Oseltamivir

In clinical trials of oseltamivir, serum aminotransferase elevations occurred in 2% of treated subjects, but were asymptomatic and transient in all and there were no reports of clinically apparent liver injury with jaundice. The rates of ALT elevations with oseltamivir were generally similar to those treated with placebo or with a comparative agents. Since its approval in 1999, oseltamivir has been widely used during influenza seasonal outbreaks. There have been a few, isolated reports of mild liver injury in patients receiving oseltamivir, but the relationship of the injury with oseltamivir has not always been very convincingly shown. There have been no reports of acute liver failure or chronic liver disease attributed to oseltamivir use. Furthermore, a proportion of patients with influenza have serum enzyme elevations and even mild jaundice during the acute illness, independent of any therapy.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 340(SRC), determined from a structure estimation method(2), indicates that oseltamivir is expected to have moderate mobility in soil(SRC). The pKa of oseltamivir is 7.7 (primary amine)(3), indicating that this compound will exist partially as a cation in the environment and cations generally have lower mobility in soil than their neutral counterparts(4). Volatilization of oseltamivir from moist soil surfaces is not expected to be an important fate process(SRC) because cations do not volatilize and based on an estimated Henry's Law constant of 2.9X10-16 atm-cu m/mole(SRC), calculated using a fragment constant estimation method(5). Oseltamivir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-8 mm Hg(SRC), determined from a fragment constant method(6). Biodegradation data were not available(SRC, 2006).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 340(SRC), determined from a structure estimation method(2), indicates that oseltamivir is expected to adsorb slightly to suspended solids and sediment(SRC). The pKa of oseltamivir is 7.7 (primary amine)(3), indicating that this compound will exist partially as a cation in the environment and cations generally adsorb to sediment more strongly than their neutral counterparts(4). Volatilization from water surfaces is not expected(5) because cations do not volatilize and based upon an estimated Henry's Law constant of 2.9X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(6). According to a classification scheme(7), an estimated BCF of 3(SRC), from an estimated log Kow of 0.95(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2006).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), oseltamivir, which has an estimated vapor pressure of 1.3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase oseltamivir may be removed from the air by wet or dry deposition(SRC). Oseltamivir does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Oseltamivir is generally well-tolerated. The most common side effects include nausea (up to 10%), vomiting (2% to 15%), abdominal pain, diarrhea, headache, insomnia, and vertigo. Vomiting is the most frequently reported side effect in children (16% of children aged 1 to 12).

Oseltamivir is generally very well tolerated and has few drug interactions. Multiple animal toxicity studies, pre-marketing, and post-marketing of oseltamivir have indicated respiratory suppression resulting from central nervous system suppression, hypothermia, hypoactivity, and sudden death. This adverse event correlates with sudden-onset-type neuropsychiatric reactions in human patients (especially children from Japan), but no definitive link has been established. The oseltamivir-induced liver injury requires discontinuation of the drug and avoidance of reexposure. Most patients recover after discontinuation of oseltamivir without specific interventions.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of oseltamivir can be estimated to be 340(SRC). According to a classification scheme(2), this estimated Koc value suggests that oseltamivir is expected to have moderate mobility in soil. The pKa of oseltamivir is 7.7 (primary amine)(3), indicating that this compound will exist partially as a cation in the environment and cations generally adsorb to soil and sediment more strongly than their neutral counterparts(4).

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

oseltamivir

Tamiflu®

Antivirals

3

less-DILI-concern drugs

An estimated BCF of 3 was calculated for oseltamivir(SRC), using an estimated log Kow of 0.95(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for oseltamivir is estimated as 2.9X10-16 atm-cu m/mole(SRC) using a fragment constant estimation method(1). The pKa of oseltamivir is 7.7 (primary amine)(2), indicating that this compound will exist partially as a cation in the environment. Based on this Henry's Law constant and the fact that cations do not volatilize, oseltamivir is expected to be essentially nonvolatile from moist soil and water surfaces(3). Oseltamivir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-8 mm Hg(SRC), determined from a fragment constant method(4).

