Pharmacokinetics, Food Effect, Ketoconazole Interaction, and Safety of JTK-853, a Novel Nonnucleoside HCV Polymerase Inhibitor, After Ascending Single and Multiple Doses in Healthy Subjects
| Autor: | Hiroyuki Yamada, Sudhakar M. Pai, Tsutomu Shibata, Thomas L. Hunt, Sekihiro Tamaki, Barbara Gerhardt |
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| Rok vydání: | 2018 |
| Předmět: |
Drug
Adult Male Adolescent media_common.quotation_subject Hepatitis C virus Metabolite Pharmaceutical Science Hepacivirus Pharmacology medicine.disease_cause 030226 pharmacology & pharmacy Antiviral Agents Drug Administration Schedule Piperazines 03 medical and health sciences chemistry.chemical_compound Food-Drug Interactions Young Adult 0302 clinical medicine Pharmacokinetics medicine Humans Pharmacology (medical) Drug Interactions media_common CYP3A4 Dose-Response Relationship Drug business.industry Middle Aged RNA-Dependent RNA Polymerase In vitro Healthy Volunteers Ketoconazole chemistry Tolerability 030220 oncology & carcinogenesis Area Under Curve Female business medicine.drug Half-Life |
| Zdroj: | Clinical pharmacology in drug development. 8(3) |
| ISSN: | 2160-7648 |
| Popis: | Pharmacokinetics, safety, and tolerability of JTK-853, a novel HCV polymerase inhibitor, were evaluated in single and multiple ascending dose (SAD, MAD) studies, with food- and ketoconazole-related effects on exposure to JTK-853 and its active (CYP3A4 mediated) metabolite M2. JTK-853 was safe and well tolerated in both studies. In the SAD study, at doses >1600 mg (with standard breakfast [SBF]), JTK-853 exposure did not increase further, was substantially higher (AUCinf increase: 3- to 8-fold) with SBF (vs fasted), with a moderate increase in AUCinf (approximately 1.5-fold [1600 mg]) with a high-fat breakfast (vs SBF). In the SAD study (400-1600 mg, SBF), mean effective half-life (t1/2(eff) ) of JTK-853 was 8.3 to 10.9 hours, and 20.3 to 27.3 hours in the MAD study (twice daily dosing, fed condition), with 2- to 3-fold accumulation in exposure (AUCtau ). At steady-state, AUCtau increased dose proportionally, and was approximately 2-fold higher with ketoconazole coadministration. Metabolite M2 (equipotent to JTK-853 in vitro) did not contribute significantly to parent drug exposure and decreased with increase in dose, repeated dosing, and ketoconazole coadministration. Trial simulation-based ratios (n = 1000/dose level) of trough JTK-853 plasma concentrations to the in vitro EC90 for HCV genotype 1b were assessed for dose selection in a separate proof-of-concept study in patients. The studies enabled delineation of key drug attributes for further assessments in the target population. |
| Databáze: | OpenAIRE |
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