Pharmacokinetics of extended-release and immediate-release formulations of galantamine at steady state in healthy volunteers

ABSTRACT

Objective: To assess the steady-state galantamine (GAL) bioavailability of the extended-release 24‐mg qd capsule (GAL‐ER) with and without food and to evaluate the relative bioavailability of GAL‐ER with the immediate-release 12‐mg bid tablet (GAL‐IR) at steady state.

Methods: This was a single-center, open-label, randomized, 3-way crossover study in 24 healthy volunteers (12 males and 12 females) aged 18 to 45 years. After 7 days of GAL‐ER 8 mg qd each morning and 7 days of GAL‐ER 16 mg qd each morning, subjects received the following treatments in randomized, crossover order (7 days each): GAL‐ER 24 mg qd each morning (fasted before Day 7 morning dose), GAL‐ER 24 mg qd each morning (fed before Day 7 morning dose), and GAL‐IR 12 mg bid (fasted before Day 7). Pharmacokinetic parameters of GAL at steady state were determined after morning intake on Day 7 of each treatment week. Safety evaluations included adverse event (AE) reporting, physical examination, clinical laboratory tests, vital signs, and electrocardiography.

Results: The treatment ratios of area under the plasma concentration-time curve of GAL from time 0–24 h post-dosing (AUC_{24 h}), peak plasma concentration (C_max), and pre-dose plasma concentration (C_min) for GAL‐ER fed/fasting were 105%, 112%, and 103%, respectively. The treatment ratios and 90% confidence intervals for all above mentioned pharmacokinetic parameters demonstrated bioequivalence (with the range of 80-125%), indicating that food had no effect on GAL‐ER bioavailability. As anticipated, GAL‐ER (fasting) had mean AUC_{24 h} similar to GAL‐IR (fasting), with lower C_max (63 ng/mL vs 84 ng/mL) and longer time to reach C_max (4.4 h vs 1.2 h). The treatment ratios and 90% confidence intervals for both AUC_{24 h} and C_min demonstrated bioequivalence (within the range of 80-125%). The treatment ratio for C_max was 75.7%, indicating a 24% lower C_max for GAL‐ER than for GAL‐IR. In this study, GAL‐ER was safe and well tolerated with or without food and was comparable to the GAL‐IR formulation.

Conclusion: Food had no effect on the GAL bioavailability of GAL‐ER at steady state. GAL‐ER was bioequivalent to GAL‐IR with respect to AUC_{24 h} and C_min.

Key words: :

• Acetylcholinesterase inhibitors
• Alzheimer's disease
• Extended release
• Food effect
• Galantamine
• Pharmacokinetics