/LABORATORY ANIMALS: Acute Exposure/ 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.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A 26-week dermal carcinogenicity study of oseltamivir carboxylate in FVB/Tg.AC transgenic mice was negative. The animals were dosed at 40, 140, 400 or 780 mg/kg/day in two divided doses. The highest dose represents the maximum feasible dose based on the solubility of the compound in the control vehicle. A positive control, tetradecanoyl phorbol-13-acetate administered at 2.5 ug per dose three times per week gave a positive response.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a rat study, minimal maternal toxicity ws reported with 1500 mg/kg per day orally and no maternal toxicities were reported with 50 and 250 mg/kg per day orally. In a rabbit study, slight and marked maternal toxicities were observed, respectively, with 150 and 500 mg/kg per day and not maternal toxicities with 50 mg/kg per day. In the rat and rabbit study there was a dose-dependent increase in the incidence rates of a variety of minor skeleton abnormalities and variants in the exposed offspring. However, the individual incidence rate of each skeletal abnormality or variant remained within the background rates of occurrence in the species studied.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Doses of oseltamivir administered to female rats 2 weeks before mating, during mating and until Day 6 of pregnancy were 50, 250, and 1500 mg/kg per day. Doses of oseltamivir were administered to male rats 4 weeks before mating, during, and for 2 weeks after mating. oseltamivir lacked an effect of fertility, mating performance, or early embryonic development at any dose level.

/GENOTOXICITY/ Oseltamivir was found to be non-mutagenic in the Ames test and the human lymphocyte chromosome assay with and without enzymatic activation and negative in the mouse micronucleus test. It was found to be positive in a Syrian Hamster Embryo (SHE) cell transformation test. Oseltamivir carboxylate was non-mutagenic in the Ames test and the L5178Y mouse lymphoma assay with and without enzymatic activation and negative in the SHE cell transformation test.

Plasma concentrations of oseltamivir declined with a half-life of 1 to 3 hours in most subjects after oral administration, although plasma concentrations of oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most subjects after oral administration.

Elimination: 1 to 3 hours for oseltamivir and 6 to 10 hours for oseltamivir carboxylate.

Oseltamivir is extensively converted to the active metabolite, oseltamivir carboxylate, by esterases located predominantly in the liver. Oseltamivir carboxylate is not further metabolized. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms. No phase 2 conjugates of either compound have been identified in vivo.

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.

Biotransformation: Hepatic; oseltamivir, ethyl ester prodrug, undergoes extensive hydrolysis to the active aster form, oseltamivir carboxylate.

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OSELTAMIVIR

Established Pharmacologic Class [EPC] - Neuraminidase Inhibitor

Mechanisms of Action [MoA] - Neuraminidase Inhibitors

Oseltamivir is a Neuraminidase Inhibitor. The mechanism of action of oseltamivir is as a Neuraminidase Inhibitor.

OSELTAMIVIR

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted by predominantly hepatic esterases to the active metabolite oseltamivir carboxylate. At least 75 % of an oral dose reaches the systemic circulation as the active metabolite. Exposure to the pro-drug is less than 5 % relative to the active metabolite. Plasma concentrations of both pro-drug and active metabolite are proportional to dose and are unaffected by co-administration with food. Pharmacokinetic parameters following twice daily dosing of oseltamivir 75mg capsules are as follows: Cmax of oseltamivir and oseltamivir carboxylate were found to be 65ng/mL and 348ng/mL, respectively, while AUC (0-12h) of oseltamivir and oseltamivir carboxylate were found to be 112ng·h/mL and 2719ng·h/mL, respectively.

Following absorption, oseltamivir is more than 90 % eliminated through conversion to oseltamivir carboxylate and subsequent elimination entirely through renal excretion. During clinical studies, less than 20 % of oral radiolabelled dose was found to be eliminated in faeces.

The mean volume of distribution at steady state of the oseltamivir carboxylate ranges approximately between 23 and 26 liters in humans, a volume that is roughly equivalent to extracellular body fluid. Since neuraminidase activity is extracellular, oseltamivir carboxylate distributes to all sites of influenza virus spread.

Renal clearance (18.8 l/h) of the drug exceeds glomerular filtration rate (7.5 l/h) indicating that tubular secretion occurs in addition to glomerular filtration.

Protein binding: Oseltamivir phosphate: Moderate (42%). Oseltamivir carboxylate: Very low < 3%.

Oseltamivir carboxylate: Volume of distribution is 23 to 26 liters following intravenous administration in 24 subjects.