbiology (12.4)].

12.2 Cardiac Electrophysiology

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

12.3 Pharmacokinetics

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

Following intravenous administration of a single dose of RAPIVAB 600 mg over 30 minutes, a maximum plasma concentration (Cmax ) of 46,800 ng/mL (46.8 µg/mL) was reached at the end of infusion. AUC0-∞ 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 RAPIVAB following IV administration to healthy subjects of 600 mg as a single dose is approximately 20 hours. The major route of elimination of RAPIVAB 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 6 months to 17 years of age with acute uncomplicated influenza. Pharmacokinetic sampling in this study was limited to approximately 3 hours after administration of peramivir. Geometric mean (GM) PK parameters are provided in Table 5.

Table 5. Geometric Mean (%CV) Cmax and AUC0-3 by Age Group in Comparison to Adults
Age Group GM Cmax (ng/mL) (%CV) GM AUC0-3 (ng.h/mL) (%CV)
6 months to < 2 years 38,000 (73.7) 46,200 (35.8)
2 to < 7 years 47,400 (48.4) 62,700 (39.7)
7 to < 13 years 61,200 (53) 76,300 (43.1)
13 to < 18 years 51,500 (33) 65,500 (28.1)
Healthy Adults (Study 113) 45,700 (21.5) 68,500 (19.1)

Peramivir pharmacokinetics in subjects 2 to 17 years of age was similar to adults. In pediatric patients 6 months to less than 2 years of age, the GM AUC0-3 and Cmax were lower than that of healthy adult subjects, with GM ratios (90% CI) of 0.68 (0.52 to 0.88) and 0.83 (0.59 to 1.18), respectively. The difference in exposure is not considered to be clinically significant.

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 (AUC0-12 ) 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 Cmax was observed (6 subjects per cohort). However, mean AUC0-∞ 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 RAPIVAB is recommended for adult and adolescent patients 13 years and older with creatinine clearance below 50 mL/min [see Dosage and Administration (2.2)].

The pharmacokinetics of peramivir has not been studied in pediatric subjects with renal impairment. Given that the pharmacokinetics in pediatric subjects with normal renal function is comparable to that observed in adults, the same proportional dose reduction is recommended in pediatric patients with renal impairment > 2 years of age [see Dosage and Administration (2.2)].

In pediatric patients with renal impairment less than 2 years of age, given the developmental immaturity of renal function in this age group, a recommendation for dose reduction cannot be made [see Dosage and Administration (2.2)].

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 RAPIVAB with other drugs is low, based on the known elimination pathway of RAPIVAB, and data from in vitro studies indicating RAPIVAB does not induce or inhibit cytochrome P450.

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

RAPIVAB is primarily cleared in the urine by glomerular filtration.

12.4 Microbiology

Mechanism of Action

Peramivir is an inhibitor of influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells. The median neuraminidase inhibitory activities (IC50 values) of peramivir in biochemical assays against influenza A/H1N1 virus, influenza A/H3N2 virus, and influenza B virus clinical isolates were 0.16 nM (n=44; range 0.01-1.77 nM), 0.13 nM (n=32; range 0.05-11 nM), and 0.99 nM (n=39; range 0.04-54.2 nM), respectively, in a neuraminidase assay with a fluorescently labeled MUNANA substrate.

Antiviral Activity

The antiviral activity of peramivir against laboratory strains and clinical isolates of influenza virus was determined in cell culture. The concentrations of peramivir required for inhibition of influenza virus in cell culture varied depending on the assay method used and the virus tested. The median 50% effective concentrations (EC50 values) of peramivir in cell culture assays were 2.6 nM (n=13; range 0.09-21 nM), 0.08 nM (n=17; range 0.01-1.9 nM) and 4.8 nM (n=11; range 0.06-120 nM) for influenza A/H1N1 virus, A/H3N2 virus, and B virus strains, respectively.

The relationship between the antiviral activity in cell culture, inhibitory activity in the neuraminidase assay, and the inhibition of influenza virus replication in humans has not been established.

Resistance

Cell culture: Influenza A and B virus isolates with reduced susceptibility to peramivir were recovered by serial passage of virus in cell culture in the presence of increasing concentrations of peramivir. Reduced susceptibility of influenza virus to inhibition by peramivir may be conferred by amino acid substitutions in the viral neuraminidase or hemagglutinin proteins (Table 6).

