Bioequivalence of a novel high-dose oral formulation of alpha-dihydroergocryptine

The plasma pharmacokinetics of alpha-dihydroergocryptine (DHEC, CAS 14271-05-7) were investigated in 24 patients with Parkinson disease after the administration of repeated oral doses of 40 mg DHEC twice daily by means of a novel 40 mg DHEC tablet (Almirid 40 mg test T) and an established 20 mg DHEC tablet (Almirid 20 mg - reference R). The trial was conducted according to a randomised, controlled, open, within-subject cross-over design; steady-state was established by means of a stepwise up-titration from 5 to 40 mg b.i.d. from day D01 to D19; investigational treatments (40 mg DHEC b.i.d. by means of formulation R and T) were administered on day D20 and D21 according to a randomised, period-balanced within-subject cross-over; treatment with DHEC was down-titrated in stepwise fashion from day D22 to D34. Morning doses of 2 x 20 mg DHEC (reference) yielded a fast and relatively short lasting peak with a geometric mean Cmax of 2157 pg/mL (CV: 0.978) after a median tmax of 1.00 h. Cmin throughout the first 12 h was on average 189 pg/mL (CV: 0.908). There was a quite distinct diurnal effect: evening doses of 2 x 20 mg DHEC (treatment R), yielded a relatively lower exposure with geometric mean Cmax, Cav- and Cmin-values of 800 pg/mL (CV: 0.870), 389 pg/mL (0.813) and 177 pg/mL (CV: 0.942). In contrast, there was relatively little within-subject distinction between the two formulations: for the day profile after the morning dose, the estimated ratios of the true means (Pr:R) for Cmax Cmin and Cav were 1.18 (90% CI: 0.96 to 1.43 - CVm: 0.394), 0.96 (90% CI: 0.86 to 1.09 - CVm: 0.230) and 1.06 (90% CI: 0.93 to 1.21 - CVm: 0.254); for the night profile after the evening dose, the estimated ratio of the true means (muT:muR) for Cmax, Cmin and Cav were 1.11 (90% CI: 0.91 to 1.35 - CVm: 0.395), 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.232) and 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.220). In view of important medical-ethical constraints not to expose an unreasonably high number of subjects, these findings could be accepted as a sufficient demonstration of bioequivalence.