Diazoxide Choline Controlled Release Tablet (DCCR) is under development for the treatment of Prader-Willi syndrome (PWS). The objective of this research was to characterize single dose and steady state pharmacokinetics, dose linearity and food effects of DCCR across five clinical studies. Single dose pharmacokinetics of DCCR were compared to diazoxide oral suspension (Proglycem®) in a study in obese subjects (PK001). Steady state pharmacokinetics were evaluated for DCCR in 4 studies in healthy normal weight, obese, and obese PWS patients (PK008, PK015, TR002, and PC025). Food effects and pharmacokinetics of the major metabolite were each evaluated in healthy volunteers (PK008 and PK015, respectively). Trough circulating drug levels at steady state were characterized in 11 PWS subjects treated with a range of doses of DCCR (PC025). Diazoxide choline rapidly hydrolyses to diazoxide. Diazoxide is readily and extensively absorbed from Proglycem® oral suspension and DCCR. On single dose administration, Tmax was 6.5 hours for Proglycem vs 22 hours for DCCR. Proglycem® Cmax was 47% higher than Cmax for DCCR (13.32 vs 9.07 μg/ml), while the AUC0-∞ was only 15% higher (678.01 vs 588.34 μg*hr/ml). The terminal half-life of the products was comparable (29.2 hr. vs 32.4 hr. for DCCR). DCCR steady state was reached after 7 days of dosing. There was no significant food effect on any pharmacokinetic parameter suggesting that the drug can be dosed with or without food. Over the DCCR dose range of 217.5 to 507.5 mg administered once daily to obese subjects, steady state peak and trough circulating drug levels increased linearly with dose (R2 > 0.997 for both). The major metabolite of diazoxide reached steady state at 10 days and the metabolite-to-parent ratio was 8.6% for both Cmax(ss) and AUC0-τ(ss). Dose-related circulating drug levels were similar in PWS and comparably obese non-PWS subjects, suggesting that the pharmacokinetic data generated in non-PWS subjects is relevant and applicable to the use of DCCR in PWS patients. The pharmacokinetics of DCCR are well characterized across the series of five studies reported here. DCCR was well tolerated and suitable for once-daily dosing in patients with PWS. Given the lower Cmax for a similar AUC, DCCR may lower the likelihood and severity of Cmax related adverse events compared to Proglycem®. The constant intraday circulating drug level that follows from the continual absorption of drug from DCCR likely results in a consistent therapeutic response in treated PWS patients.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology