生物等效性和生物利用度杂志

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Pharmacokinetic and Bioequivalence Study Evaluating a New Paracetamol/Caffeine Formulation in Healthy Human Volunteers

Dongzhou J. Liu, Mitchell Kotler and Scott Sharples

Purpose: Aim of this study was to evaluate the bioequivalence and clinical pharmacokinetics of newly developed paracetamol 500 mg and caffeine 65 mg combination (PANADOL® EXTRA ADVANCE product), compared with currently marketed conventional paracetamol/caffeine caplet (PANADOL EXTRA® product) in fasted and semi-fed states.

Methods: Thirty subjects were enrolled and all completed this 4-way crossover study. Serial blood samples were collected pre-dose until 10-hours post-dose for each period. Plasma samples were assayed for paracetamol and caffeine concentration using HPLC/MS methods. PK parameters were computed using non-compartmental model. Linear mixed-effect model was used to analyze logarithmically transformed AUC0-∞, AUC0-t and Cmax as well as AUC0-30min and AUC0-60min values. Tmax was analyzed by signed rank test on within-subject differences. Time to reach minimum therapeutic concentration in plasma of 4 μg/ml (T4) for paracetamol was evaluated. The AEs were also assessed. Ratios of AUC0-∞, AUC0-t, and Cmax were compared for new formulation vs. PANADOL EXTRA® in fasted and semi-fed states, and analyzed for bioequivalence as determined by 90% confidence intervals (CI90%).

Results: Bioequivalence was established between these two formulations in both fasted and semi-fed states, as the ratios were within 0.8-1.25, except the Cmax of paracetamol in fasted state. In addition, the new formulation showed significantly greater early absorption (AUC0‑30min and AUC0-60min), as well as significantly shorter Tmax, for both paracetamol and caffeine compared to PANADOL EXTRA® in fasted and semi-fed states. Based on T4, paracetamol absorption was twice as fast for the new formulation as compared to the corresponding conventional caplet in the fasted and fed states. The new formulation was safe and well tolerated.

Conclusions: The new Panadol® Extra Advance formulation is bioequivalent to the currently marketed conventional formulation. Both paracetamol and caffeine are absorbed significantly faster with the new formulation compared to Panadol® Extra product.