use tumor model and in the in vitro umbilical cord model.
Pharmacokinetics
Absorption
Following administration of single oral doses of Pomalyst, the Cmax for pomalidomide occurs at 2 and 3 hours post dose. The systemic exposure (AUC) of pomalidomide increases in an approximately dose proportional manner.
In patients with multiple myeloma who received Pomalyst 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC(Τ) of 400 ng.hr/ mL and maximum plasma concentration (Cmax) of 75 ng/mL. Following multiple doses, pomalidomide has an accumulation ratio of 27 to 31 %.
Distribution
Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state. Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours post-dose (~Tmax) after 4 days of once daily dosing at 2 mg. Human plasma protein binding ranges from 12% to 44% and is not concentration dependent.
Metabolism
Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4. In vitro, CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and CYP2D6.
Elimination
Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients with multiple myeloma. Pomalidomide has a mean total body clearance (CL/ F) of 7-10 L/ hr.
Following a single oral administration of [14C]-pomalidomide (2 mg) to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and feces, respectively, with approximately 2% and 8% of the radiolabeled dose eliminated unchanged as pomalidomide in urine and feces.
Drug-Drug Interactions
Pomalidomide does not inhibit or induce CYP450 enzymes or any of the transporters in vitro.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study.
Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day.
In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females.
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