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

Background: The Polycap (TM) (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 (TM) Study (TIPS). Objective: We evaluated the bioavailability of each ingredient of the Polycap (TM) and determined any drug-drug interactions relative to single component reference preparations. Methods: The bioavailability of the ingredients of the Polycap (TM) (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 chromatography-tandem 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(infinity)). The T/R ratio for C-max, AUC(t) and AUC(infinity) 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(infinity) for Ln-transformed data were significantly lower (similar to 3-4%) than the lower bound of 80%. For its active metabolite, simvastatin acid, these estimates were significantly higher (similar to 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 (TM) was found to be effective and safe in the previously published TIPS trial. The present study in healthy volunteers establishes that Polycap (TM) 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 preserved.