Preservation of Bioavailability of Ingredients and Lack of Drug-Drug Interactions in a Novel Five-Ingredient Polypill (Polycap™): A Five-Arm Phase I Crossover Trial in Healthy Volunteers

Background The Polycap™ (polypill; aspirin [acetylsalicylic acid], ramipril, simvastatin, atenolol, and hydrochlorothiazide) was found to be safe and effective for reducing multiple cardiovascular risk factors in The Indian Polycap™ Study (TIPS). Objective We evaluated the bioavailability of each ingredient of the Polycap™ and determined any drug-drug interactions relative to single component reference preparations. Methods The bioavailability of the ingredients of the Polycap™ (T; test) when formulated as a single capsule was compared with that of identical capsules with each of its ingredients administered separately (R; reference) in a five-arm, randomized, single-dose, two-period, two-treatment, two-sequence, crossover trial with at least a 2-week washout period in a total of 195 healthy volunteers. Plasma concentrations of each drug and, where applicable, its active metabolite were measured using validated liquid chromatographytandem mass spectrometry and ultra-performance liquid chromatography. Mean pharmacokinetic parameters and their standard deviations were computed for each analyte. Results Comparative bioavailability was computed and no drug-drug interactions and no difference in comparative bioavailability were concluded for each ingredient based on point estimates of the T/R ratio of the geometric means falling within 80–125% for peak plasma concentration (C max ), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC t ), and AUC from time zero to infinity (AUC ∞ ). The T/R ratio for C max , AUC t and AUC∞ was within 80–125% for atenolol, hydrochlorothiazide, ramipril, ramiprilat and dose-normalized salicylic acid. However, for simvastatin, the T/R point estimates for C max , AUC t and AUC∞ for Ln-transformed data were significantly lower (∼3–4%) than the lower bound of 80%. For its active metabolite, simvastatin acid, these estimates were significantly higher (∼25–35%) than the higher bound of 125%. Thus, the increased bioavailability of active simvastatin acid appeared to compensate for the loss of bioavailability of simvastatin. Conclusion The Polycap™ was found to be effective and safe in the previously published TIPS trial. The present study in healthy volunteers establishes that Polycap™ is safe (no serious adverse events) and well tolerated, and that there is no indication of pharmacokinetic drug-drug interactions for any of the ingredients, with their bioavailabilities being well prese