Table 6: Amino Acid Substitutions Selected by Peramivir in Cell Culture Studies
Type/Subtype
Protein A/H1N1* A/H3N2 B
*
Numbering based on A/California/04/2009
Numbering based on A/Texas/50/2012
Numbering based on B/Massachusetts/02/2012
§
Numbering begins after the predicted signal peptide.
HA § D125S, R208K N63K, G78D, N145D, K189E T139N, G141E, R162M, D195N, T198N, Y319H
NA N58D, I211T, H275Y H273Y

In vivo: Influenza A and B virus isolates with amino acid substitutions associated with reduced susceptibility to peramivir were observed in clinical isolates collected during clinical trials with peramivir (Table 7). Amino acid substitutions have also been observed in viral isolates sampled during community surveillance studies which may be associated with reduced susceptibility to peramivir (Table 7). The clinical impact of this reduced susceptibility is unknown and may be strain-dependent.

Table 7: Neuraminidase and Hemagglutinin Amino Acid Substitutions Associated with Reduced Susceptibility to Peramivir in Clinical Virus Isolates
Protein Type / Subtype
Influenza A/H1N1* Influenza A/H3N2 Influenza B
*
Numbering based on A/California/04/2009
Numbering based on A/Texas/50/2012
Numbering based on B/Massachusetts/02/2012
NA Clinical Trial R152K, H275Y R292K, N294S
Community Surveillance Studies G147R, I223R/V, S247N/R, H275Y E119V, Q136K, D151A/E/G/N/V, Q391K H134N/Y, P139S, D197E/N/Y, I221T/V, R374K, D432G
HA Clinical Trial V479F

Circulating seasonal influenza strains expressing neuraminidase resistance-associated substitutions have been observed in individuals who have not received RAPIVAB. Prescribers should consider available information from the CDC on influenza virus drug susceptibility patterns and treatment effects when deciding whether to use RAPIVAB.

Zoonotic Viruses: Amino acid substitutions have been observed in H5N1 and H7N9 clinical viral isolates that conferred reduced susceptibility to peramivir in neuraminidase biochemical assays (Table 8). The clinical impact of reduced susceptibility in these viruses is unknown, and the effects of specific substitutions on virus susceptibility to peramivir may be strain-dependent.

Table 8. Amino Acid Substitutions Observed in Avian Influenza Viruses with Zoonotic Potential and Associated with Reduced Susceptibility to Peramivir
Protein Type/Subtype
Influenza A/H5N1* Influenza A/H7N9
*
Numbering based on A/California/04/2009
Numbering based on A/Texas/50/2012
NA H275Y R292K

Cross Resistance

Cross-resistance between peramivir, oseltamivir and zanamivir was observed in neuraminidase biochemical assays and cell culture assays. The amino acid substitutions that resulted in reduced susceptibility to peramivir and either oseltamivir or zanamivir are summarized in Table 9. The clinical impact of this reduced susceptibility is unknown and may be strain-dependent.

Table 9: Summary of Amino Acid Substitutions with Cross-Resistance between Peramivir and Oseltamivir or Zanamivir in Susceptibility Assays
Type/ Subtype
Protein A/H1N1* A/H3N2 B
*
Numbering based on A/California/04/2009
Numbering based on A/Texas/50/2012
Numbering based on B/Massachusetts/02/2012
§
Numbering begins after the predicted signal peptide.
Oseltamivir HA § N63K, N145D
NA E119V, D151G/N, R152K, Y155H, D199G, I223R/T/V, S247N, G249R+I267V, H275Y, N295S, Q313R, R368K, I427T E119I/V, I222V, S247P, R292K, N294S P139S, G140R, D197E/N/Y, I221T/V, H273Y, R374K, G407S
Zanamivir HA § N63K, N145D
NA Q136K, R152K, Y155H, D199G, I223T, S247N, G249R+I267V, N295S, Q313R, R368K, I427T E119G/V, T148I, D151A/G/N/V, I222V, S247P, R292K, N294S E117A/D/G, P139S, R150K, D197E/N/Y, R292K, R374K, G407S

No single amino acid substitution has been identified that could confer cross-resistance between the neuraminidase inhibitor class (peramivir, oseltamivir, zanamivir) and the M2 ion channel inhibitor class (amantadine, rimantadine). However, a virus may carry a neuraminidase inhibitor resistance-associated substitution in neuraminidase and an M2 ion channel inhibitor resistance-associated substitution in M2 and may therefore be resistant to both classes of inhibitors. The clinical relevance of phenotypic cross-resistance evaluations has not been established and may be strain-dependent.

Immune Response

No influenza vaccine/peramivir interaction study has been conducted.

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