Chemical formula: C₁₉H₂₂F₃N₅O₂S Molecular mass: 441.47 g/mol PubChem compound: 56649450
Alpelisib is an α-specific class I phosphatidylinositol3kinase (PI3Kα) inhibitor. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and AKT-signalling, cellular transformation and the generation of tumours in in vitro and in vivo models.
In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets including AKT, and showed activity in cell lines harbouring a PIK3CA mutation.
In vivo, alpelisib inhibited the PI3K/AKT signalling pathway and reduced tumour growth in xenograft models, including models of breast cancer.
PI3K inhibition by alpelisib treatment has been shown to induce an increase in oestrogen receptor (ER) transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased anti-tumour activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines.
The PI3K/AKT signalling pathway is responsible for glucose homeostasis, and hyperglycaemia is an expected on-target adverse reaction of PI3K inhibition.
The pharmacokinetics of alpelisib were investigated in patients under an oral dosing regimen ranging from 30 to 450 mg daily. Healthy subjects received single oral doses ranging from 300 to 400 mg. The pharmcokinetics were comparable in both oncology patients and healthy subjects.
Following oral administration of alpelisib, median time to reach peak plasma concentration (Tmax) ranged between 2.0 to 4.0 hours, independent of dose, time or regimen. Based on absorption modelling bioavailability was estimated to be very high (>99%) under fed conditions but lower under fasted conditions (~68.7% at a 300 mg dose). Steady-state plasma levels of alpelisib after daily dosing can be expected to be reached on day 3 following onset of therapy in most patients.
Alpelisib absorption is affected by food. In healthy volunteers after a single 300 mg oral dose of alpelisib, compared to the fasted state, a high-fat high-calorie (HFHC) meal (985 calories with 58.1 g of fat) increased AUCinf by 73% and Cmax by 84%, and a LFLC meal (334 calories with 8.7 g of fat) increased AUCinf by 77% and Cmax by 145%. No significant difference was found for AUCinf between LFLC and HFHC with a geometric mean ratio of 0.978 (CI: 0.876, 1.09), showing that neither fat content nor overall calorific intake has a considerable impact on absorption. The increase in gastrointestinal solubility by bile, secreted in response to food intake, is the potential cause of the food effect. Hence, alpelisib should be taken immediately after food at approximately same time each day.
Alpelisib moderately binds to protein with a free fraction of 10.8% regardless of concentration. Alpelisib was equally distributed between red blood cells and plasma with a mean in vivo blood-to-plasma ratio of 1.03. As alpelisib is a substrate of human efflux transporters, penetration of the blood-brain barrier is not expected to occur in humans. The volume of distribution of alpelisib at steady state (Vss/F) is estimated at 114 litres (intersubject CV% 49%).
In vitro studies demonstrated that formation of the hydrolysis metabolite BZG791 by chemical and enzymatic amide hydrolysis was a major metabolic pathway, followed by CYP3A4-mediated hydroxylation. Alpelisib hydrolysis occurs systemically by both chemical decomposition and enzymatic hydrolysis via ubiquitously expressed, high-capacity enzymes (esterases, amidases, choline esterase) not limited to the liver. CYP3A4-mediated metabolites and glucuronides amounted to ~15% of the dose; BZG791 accounted for ~40-45% of the dose. The rest of the dose, which was found as unchanged alpelisib in urine and faeces, was either excreted as alpelisib or not absorbed.
Alpelisib exhibits low clearance with 9.2 l/h (CV% 21%) based on population pharmacokinetic analysis under fed conditions. The population-derived half-life, independent of dose and time, was 8 to 9 hours at steady state with 300 mg once daily.
In a human mass-balance study, after oral administration, alpelisib and its metabolites were primarily found in the faeces (81.0%) as alpelisib, or metabolised as BZG791. Excretion in the urine is minor (13.5%), with unchanged alpelisib (2%). Following a single oral dose of [14C]-alpelisib, 94.5% of the total administered radioactive dose was recovered within 8 days.
The pharmacokinetics were found to be linear with respect to dose and time under fed conditions between 30 and 450 mg. After multiple doses, alpelisib exposure (AUC) at steady state is only slightly higher than that of a single dose, with an average accumulation of 1.3 to 1.5 with a daily dosing regimen.
In a drug-drug interaction study, co-administration of repeated doses of alpelisib 300 mg with a single dose of sensitive substrates of CYP3A4 (midazolam), CYP2C8 (repaglinide), CYP2C9 (warfarin), CYP2C19 (omeprazole) and CYP2B6 (bupropion), administered as a cocktail, showed that there is no clinically signficant pharmacokinetic interaction. The data from CYP2B6 substrate (bupropion) should be interpreted with caution due to the small sample size.
In healthy subjects, co-administration of a CYP2C9 substrate (S-warfarin)-with repeated doses of 300 mg alpelisib at steady state, increased S-warfarin exposure on average by 34% and 19% for AUCinf and Cmax respectively, compared to administration of S-warfarin alone. This indicates that alpesilib is a mild inhibitor of CYP2C9.
In a drug-drug interaction study with the sensitive CYP3A4 and P-gp substrate everolimus, in patients with advanced solid tumours, AUC increased by 11.2%. No clinically meaningful change is expected as a result of drug interaction with CYP3A4 substrates.
In a drug-drug interaction study co-administration of alpelisib and rifampin, a strong CYP3A4 inducer, confirmed that there is a clinically significant pharmacokinetic interaction between alpelisib and strong CYP3A4 inducers.
