A phase I, randomized, open-label, single-dose, 3-period crossover study to evaluate the drug-drug interaction between ZX008 (fenfluramine HCl oral solution) and a regimen of stiripentol, clobazam, and valproate in healthy subjects
| Autor: | Bradley S. Galer, Arnold R. Gammaitoni, Gail Farfel, Steven M. Smith, Boyd Brooks M |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 050101 languages & linguistics Cmax Administration Oral 02 engineering and technology Pharmacology Dravet syndrome ‒ drug interaction ‒ fenfluramine ‒ pharmacokinetics ‒ stiripentol Young Adult chemistry.chemical_compound Pharmacokinetics Norfenfluramine Fenfluramine 0202 electrical engineering electronic engineering information engineering Stiripentol Humans Medicine Drug Interactions 0501 psychology and cognitive sciences Pharmacology (medical) Adverse effect Cross-Over Studies business.industry Valproic Acid 05 social sciences Dioxolanes Non-Smokers Middle Aged Crossover study Healthy Volunteers Regimen chemistry Adjunctive treatment Clobazam Female 020201 artificial intelligence & image processing business Research Article medicine.drug |
| Zdroj: | International Journal of Clinical Pharmacology and Therapeutics |
| ISSN: | 0946-1965 |
| DOI: | 10.5414/cp203276 |
| Popis: | Objective Phase I, open-label, randomized, single-dose, 3-period crossover study assessing pharmacokinetics (PK) and safety of ZX008, a liquid oral formulation of fenfluramine (FFA) under development for adjunctive treatment of Dravet syndrome and Lennox-Gastaut syndrome, administered with and without a combined antiepileptic drug (AED) regimen of stiripentol (STP), valproate (VPA), and clobazam (CLB) (STP regimen). Materials and methods 26 healthy adults were administered the following treatments: ZX008 0.8 mg/kg; STP 3,500 mg, CLB 20 mg, VPA 25 mg/kg (max. 1,500 mg); and ZX008 0.8 mg/kg + STP regimen. Dose periods were 17 days apart. Blood samples were obtained for 72 hours after drug administration and used to calculate non-compartmental PK parameters. Results Statistical bioequivalence-type analysis demonstrated ZX008 had no significant impact on the PK of any drug in the STP regimen, while the STP regimen moderately affected FFA PK. The 3-drug combination increased the geometric mean Cmax, AUC0-t, and AUC0-inf of FFA while reducing the Cmax and AUC0-t of its major metabolite, norfenfluramine (norFFA). Adverse events (AEs) were mild to moderate and resolved spontaneously. ZX008 + STP regimen co-administration to healthy adult subjects modestly impacted the number but not severity of AEs. Conclusion Results show that the STP regimen had a moderate impact on FFA and norFFA PK and ZX008 had no significant impact on the 3 STP regimen drugs. ZX008 would not be expected to alter the clinical response of patients to this regimen by means of an effect on PK. When administering these drugs together, a downward dose adjustment of ZX008 may be warranted. . |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|