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Tamiflu (Oseltamivir Phosphate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

TAMIFLU (oseltamivir phosphate) is available as capsules containing 30 mg, 45 mg, or 75 mg oseltamivir for oral use, in the form of oseltamivir phosphate, and as a powder for oral suspension, which when constituted with water as directed contains 12 mg/mL oseltamivir base. In addition to the active ingredient, each capsule contains pregelatinized starch, talc, povidone K 30, croscarmellose sodium, and sodium stearyl fumarate. The 30 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and red iron oxide. The 45 mg capsule shell contains gelatin, titanium dioxide, and black iron oxide. The 75 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide, and red iron oxide. Each capsule is printed with blue ink, which includes FD&C Blue No. 2 as the colorant. In addition to the active ingredient, the powder for oral suspension contains sorbitol, monosodium citrate, xanthan gum, titanium dioxide, tutti-frutti flavoring, sodium benzoate, and saccharin sodium.

Oseltamivir phosphate is a white crystalline solid with the chemical name (3R,4R,5S)-4-acetylamino-5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1). The chemical formula is C16H28N2O4 (free base). The molecular weight is 312.4 for oseltamivir free base and 410.4 for oseltamivir phosphate salt. The structural formula is as follows:

MICROBIOLOGY

Mechanism of Action

Oseltamivir phosphate is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. Oseltamivir carboxylate is an inhibitor of influenza virus neuraminidase affecting release of viral particles.

Antiviral Activity

The antiviral activity of oseltamivir carboxylate against laboratory strains and clinical isolates of influenza virus was determined in cell culture assays. The concentrations of oseltamivir carboxylate required for inhibition of influenza virus were highly variable depending on the assay method used and the virus tested. The 50% and 90% effective concentrations (EC50 and EC90) were in the range of 0.0008 然 to >35 然 and 0.004 然 to >100 然, respectively (1 然=0.284 痢/mL). The relationship between the antiviral activity in cell culture and the inhibition of influenza virus replication in humans has not been established.

Resistance

Influenza A virus isolates with reduced susceptibility to oseltamivir carboxylate have been recovered by serial passage of virus in cell culture in the presence of increasing concentrations of oseltamivir carboxylate. Genetic analysis of these isolates showed that reduced susceptibility to oseltamivir carboxylate is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Resistance substitutions selected in cell culture in neuraminidase are I222T and H274Y in influenza A N1 and I222T and R292K in influenza A N2. Substitutions E119V, R292K and R305Q have been selected in avian influenza A neuraminidase N9. Substitutions A28T and R124M have been selected in the hemagglutinin of influenza A H3N2 and substitution H154Q in the hemagglutinin of a reassortant human/avian virus H1N9.

In clinical studies in the treatment of naturally acquired infection with influenza virus, 1.3% (4/301) of posttreatment isolates in adult patients andadolescents, and 8.6% (9/105) in pediatric patients aged 1 to 12 years showed emergence of influenza variants with decreased neuraminidase susceptibility in cell culture to oseltamivir carboxylate. Substitutions in influenza A neuraminidase resulting in decreased susceptibility were H274Y in neuraminidase N1 and E119V and R292K in neuraminidase N2. Insufficient information is available to fully characterize the risk of emergence of TAMIFLU resistance in clinical use.

In clinical studies of postexposure and seasonal prophylaxis, determination of resistance by population nucleotide sequence analysis was limited by the low overall incidence rate of influenza infection and prophylactic effect of TAMIFLU.

Cross-resistance

Cross-resistance between zanamivir-resistant influenza mutants and oseltamivir-resistant influenza mutants has been observed in cell culture. Due to limitations in the assays available to detect drug-induced shifts in virus susceptibility, an estimate of the incidence of oseltamivir resistance and possible cross-resistance to zanamivir in clinical isolates cannot be made. However, two of the three oseltamivir-induced substitutions (E119V, H274Y and R292K) in the viral neuraminidase from clinical isolates occur at the same amino acid residues as two of the three substitutions (E119G/A/D, R152K and R292K) observed in zanamivir-resistant virus.

Immune Response

No influenza vaccine interaction study has been conducted. In studies of naturally acquired and experimental influenza, treatment with TAMIFLU did not impair normal humoral antibody response to infection.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption and Bioavailability

Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted predominantly by hepatic esterases to oseltamivir carboxylate. At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate. Exposure to oseltamivir is less than 5% of the total exposure after oral dosing (see Table 1).

Table 1 Mean (% CV) Pharmacokinetic Parameters of Oseltamivir and Oseltamivir Carboxylate After a Multiple 75 mg Capsule Twice Daily Oral Dose (n=20)
Parameter Oseltamivir Oseltamivir Carboxylate
Cmax (ng/mL) 65.2 (26) 348 (18)
AUC0-12h (ngh/mL) 112 (25) 2719 (20)

Plasma concentrations of oseltamivir carboxylate are proportional to doses up to 500 mg given twice daily (see DOSAGE AND ADMINISTRATION).

