ITOVEBI Film-coated tablet Ref.[115587] Active ingredients: Inavolisib

The pharmacokinetics of inavolisib were characterised in healthy subjects and in patients with locally advanced or metastatic PIK3CA-mutated solid tumours, including breast cancer, under an oral dosing regimen ranging from 6 mg to 12 mg daily and in healthy subjects at 9 mg single dose.

Inavolisib pharmacokinetics are presented as geometric mean (geometric coefficient of variation [geo CV]%) following administration of the approved recommended dosage unless otherwise specified. Based on population pharmacokinetics analysis, the inavolisib steady-state AUC was 1 019 h*ng/mL (29%) and C_max was 67 ng/mL (28%). Steady-state concentrations were predicted to be attained by day 5.

With 9 mg once daily dosing, the geometric mean accumulation ratio was about 2-fold.

Absorption

The time to maximum plasma concentration (T_max) was reached after a median of 3 hours (range: 0.5 to 4 hours) at steady state following 9 mg daily dosing of inavolisib, under fasted conditions.

The absolute oral bioavailability of inavolisib was 76%.

Food effect

No clinically significant effect of food on inavolisib exposure was observed. The geometric mean ratio (GMR) (90% CI) for AUC_0-24 comparing the fed to the fasted state was 0.895 (0.737–1.09) after a single dose and 0.876 (0.701–1.09) at steady state. The GMR (90% CI) for C_max comparing the fed to the fasted state was 0.925 (0.748–1.14) after a single dose and 0.910 (0.712–1.16) at steady state.

Distribution

Plasma protein binding of inavolisib in humans is 37% and did not appear to be concentration-dependent over the concentration range tested (0.1–10 μM). In humans, the estimated steady state oral volume of distribution is 155 L (26%) based on population pharmacokinetics analysis.

Biotransformation

Following oral administration of a single radio-labeled 9 mg dose of inavolisib to healthy subjects, parent drug was the most prominent drug-related compound in plasma and urine. Hydrolysis was the major metabolic pathway. No specific hydrolysis enzymes involved in the metabolism of inavolisib were identified.

Elimination

Following oral administration of a single radio-labeled 9 mg dose of inavolisib to healthy subjects, 48.5% of the administered dose was recovered in urine (40.4% unchanged) and 48% in faeces (10.8% unchanged).

In clinical studies, based on population pharmacokinetics analysis, the geometric mean of the individual elimination half-life estimates for inavolisib was 15 hours (24%) following a single 9 mg dose. The estimated total clearance of inavolisib is 8.8 L/hr (29%).

Linearity/non-linearity

Limited data suggest dose proportionality within the dose range tested (6 to 12 mg) for single-dose C_max and AUC_0-24 and steady-state AUC_0-24; however, for steady-state C_max, the data suggest non- proportionality.

Drug-drug interactions

Clinical study results indicated that the predominant metabolites of inavolisib are not mediated by CYP enzymes, suggesting a low likelihood of clinically relevant interactions between inavolisib and CYP inhibitors or inducers. Moreover, in vitro results indicated that inavolisib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 enzymes.

In vitro studies have shown that inavolisib does not appear to have the potential to inhibit any of the relevant drug transporters tested. Furthermore, inavolisib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro. However, based on the overall pharmacokinetic characteristics of inavolisib, inhibitors or inducers of P-gp and/or BCRP are not expected to cause a clinically relevant drug-drug interaction with inavolisib.

Special populations

Elderly

No clinically relevant differences in inavolisib pharmacokinetics were noted between patients 65 years of age and older and those under 65 years based on population pharmacokinetic analysis. Of the 162 patients who received Itovebi in the INAVO120 study, 24 patients were ≥65 years of age.

Renal impairment

Population pharmacokinetic analyses indicated that mild renal impairment is not a clinically relevant covariate on inavolisib exposure. The pharmacokinetics of inavolisib in patients with mild renal impairment (eGFR 60 to <90 mL/min) were similar to those in patients with normal renal function. Inavolisib AUC and C_max were 73% and 11% higher in patients with moderate renal impairment compared to patients with normal renal function (eGFR ≥90 mL/min), respectively. The effect of severe renal impairment on inavolisib pharmacokinetics has not been established.

Hepatic impairment

Population pharmacokinetic analyses indicated that mild hepatic impairment is not a clinically relevant covariate on inavolisib exposure. The pharmacokinetics of inavolisib in patients with mild hepatic impairment (total bilirubin > ULN to ≤ 1.5 × ULN or AST > ULN and total bilirubin ≤ ULN) were similar to those in patients with normal hepatic function. The effect of moderate to severe hepatic impairment on inavolisib pharmacokinetics has not been studied.

Genotoxicity

Inavolisib was not mutagenic in the bacterial mutagenesis assay.

Inavolisib showed clastogenicity in vitro; however, there was no evidence of inavolisib-induced in vivo genotoxicity (clastogenicity, aneugenicity, or DNA damage) in the micronucleus and comet study in rats at doses up to a maximum tolerated dose (MTD) of 16 times the exposure at a clinical dose of 9 mg.

Carcinogenicity

No carcinogenicity studies with inavolisib have been conducted.

Developmental toxicity

An embryo-foetal development study in Sprague-Dawley rats identified inavolisib-related dose-dependent effects on embryo-foetal development that included decreases in foetal body weight and placental weight, post-implantation loss, lower foetal viability, and teratogenicity (foetal external, visceral, and skeletal malformations), with the maternal exposure at NOAEL being 0.2 times the exposure at a clinical dose of 9 mg.

Fertility

No dedicated fertility studies with inavolisib have been conducted.

In male rats, dose-dependent atrophy of the prostate and seminal vesicle and decreased organ weights without microscopic correlate in the epididymis and testis were observed (at ≥ NOAEL of 0.4 times the exposure at a clinical dose of 9 mg). These findings were reversible. 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 ≥2 times the exposure at a clinical dose of 9 mg). Following 3 months of dosing at up to 1.2 times the exposure at a clinical dose of 9 mg, a reversible decrease in total sperm count was observed with a no observed adverse effect level (NOAEL) of 0.4 times the exposure at a clinical dose of 9 mg but there were no inavolisib-related microscopic findings in the testes or epididymides or effects on sperm concentration, motility, or morphology.

In female rats, minimal to mild atrophy in the uterus and vagina, decreased ovarian follicles, and findings suggestive of an interruption/alteration of the oestrus cycle were observed (at ≥1.2 times the exposure at a clinical dose of 9 mg), with a NOAEL of 0.5 times the exposure at a clinical dose of 9 mg. These findings were not observed following the recovery period in the 4-week toxicity study. Recovery was not assessed in the 3-month study in rats.

Other

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use, included inflammation in dogs and eye lens degeneration in rats. The inflammation is consistent with the anticipated pharmacologic effects of PI3K inhibition, was generally dose-dependent and reversible. Minimal lens fiber degeneration observed in some rats (at ≥3.6 times the exposure at a clinical dose of 9 mg) was considered irreversible.