Based on in vitro data, inhibition of the renal organic anion transporter OAT3 by alpelisib (and/or its metabolite BZG791) cannot be discarded in patients at the therapeutic dose.
Alpelisib showed only weak in vitro inhibition towards the ubiquitously expressed efflux transporters (P-gp, BCRP, MRP2, BSEP), solute carrier transporters at the liver inlet (OATP1B1, OATP1B3, OCT1) and solute carrier transporters in the kidney (OAT1, OCT2, MATE1, MATE2K). As unbound systemic steady-state concentrations (or concentrations at the liver inlet) at both the therapeutic dose and maximum tolerated dose are significantly lower than the experimentally determined unbound inhibition constants or IC50, the inhibition will not translate into clinical significance. Due to high alpelisib concentrations in the intestinal lumen, an effect on intestinal P-gp and BCRP cannot be fully excluded.
The population pharmacokinetic analysis showed that there are no clinically relevant effects of age, body weight, or gender on the systemic exposure of alpelisib that would require alpelisib dose adjustment.
The pharmacokinetics of alpelisib in children aged 0-18 years have not been established. No data are available.
Of 284 patients who received alpelisib in the phase III study (in the alpelisib plus fulvestrant arm), 117 patients were ≥65 years of age and 34 patients were between 75 and 87 years of age. No overall differences in exposure of alpelisib were observed between these patients and younger patients.
Population pharmacokinetic analyses and pharmacokinetic analyses from a phase I study in Japanese cancer patients showed that there are no clinically relevant effects of ethnicity on the systemic exposure of alpelisib.
Non-compartmental pharmacokinetic parameters after single and multiple daily doses of alpelisib for Japanese patients were very similar to those reported in the Caucasian population.
Based on a population pharmacokinetic analysis that included 117 patients with normal renal function (eGFR ≥90 ml/min/1.73 m²) / (CLcr ≥90 ml/min), 108 patients with mild renal impairment (eGFR 60 to <90 ml/min/1.73 m²) / (CLcr 60 to <90 ml/min), and 45 patients with moderate renal impairment (eGFR 30 to <60 ml/min/1.73 m²), mild and moderate renal impairment had no effect on the exposure of alpelisib.
Based on a pharmacokinetic study in patients with hepatic impairment, moderate and severe hepatic impairment had negligible effect on the exposure of alpelisib. The mean exposure for alpelisib was increased 1.26-fold in patients with severe (GMR: 1.00 for Cmax; 1.26 for AUClast/AUCinf) hepatic impairment.
Based on a population pharmacokinetic analysis that included 230 patients with normal hepatic function, 41 patients with mild hepatic impairment and no patients with moderate hepatic impairment, further supporting the findings from the dedicated hepatic impairment study, mild and moderate hepatic impairment had no effect on the exposure of alpelisib.
The majority of the observed alpelisib effects were related to the pharmacological activity of alpelisib as a p110α-specific inhibitor of the PI3K pathway, such as the influence on the glucose homeostasis resulting in hyperglycaemia and the risk of increased blood pressure. The bone marrow and lymphoid tissue, pancreas and some reproductive organs of both genders were the main target organs for adverse effects. Effects on bone marrow and lymphoid tissue were generally reversible on cessation of treatment. Effects on the pancreas and reproductive organs did not fully reverse but showed a tendency towards reversion. In exploratory rat studies evidence of inflammatory changes of the skin was found.
In vitro inhibition of hERG channels (IC50 of 9.4 µM) was shown at concentrations ~13-fold higher than the exposure in humans, at the recommended dose of 300 mg/day. No relevant electrophysiological effect was seen in dogs.
No carcinogenicity studies have been conducted. Results of standard genotoxicity in vitro studies with alpelisib were negative. Alpelisib was not genotoxic in a repeated-dose rat toxicity study where micronucleus analysis was integrated, up to exposure levels approximately twice the estimated exposure (AUC) in humans at the recommended dose of 300 mg.
Embryo-foetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity. In rats and rabbits, following prenatal exposure to alpelisib, increased incidences of pre- and post-implantation losses, reduced foetal weights and increased incidences of foetal abnormalities (enlarged brain ventricle, decreased bone ossification and skeletal malformations) were observed starting at exposures below those in humans at the highest recommended dose of 300 mg, indicating potential clinical relevance.
In repeated dose toxicity studies, adverse effects were observed in reproductive organs, such as vaginal or uterine atrophy and oestrus cycle variations in rats, decreases in prostate and testes weight in rats and dogs and prostate atrophy in dogs at clinically relevant doses based on AUC.
In fertility studies conducted in male and female rats, similar effects on fertility were observed. In females, increased pre- and post-implantation losses, which led to reduced numbers of implantation sites and live embryos, were observed at exposure levels (AUC) approximately twice the recommended human dose of 300 mg. In males, fertility and reproductive performance, including sperm count and motility parameters, were unaffected at exposure levels approximately twice the estimated exposure (AUC) in humans at the recommended dose of 300 mg. However, at exposure levels (AUC) at or below the recommended human dose of 300 mg, accessory gland weights (seminal vesicles, prostate) were reduced and correlated microscopically with atrophy and/or reduced secretion in prostate and seminal vesicles, respectively.
An in vitro phototoxicity test on the mouse Balb/c 3T3 fibroblast cell line did not identify a relevant phototoxicity potential for alpelisib.
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