Clinical Pharmacology & Pharmacometrics, Teva Pharmaceutical Industries Ltd, Malvern PA, USA.
Drug Metabolism and Pharmacokinetics, Teva Pharmaceutical Industries Ltd, Netanya, Israel.
Br J Clin Pharmacol. 2017 Oct;83(10):2214-2224. doi: 10.1111/bcp.13317. Epub 2017 Jun 21.
Pridopidine is an oral drug in clinical development for treatment of patients with Huntington's 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.
The ability of pridopidine to inhibit and/or induce in vitro activity of drug metabolizing 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 twice daily. 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.
Pridopidine was found to be a metabolism dependent inhibitor of CYP2D6, the main enzyme catalysing its own metabolism. Flavin-containing monooxygenase 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 FeCN . Exposure to metoprolol was markedly increased when coadministered with pridopidine; the ratio of the geometric means (90% confidence interval) for maximum observed plasma concentration, and area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration and extrapolated to infinity 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.
As pridopidine is a metabolism-dependent inhibitor of CYP2D6, systemic levels of drugs metabolized by CYP2D6 may increase with chronic coadministration of pridopidine. Pridopidine can be administered without regard to food.
普里多吡啶是一种正在临床开发用于治疗亨廷顿病患者的口服药物。本研究考察了普里多吡啶与体外细胞色素 P450 活性的相互作用，并使用美托洛尔作为探针底物，研究了普里多吡啶对健康志愿者中 CYP2D6 活性的影响。评估了食物对普里多吡啶暴露的影响。
在人肝微粒体和新鲜肝细胞中考察了普里多吡啶抑制和/或诱导药物代谢酶体外活性的能力。使用右美沙芬评估了 CYP2D6 抑制效力和可逆性。对于临床评估，22 名健康受试者单独给予美托洛尔 100mg 以及同时给予稳态普里多吡啶 45mg，每日两次。以交叉方式评估了食物对单次 90mg 剂量普里多吡啶的影响。整个研究过程中进行安全性评估和药代动力学采样。
发现普里多吡啶是 CYP2D6 的代谢依赖性抑制剂，CYP2D6 是催化其自身代谢的主要酶。黄素单加氧酶肝微粒体热失活不影响普里多吡啶对 CYP2D6 的代谢依赖性抑制作用，且添加 FeCN 并不能使其对 CYP2D6 的抑制作用可逆。当与普里多吡啶同时给药时，美托洛尔的暴露量明显增加；最大观测血浆浓度的几何均值（90%置信区间）、从 0 时间到最后可定量浓度的时间的血浆浓度-时间曲线下面积和外推至无穷大的比值分别为 3.5（2.9, 4.22）、6.64（5.27, 8.38）和 6.55（5.18, 8.28）。食物条件不影响普里多吡啶的系统暴露。
由于普里多吡啶是 CYP2D6 的代谢依赖性抑制剂，因此与普里多吡啶慢性联合用药时，可能会增加由 CYP2D6 代谢的药物的全身水平。普里多吡啶可以不受食物影响给药。
