Molecular mass: 407.378 g/mol PubChem compound: 124173720
Inavolisib is an inhibitor of phosphatidylinositol 3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα. In vitro, inavolisib induced the degradation of mutated PI3K catalytic alpha subunit p110α (encoded by the PIK3CA gene), inhibited phosphorylation of the downstream target AKT, reduced cellular proliferation, and induced apoptosis in PIK3CA-mutated breast cancer cell lines. In vivo, inavolisib reduced tumor growth in PIK3CA-mutated, estrogen receptor-positive, breast cancer xenograft models. The combination of inavolisib with palbociclib and fulvestrant increased tumor growth inhibition compared to each treatment alone or the doublet combinations.
The exposure-response relationship for the efficacy of inavolisib has not been fully characterized. Inavolisib time course of pharmacodynamic response is unknown. Higher systemic exposure of inavolisib was associated with higher incidence of Grade ≥2 anemia, Grade ≥2 hyperglycemia, and inavolisib dosage modifications due to adverse reactions.
At the recommended approved dosage, a mean increase in the QTc interval of >20 ms is unlikely.
Inavolisib pharmacokinetics are presented as geometric mean (geometric coefficient of variation [geo CV]) following administration of the approved recommended dosage unless otherwise specified. The inavolisib steady-state AUC is 1,010 h*ng/mL (25) and Cmax is 69 ng/mL (27%). Steady-state concentrations are predicted to be attained by day 5.
Inavolisib accumulation is approximately 2-fold.
Inavolisib steady-state AUC is proportional with dose from 6 to 12 mg (0.7 to 1.3 times the approved recommended dosage).
Inavolisib absolute oral bioavailability is 76%. Inavolisib steady-state median (min, max) time to maximum plasma concentration (Tmax) is 3 hours (0.5, 4 hours).
No clinically significant differences in inavolisib pharmacokinetics were observed following administration of inavolisib with a high-fat meal (approximately 1,000 calories, 50% fat).
Inavolisib apparent (oral) volume of distribution is 155 L (26%). Inavolisib plasma protein binding is 37% and is not concentration-dependent in vitro. Inavolisib blood-to-plasma ratio is 0.8.
Inavolisib elimination half-life is 15 hours (24%) with a total clearance of 8.8 L/hr (29%).
Inavolisib is primarily metabolized by hydrolysis. In vitro, inavolisib was minimally metabolized by CYP3A.
Following oral administration of a single radiolabeled dose, 49% of the administered dose was recovered in urine (40% unchanged) and 48% in feces (11% unchanged).
No clinically significant differences in the pharmacokinetics of inavolisib were observed based on age (27 to 85 years), sex, race (Asian or White), body weight (39 to 159 kg), or mild hepatic impairment (total bilirubin > ULN to ≤ 1.5 × ULN or AST > ULN and total bilirubin ≤ ULN). The effect of moderate to severe hepatic impairment on inavolisib pharmacokinetics is unknown.
Inavolisib AUC was 73% higher in patients with moderate renal impairment compared to patients with normal renal function (eGFR ≥90 mL/min). No clinically significant differences in the pharmacokinetics of inavolisib were observed in patients with mild renal impairment compared to patients with normal renal function. The effect of severe renal impairment (eGFR <30 mL/min) on the pharmacokinetics of inavolisib is unknown.
Proton Pump Inhibitors: No clinically significant difference in steady-state inavolisib pharmacokinetics were observed based upon concomitant use of a proton pump inhibitor (lansoprazole, omeprazole, esomeprazole, pantoprazole, or rabeprazole).
CYP450 Enzymes: Inavolisib induces CYP3A and CYP2B6. Inavolisib is a time-dependent inhibitor of CYP3A. Inavolisib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
Transporter Systems: Inavolisib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2K, OAT1, OAT2. Inavolisib does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.
Carcinogenicity studies with inavolisib have not been conducted.
Inavolisib was not mutagenic in the bacterial reverse mutation (Ames) assay. Inavolisib was clastogenic in an in vitro human lymphocyte micronucleus assay. Inavolisib was not genotoxic in an in vivo rat bone marrow micronucleus test and did not induce DNA break in a liver comet assay.
Fertility studies with inavolisib have not been conducted. In repeat-dose toxicity studies, inavolisib was administered orally once daily for up to 3 months duration in rats and dogs.
In male rats, dose-dependent atrophy of the prostate and seminal vesicle and decreased organ weights of the prostate, seminal vesicle, epididymis and testis were observed at doses ≥1.5 mg/kg/day (≥0.4 times the human exposure at the recommended dose of 9 mg/day based on AUC). In male dogs, focal inspissation of seminiferous tubule contents and multinucleated spermatids in the testis and epithelial degeneration/necrosis in the epididymis were observed following 4 weeks of dosing at ≥1.5 mg/kg/day (≥2 times the human exposure at the recommended dose of 9 mg/day based on AUC) and decreased sperm count was observed following 3 months of dosing at ≥1 mg/kg/day (≥1.2 times the human exposure at the recommended dose of 9 mg/day based on AUC). Findings in dogs were not observed following a recovery period.
In female rats, atrophy in the uterus and vagina, decreased ovarian follicles, and findings suggestive of an interruption/alteration of the estrous cycle were observed following up to 3 months of dosing at doses ≥3 mg/kg/day (≥1.2 times the human exposure at the recommended dose of 9 mg/day based on AUC). Findings in the uterus, vagina, and estrous cycle observed in the 4-week toxicity study were not observed following recovery. Recovery was not assessed in the 3-month study in rats.
Lens degeneration, characterized by lens fiber swelling, separation of lens fibers, and/or accumulation of subcapsular proteinaceous material, was observed in rats at an oral inavolisib dose of 10 mg/kg/day (6.3 times the human exposure at the recommended dose of 9 mg/day based on AUC). In dogs, lens fiber swelling and lens cortex vacuolation were observed at oral inavolisib doses ≥0.3 mg/kg/day (≥0.5 times the human exposure at the recommended dose based on AUC) and ≥1 mg/kg/day (≥1.2 times the human exposure at the recommended dose based on AUC), respectively. Lens degeneration was present in rats following a 4-week recovery period but was not present in dogs following a 12-week recovery period.
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