p450 - publications
Pharmacokinetic and tolerability profile of pridopidine in healthy-volunteer poor and extensive CYP2D6 metabolizers, following single and multiple dosing.
Eur J Drug Metab Pharmacokinet. 2012 Sep 5;
Authors: Lindskov Krog P, Osterberg O, Gundorf Drewes P, Rembratt A, Schultz A, Timmer W
Pridopidine is being developed for the treatment of impaired motor function associated with Huntington's disease and belongs to a new class of compounds known as dopidines, which act as dopaminergic stabilizers. In vitro studies have shown that pridopidine is a substrate for the P450 cytochrome 2D6 enzyme (CYP2D6), and clinical data show that the half-life of pridopidine is different following single dosing versus at steady state. To further investigate the pharmacokinetic profile of pridopidine and to establish whether dose adjustment is needed in poor CYP2D6 metabolizers, a single-centre, open-label, multiple-dose study in healthy volunteers was performed. In total, 24 extensive CYP2D6 metabolizers (EMs) and 12 poor CYP2D6 metabolizers (PMs) were enrolled. Both groups received 45 mg pridopidine twice daily (b.i.d.). Plasma samples were taken during the first day of b.i.d. dosing (Day 1) and at steady state, following 14 days of b.i.d. dosing. At Day 1, total exposure in PMs was almost three times higher than those in EMs (AUC(0-∞) = 11,192 and 3,782 h·ng/mL, respectively; PM/EM ratio = 2.96; p < 0.001). However, at steady state, PMs and EMs had comparable exposure due to a reduction in pridopidine elimination in EMs over time. Thus, at steady-state peak (C (max)) and total (AUC(0-24)) exposures were only 1.24 and 1.29 times higher, respectively, in PMs than EMs. These results support that pridopidine is a CYP2D6 auto-inhibitor. Pridopidine was well tolerated in both EMs and PMs. The slightly higher exposure level in PMs at steady state does not indicate a need for dose adjustment or genotyping for CYP2D6 metabolizer status.
PMID: 22948856 [PubMed - as supplied by publisher]