Coadministration with food has no significant effect on the peak plasma concentration (551 ng/mL under fasted conditions and 441 ng/mL under fed conditions) and the area under the plasma concentration time curve (6218 ngh/mL under fasted conditions and 6069 ngh/mL under fed conditions) of oseltamivir carboxylate.

Distribution

The volume of distribution (Vss) of oseltamivir carboxylate, following intravenous administration in 24 subjects, ranged between 23 and 26 liters.

The binding of oseltamivir carboxylate to human plasma protein is low (3%). The binding of oseltamivir to human plasma protein is 42%, which is insufficient to cause significant displacement-based drug interactions.

Metabolism

Oseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms.

Elimination

Absorbed oseltamivir is primarily (>90%) eliminated by conversion to oseltamivir carboxylate. Plasma concentrations of oseltamivir declined with a half-life of 1 to 3 hours in most subjects after oral administration. Oseltamivir carboxylate is not further metabolized and is eliminated in the urine. Plasma concentrations of oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most subjects after oral administration. Oseltamivir carboxylate is eliminated entirely (>99%) by renal excretion. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h) indicating that tubular secretion occurs, in addition to glomerular filtration. Less than 20% of an oral radiolabeled dose is eliminated in feces.

Special Populations

Renal Impairment

Administration of 100 mg of oseltamivir phosphate twice daily for 5 days to patients with various degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional to declining renal function. Oseltamivir carboxylate exposures in patients with normal and abnormal renal function administered various dose regimens of oseltamivir are described in Table 2.

Table 2 Oseltamivir Carboxylate Exposures in Patients With Normal and Reduced Serum Creatinine Clearance
Parameter Normal Renal Function Impaired Renal Function
75mg qd 75mg bid 150mg bid CreatinineClearance
<10 mL/min
CreatinineClearance
>10 and <30 mL/min
CAPD Hemodialysis
30 mg weekly 30 mg alternate HD cycle 75 mg daily 75 mg
alternate days
30 mg daily
AUC normalized to 48 hours.
Cmax 259 1 348 705 766 850 1638 1175 655
Cmin 39 138 288 62 48 864 209 346
AUC48 7476 10876 21864 17381 12429 62636 21999 25054

1 Observed values. All other values are predicted.

Hepatic Impairment

In clinical studies oseltamivir carboxylate exposure was not altered in patients with mild or moderate hepatic impairment (see PRECAUTIONS: Hepatic Impairment and DOSAGE AND ADMINISTRATION).

Pediatric Patients

The pharmacokinetics of oseltamivir and oseltamivir carboxylate have been evaluated in a single dose pharmacokinetic study in pediatric patients aged 5 to 16 years (n=18) and in a small number of pediatric patients aged 3 to 12 years (n=5) enrolled in a clinical trial. Younger pediatric patients cleared both the prodrug and the active metabolite faster than adult patients resulting in a lower exposure for a given mg/kg dose. For oseltamivir carboxylate, apparent total clearance decreases linearly with increasing age (up to 12 years). The pharmacokinetics of oseltamivir in pediatric patients over 12 years of age are similar to those in adult patients.

Geriatric Patients

Exposure to oseltamivir carboxylate at steady-state was 25% to 35% higher in geriatric patients (age range 65 to 78 years) compared to young adults given comparable doses of oseltamivir. Half-lives observed in the geriatric patients were similar to those seen in young adults. Based on drug exposure and tolerability, dose adjustments are not required for geriatric patients for either treatment or prophylaxis (see DOSAGE AND ADMINISTRATION: Special Dosage Instructions).

ANIMAL TOXICOLOGY

In a 2-week study in unweaned rats, administration of a single dose of 1000 mg/kg oseltamivir phosphate to 7-day-old rats resulted in deaths associated with unusually high exposure to the prodrug. However, at 2000 mg/kg, there were no deaths or other significant effects in 14-day-old unweaned rats. Further follow-up investigations of the unexpected deaths of 7-day-old rats at 1000 mg/kg revealed that the concentrations of the prodrug in the brains were approximately 1500-fold those of the brains of adult rats administered the same oral dose of 1000 mg/kg, and those of the active metabolite were approximately 3-fold higher. Plasma levels of the prodrug were 10-fold higher in 7-day-old rats as compared with adult rats. These observations suggest that the levels of oseltamivir in the brains of rats decrease with increasing age and most likely reflect the maturation stage of the blood-brain barrier. No adverse effects occurred at 500 mg/kg/day administered to 7- to 21-day-old rats. At this dosage, the exposure to prodrug was approximately 800-fold the exposure expected in a 1-year-old child.

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