Bioequivalence of single and multiple doses of venlafaxine extended-release tablets and capsules in the fasted and fed states: four open-label, randomized crossover trials in healthy volunteers

Abstract

Background: Venlafaxine extended-release (ER) tablets use osmotic pressure to deliver venlafaxine hydrochloride at a controlled rate over approximately 24 hours.

Objective: These studies were conducted to evaluate the bioequivalence of venlafaxine ER tablets and capsules based on the US Food and Drug Administration (FDA) definition.

Methods: Four pharmacokinetic studies of the capsule (reference) and tablet (test) formulations were conducted in healthy adult volunteers. The first 2 were randomized, single-dose, 4-way crossover studies of either a 37.5-mg dose (study A) or a 75-mg dose (study B) of the reference and test products under fasting and fed conditions. The other 2 were randomized, 2-way crossover studies of either a single dose (study C) or multiple doses (study D) of venlafaxine ER 225 mg, delivered as one venlafaxine ER 225-mg tablet or one 150-mg + one 75-mg venlafaxine ER capsules under fed conditions. The primary outcome measures were the log-transformed C(max), AUC(0-t), and AUC(0-infinity). If the 90% CIs for the ratios of the least squares means of the primary outcome measures between the reference and test formulations fell within the regulatory range (80%-125%), the 2 formulations would be considered bioequivalent according to the FDA definition.

Results: Thirty-six subjects (21 men, 15 women; mean [SD] age, 28.0 [8.7] years; mean weight, 161.0 [26.0] lb) were enrolled in study A and completed all treatment periods. Thirty-six subjects were enrolled in study B, of whom 30 (22 men, 8 women; mean age, 33.5 [9.6] years; mean weight, 172.7 [23.9] lb) completed all treatment periods. Thirty-six subjects were enrolled in study C, of whom 28 (16 men, 12 women; mean age, 33.1 [12.9] years; mean weight, 160.6 [29.6] lb) completed the study. Thirty-four subjects were enrolled in study D, of whom 33 (29 men, 4 women; mean age, 26.0 [8.1] years; mean weight, 178.0 [30.3] lb) completed the study. In study A, the 90% CIs for the log-transformed ratio (test vs reference) of C(max), AUC(0-t), and AUC(0-infinity) in the fasted state were 95.58 to 107.48, 97.58 to 111.09, and 100.31 to 112.85, respectively; in the fed state, the corresponding values were 84.26 to 94.86, 93.49 to 106.58, and 98.98 to 111.91. In study B, the respective values in the fasted state were 113.07 to 126.10, 111.11 to 124.57, and 106.86 and 120.71; in the fed state, the values were 90.50 to 100.90, 96.80 to 108.50, and 95.05 to 107.21. In study C, fed values were 94.15 to 109.37, 103.8 to 115.85, and 102.64 to 113.39. In study D, which involved multiple doses, fed values for C(max) and AUC(0-t) were 82.26 to 88.77 and 101.16 to 109.45, respectively. Adverse effects included nausea, vomiting, dizziness, syncope, and somnolence.

Conclusions: In these single- and multiple-dose studies, all doses of venlafaxine ER tablets tested met the FDA criterion for bioequivalence to the equivalent doses of venlafaxine ER capsules in the fed state. In the fasted state, the bioequivalence criterion was met for venlafaxine ER 37.5-mg tablets but not venlafaxine 75-mg tablets.