Chemical formula: C₄₅H₅₀ClN₇O₇S Molecular mass: 868.45 g/mol PubChem compound: 49846579
Venetoclax is a potent, selective inhibitor of B-cell lymphoma (BCL)-2, an anti-apoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL and AML cells where it mediates tumour cell survival and has been associated with resistance to chemotherapeutics. Venetoclax binds directly to the BH3-binding groove of BCL-2, displacing BH3 motif-containing pro-apoptotic proteins like BIM, to initiate mitochondrial outer membrane permeabilization (MOMP), caspase activation, and programmed cell death. In non-clinical studies, venetoclax has demonstrated cytotoxic activity in tumour cells that overexpress BCL-2.
The effect of multiple doses of venetoclax up to 1200 mg once daily on the QTc interval was evaluated in an open-label, single-arm study in 176 patients. Venetoclax had no effect on QTc interval and there was no relationship between venetoclax exposure and change in QTc interval.
Following multiple oral administrations, maximum plasma concentration of venetoclax was reached 5-8 hours after dose. Venetoclax steady state AUC increased proportionally over the dose range of 150-800 mg. Under low-fat meal conditions, venetoclax mean (± standard deviation) steady state Cmax was 2.1 ± 1.1 mcg /ml and AUC24 was 32.8 ± 16.9 mcg •h/ml at the 400 mg once daily dose.
Administration with a low-fat meal increased venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal increased venetoclax exposure by 5.1- to 5.3-fold compared to fasting conditions. It is recommended that venetoclax should be administered with a meal.
Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 micromolar (0.87-26 mcg/ml). The mean blood-to-plasma ratio was 0.57.
The population estimate for apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L in patients.
In vitro studies demonstrated that venetoclax is predominantly metabolised by cytochrome P450 CYP3A4. M27 was identified as a major metabolite in plasma with an inhibitory activity against BCL-2 that is at least 58-fold lower than venetoclax in vitro.
Co-administration with CYP and UGT substrates:
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. Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9 and UGT2B7.
Co-administration with transporter substrates/inhibitors:
Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and a weak OATP1B1 inhibitor in vitro. Venetoclax is not expected to inhibit OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K at clinically relevant concentrations.
The population estimate for the terminal phase elimination half-life of venetoclax was approximately 26 hours. Venetoclax shows minimal accumulation with accumulation ratio of 1.30-1.44. After a single oral administration of 200 mg radiolabeled [14C]-venetoclax to healthy subjects, >99.9% of the dose was recovered in faeces and <0.1% of the dose was excreted in urine within 9 days. Unchanged venetoclax accounted for 20.8% of the administered radioactive dose excreted in faeces. The pharmacokinetics of venetoclax do not change over time.
Based on a population pharmacokinetic analysis that included 321 subjects with mild renal impairment (CrCl ≥60 and <90 ml/min), 219 subjects with moderate renal impairment (CrCl ≥30 and <60 ml/min), 5 subjects with severe renal impairment (CrCl ≥15 and <30 ml/min) and 224 subjects with normal renal function (CrCl ≥90 ml/min), venetoclax exposures in subjects with mild, moderate or severe renal impairment are similar to those with normal renal function. The pharmacokinetics of venetoclax has not been studied in subjects with CrCl <15 ml/min or patients on dialysis.
Based on a population pharmacokinetic analysis that included 74 subjects with mild hepatic impairment, 7 subjects with moderate hepatic impairment and 442 subjects with normal hepatic function, venetoclax exposures are similar in subjects with mild and moderate hepatic impairment and normal hepatic function. Mild hepatic impairment was defined as normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin >1.0 to 1.5 times ULN, moderate hepatic impairment as total bilirubin >1.5 to 3.0 times ULN, and severe hepatic impairment as total bilirubin >3.0 ULN.
In a dedicated hepatic impairment study, venetoclax Cmax and AUC in subjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B; n=6) hepatic impairment were similar to subjects with normal hepatic function, after receiving a 50 mg single dose of venetoclax. In subjects with severe (Child-Pugh C; n=5) hepatic impairment, the mean venetoclax Cmax was similar to subjects with normal hepatic function but venetoclax AUCinf was on average 2.7-fold higher (range: no change to 5-fold higher) than venetoclax AUCinf in the subjects with normal hepatic function.
Based on population pharmacokinetic analyses, age, sex, and weight do not have an effect on venetoclax clearance. The exposure is 67% higher in Asian subjects as compared to non-Asian subjects. This difference is not considered clinically relevant.
Toxicities observed in animal studies with venetoclax included dose-dependent reductions in lymphocytes and red blood cell mass. Both effects were reversible after cessation of dosing with venetoclax, with recovery of lymphocytes occurring 18 weeks post treatment. Both B- and T-cells were affected, but the most significant decreases occurred with B-cells.
Venetoclax also caused single cell necrosis in various tissues, including the gallbladder and exocrine pancreas, with no evidence of disruption of tissue integrity or organ dysfunction; these findings were minimal to mild in magnitude.
After approximately 3 months of daily dosing in dogs, venetoclax caused progressive white discoloration of the hair coat, due to loss of melanin pigment in the hair.
Venetoclax and the M27 major human metabolite were not carcinogenic in a 6-month transgenic (Tg.rasH2) mouse carcinogenicity study at oral doses up to 400 mg/kg/day of venetoclax and at a single dose level of 250 mg/kg/day of M27. Exposure margins (AUC), relative to the clinical AUC at 400 mg/day, were approximately 2-fold for venetoclax and 5.8-fold for M27.
Venetoclax was not genotoxic in bacterial mutagenicity assay, in vitro chromosome aberration assay and in vivo mouse micronucleus assay. The M27 metabolite was negative for genotoxicity in the bacterial mutagenicity and chromosomal aberration assays.
No effects on fertility were observed in fertility and early embryonic development studies in male and female mice. Testicular toxicity (germ cell loss) was observed in general toxicity studies in dogs at exposures of 0.5 to 18 times the human AUC exposure at a dose of 400 mg. Reversibility of this finding has not been demonstrated.
In embryo-foetal development studies in mice, venetoclax was associated with increased post-implantation loss and decreased foetal body weight at exposures of 1.1 times the human AUC exposure at a dose of 400 mg. The major human metabolite M27 was associated with post- implantation loss and resorptions at exposures approximately 9-times the human M27-AUC exposure at a 400 mg dose of venetoclax. In rabbits, venetoclax produced maternal toxicity, but no foetal toxicity at exposures of 0.1 times the human AUC exposure at a 400 mg dose.
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