Abstract
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.
Highlights
Paracetamol is a non-opioid widely distributed as an over-the-counter (OTC) drug for treating pain and reducing fever
Unlike non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol does not inhibit the peripheral generation of prostaglandins and exhibit a clinical anti-inflammatory effect
Paracetamol does not alter the generation of prostaglandins in gastric mucosa [2] and, it is suitable for patients with a history of GI disease or on concomitant medication where peripheral prostaglandin inhibition would be undesirable
Summary
Paracetamol ( known as acetaminophen) is a non-opioid widely distributed as an over-the-counter (OTC) drug for treating pain and reducing fever. It has both analgesic and antipyretic properties and is used for the treatment of mild and moderate pain. Study suggests that caffeine induces changes in mood [9] which are probably due to its psychotropic actions and which may influence pain perception. It has been demonstrated in an experimental pain model that the addition of caffeine 130 mg enhances and prolongs the analgesic effect of paracetamol 1000 mg [10]. It is postulated that calcium alginate, formed by the reaction of calcium ions with alginic acid in the acidic environment of the stomach, combine with carbon dioxide generated from calcium carbonate, facilitate the formation of a uniform suspension of fine particles with increased surface area leading to enhanced dissolution [11]
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