Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors
| Autor: | Jerry Nedelman, Ovidiu Chiparus, Pai-Hsi Huang, Dalila Sellami, Eunju Hurh, Andrew M. Stein, Varun Goel, Jocelyn Zhou, Sven Gogov |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Cancer Research Pyridines Bilirubin Population Administration Oral Renal function Pharmacology Toxicology Models Biological Sonidegib 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Humans Medicine Hedgehog Proteins Pharmacology (medical) education Aged Aged 80 and over Volume of distribution education.field_of_study business.industry Biphenyl Compounds Middle Aged NONMEM Bioavailability 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Female business Signal Transduction |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 77:745-755 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | Sonidegib (Odomzo) selectively inhibits smoothened and suppresses the growth of hedgehog pathway-dependent tumors. A population pharmacokinetic (PK) analysis of sonidegib in healthy subjects and patients with advanced solid tumors was conducted to characterize PK, determine variability, and estimate covariate effects. PK data from five phase 1 or 2 studies (N = 436) in the dose range from 100 to 3000 mg were analyzed using NONMEM. A two-compartment base model with first-order absorption, lag time, linear elimination, and bioavailability that decreased with dose was updated to describe the PK of sonidegib. Covariate analyses were performed and were incorporated into the population PK full model. The base and full models were robust with a good fit to the study data. Population-predicted geometric means (inter-individual variability, CV%) of apparent oral clearance, apparent volume of distribution at steady state, accumulation ratio, and elimination half-life were 9.5 L/h (71.4 %), 9163 L (74.9 %), 21 (131 %) and 29.6 days (109 %). Clinically relevant covariate effects were: A high-fat meal increased sonidegib bioavailability fivefold, healthy volunteers had threefold higher clearance, sonidegib bioavailability decreased with increasing dose levels, and PPI coadministration reduced sonidegib bioavailability by 30 %. Sonidegib PK was not significantly impacted by baseline age, weight, total bilirubin, alanine aminotransferase, albumin, creatinine clearance, gender, and ethnicity (Western countries versus Japanese). No dose adjustment is needed for mild hepatic impairment, mild and moderate renal impairment, age, weight, gender, or ethnicity. This population PK model adequately characterizes sonidegib PK characteristics and can be used for various simulations and applications. |
| Databáze: | OpenAIRE |
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