Pharmacokinetics of Venlafaxine Extended Release 75 mg and Desvenlafaxine 50 mg in Healthy CYP2D6 Extensive and Poor Metabolizers: A Randomized, Open-Label, Two-Period, Parallel-Group, Crossover Study

• Published in: Clinical drug investigation 2011-03, Vol.31 (3), p.155-167
• Main Authors: Nichols, Alice I., Focht, Kristen, Jiang, Qin, Preskorn, Sheldon H., Kane, Cecelia P.
• Format: Article
• Language: English
• Subjects: Adult; Area Under Curve; Chromatography, Liquid; Cross-Over Studies; Cyclohexanols - pharmacokinetics; Cytochrome P-450; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Delayed-Action Preparations; Desvenlafaxine; Desvenlafaxine Succinate; Dosage and administration; Female; Genotype; Health aspects; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Physiological aspects; Polymorphism, Genetic; Serotonin Uptake Inhibitors - pharmacokinetics; Tandem Mass Spectrometry; Venlafaxine; Venlafaxine Hydrochloride; Young Adult
• ISSN: 1173-2563; 1179-1918
• DOI: 10.2165/11586630-000000000-00000

Background Genetically driven variations in the level of cytochrome P450 (CYP) 2D6 metabolic activity have been shown to significantly affect the pharmacokinetic behaviour of medications that are substrates of this enzyme. Objective To evaluate the impact of CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) phenotypes on the pharmacokinetics of single doses of venlafaxine extended release (ER) and desvenlafaxine (administered as desvenlafaxine succinate). Methods This study used a randomized, open-label, two-period, parallel-group, crossover design. The enrolled healthy subjects participated in the study for approximately 8 weeks, which included ≤6 weeks of screening procedures and two separate 1-week partial inpatient confinement periods (separated by a 4-day washout period), during which venlafaxine ER or desvenlafaxine was administered and blood samples were collected. Subjects were admitted to partial inpatient confinement in a laboratory setting for the two separate study periods where each study drug was individually administered. Blood samples for pharmacokinetic analyses were collected during the 120 hours following administration of each study drug. Plasma concentrations of the study drugs were measured by a third-party analyst using liquid chromatography-tandem mass spectrometry. Healthy subjects were recruited through newspaper advertisements and genotyped to determine their CYP2D6 metabolic phenotype (i.e. EM or PM) using internally developed and commercially available assays. Subjects were reimbursed for their participation in this study. Single, sequentially administered oral doses of the dual-acting, serotonin and norepinephrine reuptake inhibiting antidepressants venlafaxine ER (75 mg) and desvenlafaxine (50 mg) were administered. The main outcome measures were differences in the geometric means for area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) and peak plasma concentration (C max ) between EMs and PMs. Comparisons were made using a 2-tailed Wilcoxon exact test. Results No carryover effect was observed between treatment sequence groups. There was no statistically significant difference in either C max or AUC ∞ of O -desmethylvenlafaxine between PMs (n = 7) and EMs (n=7) following administration of desvenlafaxine 50 mg. However, when subjects received venlafaxine ER 75 mg, the AUC ∞ and C max of O -desmethylvenlafaxine (the primary active metabolite) were 445% and 434% higher, respectively, in E