Dataset Information

Pharmacokinetics and Safety of Multiple-Dose Alpelisib in Participants with Moderate or Severe Hepatic Impairment: A Phase 1, Open-Label, Parallel Group Study.

ABSTRACT: 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 [C_max], area under the curve [AUC]_inf and AUC_last) and secondary PK parameters (AUC_0-t, apparent total body clearance [CL/F], apparent volume of distribution [Vz/F], time of maximum observed concentration [T_max], and half-life [T_1/2]) of oral alpelisib 300 mg were determined from individual plasma concentration-time profiles using non‑compartmental analysis. C_max 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]). C_max in the severe hepatic impairment group was comparable to that of the healthy control group (GMR [90% CI], 1.00 [0.636, 1.58]). AUC_last 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]). AUC_last 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.

SUBMITTER: Marbury T

PROVIDER: S-EPMC10266244 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Pharmacokinetics and Safety of Multiple-Dose Alpelisib in Participants with Moderate or Severe Hepatic Impairment: A Phase 1, Open-Label, Parallel Group Study.

Marbury Thomas T El-Hashimy Mona M Blumenstein Lars L Letellier Franck F Sengupta Tirtha T Lorenzo Sebastien S Preston Richard Alfred RA

Journal of Cancer 20230521 9

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 seconda ...[more]

PMID: 37325049

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Project description:BackgroundPatients with hepatic impairment receiving antithrombotic agents metabolized primarily through the liver can be at risk for bleeding. Milvexian (BMS-986177/JNJ-70033093) is a small-molecule, active-site inhibitor of activated Factor XI (FXIa). Modulation of FXI may provide systemic anticoagulation without increased risk of clinically significant bleeding.ObjectiveThis open-label study evaluated the effects of mild or moderate hepatic impairment on the pharmacokinetics of milvexian to assess their impact on safety and dosing.MethodsSingle doses of milvexian 60 mg were administered to participants with mild hepatic impairment (n = 9), moderate hepatic impairment (n = 8), and normal hepatic function (n = 9). Healthy participants were matched to participants with hepatic impairment by body weight, age, and sex. Analysis of variance was performed on natural log-transformed milvexian exposure parameters, with hepatic function group as a fixed effect.ResultsSingle doses of milvexian 60 mg were generally well tolerated, with no serious adverse events (AEs), bleeding AEs, or discontinuations due to AEs. Geometric mean ratios (90% confidence interval) for total milvexian maximum observed plasma concentration and area under the plasma concentration-time curve from time zero extrapolated to infinite time were 1.180 (0.735-1.895) and 1.168 (0.725-1.882), respectively, for mild hepatic impairment versus normal hepatic function and 1.140 (0.699-1.857) and 0.996 (0.609-1.628), respectively, for moderate hepatic impairment versus normal hepatic function. Across groups, milvexian exposure-related increases were observed for activated partial thromboplastin time.ConclusionMilvexian was well tolerated in participants with normal, mildly impaired, and moderately impaired hepatic function. Observed pharmacokinetic changes suggest it is unlikely that dose adjustments will be necessary in patients with mild or moderate hepatic impairment. Clinical Trial RegistrationClinicaltrials.gov identifier: NCT02982707.

Project description:IntroductionSomapacitan is a long-acting growth hormone (GH) derivative being developed for once-weekly dosing in patients with GH deficiency (GHD). Our objective was to evaluate the impact of kidney or hepatic impairment on somapacitan exposure in adults.MethodsIn two open-label, parallel-group, single-center, 6-week trials, eligible subjects (18-75 years of age, body mass index 18.5-34.9 kg/m2, GH-naïve, without GHD) were divided into five kidney (total n = 44) or three hepatic (n = 34) function groups. Subjects with normal kidney/hepatic function were matched to those with kidney/hepatic impairment by age, sex, and body weight. Subjects received three subcutaneous somapacitan administrations (0.08 mg/kg) on days 1, 8, and 15. Blood samples were collected before each dose, at 28 time points throughout 2 weeks after the last dose, and at follow-up (3-4 weeks after the last dose). The primary endpoint was area under the somapacitan serum concentration-time curve up to 1 week after the last dose (AUC0-168 h), while secondary endpoints included AUC0-168 h of insulin-like growth factor (IGF)-I.ResultsIn the kidney impairment trial, somapacitan AUC0-168 h was higher in groups with severe kidney impairment and requiring hemodialysis versus the normal kidney function group (estimated ratio and 90% confidence interval 1.75 [1.00-3.06] and 1.63 [1.01-2.61], respectively). AUC0-168 h of IGF-I was increased in the moderate impairment group (1.35 [1.09-1.66]), severe impairment group (1.40 [1.10-1.78]), and requiring hemodialysis group (1.24 [1.01-1.52]), compared with the normal function group. In the hepatic impairment trial, somapacitan AUC0-168 h was significantly higher in the moderate impairment group compared with the normal hepatic function group (4.69 [2.92-7.52]). IGF-I AUC0-168 h was lower in both hepatic impairment groups (0.85 [0.67-1.08] for the mild impairment group and 0.75 [0.60-0.95] for the moderate impairment group) compared with the normal function group. No new safety or tolerability issues were observed.ConclusionsIn summary, somapacitan exposure increased with level of kidney/hepatic impairment. Clinically, this will be taken into account when treating adults with GHD with somapacitan, as doses should be individually titrated.Clinical trial registrationNCT03186495 (kidney impairment trial, registered 12 June 2017); NCT03212131 (hepatic impairment trial, registered 30 June 2017).

Dataset Information

Pharmacokinetics and Safety of Multiple-Dose Alpelisib in Participants with Moderate or Severe Hepatic Impairment: A Phase 1, Open-Label, Parallel Group Study.

Publications

Pharmacokinetics and Safety of Multiple-Dose Alpelisib in Participants with Moderate or Severe Hepatic Impairment: A Phase 1, Open-Label, Parallel Group Study.

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