1B1/1B3 and P-gp inhibitor, in 11 healthy subjects increased venetoclax Cmax by 106% and AUC∞ by 78% [see Drug Interactions (7.1)].
Gastric Acid Reducing Agents
Based on population pharmacokinetic analysis, gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect venetoclax bioavailability.
Warfarin
In a drug-drug interaction study in three healthy subjects, administration of a single 400 mg dose of venetoclax with 5 mg warfarin resulted in 18% to 28% increase in Cmax and AUC∞ of R-warfarin and S-warfarin [see Drug Interactions (7.2)].
In vitro Studies
In vitro studies indicated that venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant concentrations. Venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1 in vitro, but it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9, or UGT2B7.
Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and weak OATP1B1 inhibitor in vitro. To avoid a potential interaction in the gastrointestinal tract, co-administration of narrow therapeutic index P-gp substrates such as digoxin with VENCLEXTA should be avoided. If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before VENCLEXTA. Venetoclax is not expected to inhibit OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K at clinically relevant concentrations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity studies have not been conducted with venetoclax.
Venetoclax was not mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce numerical or structural aberrations in an in vitro chromosome aberration assay using human peripheral blood lymphocytes, and was not clastogenic in an in vivo mouse bone marrow micronucleus assay at doses up to 835 mg/kg. The M27 metabolite was negative for genotoxic activity in in vitro Ames and chromosome aberration assays.
Fertility and early embryonic development studies were conducted in male and female mice. These studies eva luate mating, fertilization, and embryonic development through implantation. There were no effects of venetoclax on estrus cycles, mating, fertility, corpora lutea, uterine implants or live embryos per litter at dosages up to 600 mg/kg/day. However, a risk to human male fertility exists based on testicular toxicity (germ cell loss) observed in dogs at exposures as low as 0.5 times the human AUC exposure at the recommend dose.
13.2 Animal Toxicology and/or PharmacologyIn dogs, venetoclax caused single-cell necrosis in various tissues, including the gallbladder, exocrine pancreas, and stomach with no evidence of disruption of tissue integrity or organ dysfunction; these findings were minimal to mild in magnitude. Following a 4-week dosing period and subsequent 4-week recovery period, minimal single-cell necrosis was still present in some tissues and reversibility has not been assessed following longer periods of dosing or recovery.
In addition, after approximately 3 months of daily dosing in dogs, venetoclax caused progressive white discoloration of the hair coat, due to loss of melanin pigment.
14 CLINICAL STUDIES
The efficacy of VENCLEXTA was established in an open-label, single-arm, multicenter clinical trial of 106 patients with CLL w |
