1. Orlando Clinical Research Center, Orlando, USA.
2. Novartis Pharmaceuticals Corporation, East Hanover, USA.
3. Novartis Institutes for BioMedical Research, Basel, Switzerland.
4. Novartis Pharma S.A.S, Paris, France.
5. Novartis Healthcare Pvt. Ltd, Hyderabad, India.
6. Novartis Pharma AG, Basel, Switzerland.
7. Clinical Pharmacology Research Unit, Division of Clinical Pharmacology Department of Medicine, Miller School of Medicine, University of Miami, Miami, USA.
8. Katz Family Drug Discovery Center, University of Miami, Miami, USA.
The pharmacokinetics (PK) and safety of single-dose alpelisib (300 mg) were assessed in participants with moderate to severe hepatic impairment (n = 6 each) compared with their matching healthy controls (n = 11). Blood samples were collected upto 144 hours post-dose and evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary PK parameters (maximum plasma concentration [Cmax], area under the curve [AUC]inf and AUClast) and secondary PK parameters (AUC0-t, apparent total body clearance [CL/F], apparent volume of distribution [Vz/F], time of maximum observed concentration [Tmax], and half-life [T1/2]) of oral alpelisib 300 mg were determined from individual plasma concentration-time profiles using non‑compartmental analysis. Cmax of alpelisib decreased by approximately 17% in the moderate hepatic impairment group vs. the healthy control group (geometric mean ratio; GMR [90% confidence interval; CI], 0.833 [0.530, 1.31]). Cmax in the severe hepatic impairment group was comparable to that of the healthy control group (GMR [90% CI], 1.00 [0.636, 1.58]). AUClast for alpelisib decreased by approximately 27% in the moderate hepatic impairment group vs. the healthy control group (GMR [90% CI], 0.726 [0.487, 1.08]). AUClast was 26% higher in the severe hepatic impairment group compared with the healthy control group (GMR [90% CI], 1.26 [0.845, 1.87]). Overall, 3 participants (13.0%) experienced at least 1 adverse event which were either grade 1 or 2. Adverse events did not lead to study drug discontinuation. No grade 3 or 4 adverse events, serious adverse events or deaths were reported. The results indicate that a single dose of alpelisib was well tolerated in this study population. There was no significant impact of moderate or severe hepatic impairment on the exposure of alpelisib.
Keywords: Alpelisib, BYL719, Hepatic impairment, Pharmacokinetics