- : Metoprolol-pridopidine drug-drug interaction and food effect assessments of pridopidine, a new drug for treatment of Huntington Disease. - pubmed: huntington's or hunt...
Metoprolol-pridopidine drug-drug interaction and food effect assessments of pridopidine, a new drug for treatment of Huntington Disease.
Br J Clin Pharmacol. 2017 Apr 27;:
Authors: Rabinovich-Guilatt L, Steiner L, Hallak H, Pastino G, Muglia P, Spiegelstein O
AIM: Pridopidine is an oral drug in clinical development for treatment of patients with Huntington disease. This study examined the interactions of pridopidine with in vitro cytochrome P450 activity and characterized the effects of pridopidine on CYP2D6 activity in healthy volunteers using metoprolol as a probe substrate. The effect of food on pridopidine exposure was assessed.
METHODS: The ability of pridopidine to inhibit and/or induce in vitro activity of drug metabolising enzymes was examined in human liver microsomes and fresh hepatocytes. CYP2D6 inhibition potency and reversibility was assessed using dextromethorphan. For the clinical assessment, 22 healthy subjects were given metoprolol 100 mg alone and concomitantly with steady-state pridopidine 45 mg bid. Food effect on a single 90 mg dose of pridopidine was evaluated in a crossover manner. Safety assessments and pharmacokinetic sampling occurred throughout the study.
RESULTS: Pridopidine was found to be a dependent inhibitor of CYP2D6, the main enzyme catalyzing its own metabolism. FMO heat inactivation of liver microsomes did not affect pridopidine metabolism-dependent inhibition of CYP2D6 and its inhibition of CYP2D6 was not reversible with addition of FeCN3 . Exposure to metoprolol was markedly increased when co-administered with pridopidine; the ratio of the geometric means (90% CI) for Cmax, AUC0-last and AUC0-∞ were 3.5 (2.9, 4.22), 6.64 (5.27, 8.38) and 6.55 (5.18, 8.28), respectively. Systemic exposure to pridopidine was unaffected by food conditions.
CONCLUSIONS: As pridopidine is a metabolism-dependent inhibitor of CYP2D6, systemic levels of drugs metabolized by CYP2D6 may increase with chronic co-administration of pridopidine. Pridopidine can be administered without regard to food.
PMID: 28449367 [PubMed - as supplied by publisher]