Evaluation of Cytochrome P450 (CYP) 3A4-Based Interactions of Levomilnacipran with Ketoconazole, Carbamazepine or Alprazolam in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor with balanced potency for the reuptake inhibition of norepinephrine and serotonin, approved in the USA for the treatment of major depressive disorder (MDD) in adults. We conducted studies in healthy human subjects to investigate pharmacokinetic interactions when levomilnacipran extended-release (ER) is administered in combination with an inhibitor (ketoconazole), an inducer (carbamazepine), or a substrate (alprazolam) of cytochrome P450 (CYP) 3A4. METHODS: Randomised, open-label studies were conducted in healthy volunteers (n = 34 ketoconazole, n = 34 carbamazepine, n = 30 alprazolam) and pharmacokinetic parameters were determined when levomilnacipran was administered alone or together with the relevant study drug. RESULTS: Co-administration of ketoconazole with levomilnacipran ER increased levomilnacipran maximum concentration (C max) by 39% [90% confidence interval (CI) 31-47%] and area under the concentration-time curve (AUC) by 57% (90% CI 47-67%), whereas carbamazepine reduced the C max and AUC of levomilnacipran by 26% (90% CI 22-30%) and 29% (90% CI 26-32%), respectively. Levomilnacipran at steady state had no significant effect on the pharmacokinetics of a single 1 mg dose of alprazolam extended release (XR); neither did single-dose alprazolam XR affect the steady-state pharmacokinetics of levomilnacipran. No new safety concerns were noted in these studies. CONCLUSIONS: Based on these results, the levomilnacipran ER dose should not exceed 80 mg once daily when used with ketoconazole, compared to 120 mg once daily in the absence of ketoconazole. No dose adjustment for levomilnacipran is suggested when levomilnacipran ER is co-administered with carbamazepine or other CYP3A4 inducers. Co-administration with levomilnacipran of drugs metabolised by CYP3A4, such as alprazolam, requires no dose adjustment due to pharmacokinetic considerations.

Influence of CYP3A4 induction/inhibition on the pharmacokinetics of vilazodone in healthy subjects.

PURPOSE: Vilazodone is a serotonin reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of major depressive disorder in adults. Vilazodone seems to be metabolized primarily by the cytochrome P-450 (CYP) 3A4 isozyme and non-CYP-mediated pathways; concomitant use of drugs that affect CYP3A4 activity could potentially alter systemic exposure to vilazodone. The present studies evaluated whether CYP3A4 inhibition (study 1) or induction (study 2) affected the pharmacokinetics of vilazodone. METHODS: Participants were healthy adult volunteers. Study 1 was conducted in 2 parts and evaluated the pharmacokinetics of single-dose vilazodone administered with multiple-dose (200 mg once daily) ketoconazole, a CYP3A4 inhibitor. Part 1 was an open-label pharmacokinetic assessment of a single 5-mg vilazodone dose with or without ketoconazole. Part 2 was a randomized, double-blind, placebo-controlled, crossover study comparing vilazodone pharmacokinetics after a single 10-mg dose alone or co-administered with ketoconazole or placebo. Study 2 was an open-label, multiple-dose, single-sequence study evaluating the effect of steady-state carbamazepine, a CYP3A4 substrate and inducer, on the pharmacokinetics of steady-state vilazodone (40 mg once daily). Primary pharmacokinetic parameters for both studies were AUC and Cmax for vilazodone. Lack of pharmacokinetic interaction was concluded if the 90% CIs of the ratio of vilazodone plus the CYP3A4 inhibitor/inducer relative to vilazodone alone (or plus placebo) for AUC and Cmax were within the 80% to 125% range. Subject-reported and investigator-identified adverse events (AEs), laboratory values, vital signs, and 12-lead ECG parameters were recorded. FINDINGS: In study 1/parts 1 and 2 (n = 15 and 22 enrolled, respectively), mean vilazodone AUC increased 42% and 51%, respectively, in the presence of ketoconazole (expected to be at steady state) versus vilazodone alone (part 1) or with placebo (part 2). The upper limit of the 90% CIs for the vilazodone AUC and Cmax geometric mean ratios exceeded 125%. In study 2 (n = 30 enrolled), co-administration of vilazodone and the carbamazepine extended-release formulation decreased mean steady-state vilazodone exposure ~45%, and the 90% CIs for the vilazodone AUC and Cmax geometric mean ratios were not within the range of 80% to 125%. In both studies, most AEs were of mild intensity, and gastrointestinal AEs predominated. IMPLICATIONS: These results suggest that up to a 50% decrease of vilazodone dosage should be considered when it is given in combination with strong CYP3A4 inhibitors; conversely, increasing the vilazodone dosage up to a maximum of 80 mg/d should be considered when it is given in combination with strong CYP3A4 inducers. (Study registration numbers: SB-659746/029; VLZ-PK-02.).