Effects of desvenlafaxine on the pharmacokinetics of desipramine in healthy adults

Abstract

The results of two single-center, two-period, open-label trials that evaluated the effects of multiple doses of desvenlafaxine on the pharmacokinetics of desipramine, a cytochrome P450 (CYP) 2D6 enzyme substrate, are presented. Healthy individuals aged 18-45 years were administered a single oral dose of 50 mg desipramine with and without 100 mg daily (n=34) or 400 mg daily (n=23) desvenlafaxine for 5 days. After coadministration of 100 mg desvenlafaxine, desipramine exposure, measured by peak plasma concentration (C(max)) and total area under the plasma concentration-versus-time curve (AUC), showed minimal increases of 25 and 17%, respectively; coadministration of 400 mg desvenlafaxine resulted in a 52% increase in desipramine C(max) and a 90% increase in AUC. For the 100 mg dose, the geometric least squares mean ratios and 90% confidence intervals (CIs) for desipramine AUC (117%; 90% CI 110-125%), 2-hydroxydesipramine AUC (114%; 90% CI 110-119%), and C(max) (110%; 90% CI 104-116%) were all within the 80-125% interval, showing the bioequivalence for AUC between desipramine administered alone and in combination with 100 mg desvenlafaxine. These results indicate that desvenlafaxine is a relatively weak inhibitor of CYP2D6 and that desvenlafaxine 100 mg, twice the recommended therapeutic dose of 50 mg, is unlikely to cause drug-drug interactions with CYP2D6 substrates.

Therapy Response Prediction in Major Depressive Disorder: Current and Novel Genomic Markers Influencing Pharmacokinetics and Pharmacodynamics

“…Desvenlafaxine is predominantly eliminated through renal excretion of its glucuronide metabolite and as unchanged drug (64%). Phase 1 hepatic metabolism through the CYP450 3A4 pathway plays a minor role (<5%) [99]. Thus, and in contrast to the parent drug venlafaxine, CYP2D6 variants do not play a relevant role for safety and efficacy of desvenlafaxine [99][100][101].…”

“…Phase 1 hepatic metabolism through the CYP450 3A4 pathway plays a minor role (<5%) [99]. Thus, and in contrast to the parent drug venlafaxine, CYP2D6 variants do not play a relevant role for safety and efficacy of desvenlafaxine [99][100][101]. No relevant impact of P-gp genetic variants on desvenlafaxine kinetics has been shown [102].…”

Population Pharmacokinetics of Desvenlafaxine: Pharmacokinetics in Korean Versus US Populations

“…Blood samples for PK analysis in plasma were collected before (predose) and at 0.5, 1,2,4,6,8,10,12,16,24,36,48, and 72 hours after study drug administration on days 1 and 8. Bioanalytical and PK methods have been previously described.…”

“…20,21 A modest increase in exposure has been observed in subjects with moderate to severe hepatic impairment. 22 Concomitant administration of desvenlafaxine has a minimal effect on exposure to drugs metabolized via the CYP2D6 23,24 and/or CYP3A4 pathway. 25 Desvenlafaxine exposure also is not significantly affected by CYP2D6 phenotype (ie, poor vs extensive metabolizer status), 26,27 suggesting that desvenlafaxine PK would not be expected to vary between groups that differ in the prevalence of CYP2D6 genotypes, including races or ethnic populations.…”

A novel prodrug strategy to improve the oral absorption of O-desmethylvenlafaxine

“…O-desmethylvenlafaxine (ODV), also known as desvenlafaxine succinate, is a synthetic form of the major active metabolite of venlafaxine with antidepressant activity similar to that of venlafaxine but with a longer half-life (9,10). Compared with venlafaxine, direct intake of ODV for the treatment of diseases of the central nervous system has the advantages of being a single compound that is conducive to dosing adjustments and reducing the risk of interactions with other drugs (11)(12)(13)(14)(15). However, ODV contains a more exposed hydroxy group compared with venlafaxine, and therefore it has increased hydrophilicity, resulting in lower oral bioavailability.…”