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

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

Clinical therapeutics (2014-09-23)
Ramesh Boinpally, Nayra Gad, Samir Gupta, Antonia Periclou
ABSTRACT

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. 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. 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. 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.).

MATERIALS
Product Number
Brand
Product Description

Supelco
Carbamazepine, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Ammonium formate, SAJ first grade, ≥95.0%
Supelco
Ammonium formate, eluent additive for LC-MS, LiChropur, ≥99.0%
Sigma-Aldrich
Ammonium formate, BioUltra, ≥99.0% (calc. based on dry substance, NT)
Sigma-Aldrich
Ammonium formate, ≥99.995% trace metals basis
Supelco
Carbamazepine 10,11-epoxide, analytical standard
Sigma-Aldrich
Carbamazepine, meets USP testing specifications
Sigma-Aldrich
Carbamazepine, powder
Carbamazepine, European Pharmacopoeia (EP) Reference Standard
USP
Carbamazepine, United States Pharmacopeia (USP) Reference Standard
Supelco
Carbamazepine, analytical standard
Sigma-Aldrich
Ammonium formate, reagent grade, 97%
Supelco
Carbamazepine 10,11-epoxide, analytical standard
Sigma-Aldrich
Formic acid, JIS special grade, ≥98.0%
Supelco
Ammonium formate solution, 10 mM in H2O, suitable for HPLC
Sigma-Aldrich
Butyric acid, SAJ special grade, ≥99.5%
Sigma-Aldrich
Ketoconazole
Sigma-Aldrich
Butyric acid, ≥99%
Sigma-Aldrich
Butyric acid, ≥99%, FG
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Butyric acid, natural, ≥99%, FCC, FG
Sigma-Aldrich
Ketoconazole, 99.0-101.0% (EP, titration)
Ketoconazole, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Formic acid solution, BioUltra, 1.0 M in H2O
Sigma-Aldrich
Formic acid, reagent grade, ≥95%
Sigma-Aldrich
Formic acid, ≥95%, FCC, FG
Supelco
Butyric acid, analytical standard
Sigma-Aldrich
Ammonium formate solution, BioUltra, 10 M in H2O
Sigma-Aldrich
Formic acid, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥98%
USP
Ketoconazole, United States Pharmacopeia (USP) Reference Standard
Supelco
Ketoconazole, Pharmaceutical Secondary Standard; Certified Reference Material