Mechanistic Considerations About an Unexpected Ramipril Drug-Drug Interaction in the Development of a Triple Fixed-Dose Combination Product Containing Ramipril, Amlodipine, and Atorvastatin

This open-label, repeat-dose, fixed-sequence study in healthy subjects examined pharmacokinetic drug-drug interactions between the components of a novel fixed-dose combination product containing ramipril, amlodipine, and atorvastatin. Sequential 5-day monotreatments (MTs) of ramipril (5 mg/d) and atorvastatin (40 mg/d) were followed by a 9-day amlodipine MT (5 mg/d), separated by 96 hours washout intervals. After amlodipine MT, all 3 single-entity drugs were coadministered for 5 days. Blood samples were taken over the dosing intervals and drug concentrations quantified by high-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were assessed and compared between the MTs and combination treatments by analysis of variance. Eighteen healthy subjects were enrolled and completed the study. No significant difference in maximum concentration (C-max) and area under the plasma concentration-time curve over the dosing interval (AUC(0-tau)) for amlodipine and AUC(0-tau) of atorvastatin was observed upon combination treatments versus MTs. C-max of atorvastatin was slightly decreased (C-max ratio, 89.3%) when given in combination. Increased exposure of ramipril and less pronounced exposure of ramiprilat were observed in the presence of amlodipine and atorvastatin, with C-max ratios for ramipril and ramiprilat of 182.6% and 155.9%, and corresponding AUC(0-tau) ratios of 150.0% and 112.1%, respectively. These ramiprilat increases are unlikely of clinical relevance, because complete angiotensin-converting enzyme occupation is achieved with >= 5-mg ramipril doses, and free ramiprilat is rapidly eliminated. As ramipril is known to be subject to a site-dependent absorption in the upper small intestine, it is hypothesized that slowing of intestinal motility by atorvastatin or amlodipine or a combined effect of both, increased the residence time of ramipril in its "absorption window," thereby enhancing its bioavailability.