A fixed-dose combination (FDC) tablet of the Olmesartan medoxomil, Amlodipine besylate and Rosuvastatin calcium was developed to enhance the dosing convenience and thus to increase patient compliance. Olmesartan and Amlodipine have been widely used in combination with Rosuvastatin for the treatment of hypertension accompanied by dyslipidemia. Drug-Drug Interaction (DDI) study was conducted to investigate the pharmacokinetic profile of co-administration of 3 drugs. And a FDC of these 3 drugs was prepared and its bioequivalence (BE) with each reference drug was investigated. It was previously found that the BE could not be achieved even if the in vitro dissolution of drug substances from the FDC is similar to that of each drug tablet. The purpose of this study is to investigate relevant dissolution requirements of the FDC in order to achieve BE.
DDI study of a phase I randomized, open-label, 2-period, multiple-dose, crossover design in healthy Korean subjects was investigated to test the pharmacokinetic interaction of co-administration of Olmesartan/Amlodipine 40/10mg and Rosuvastatin 20mg.
The FDC was developed as a film-coated tablet avoiding any physical or pharmacological interaction among the each drug substances. Various formulations with different dissolution profiles were prepared and the final formulation was selected based on pattern of dissolution profiles and pilot PK studies.
With the final formulation, BE study of a phase I randomized, open-label, 2-period, single-dose, crossover design in healthy Korean subjects was carried out to compare the pharmacokinetic profiles of single-dose administration of Olmesartan/Amlodipine /Rosuvastatin 40/10/20mg (test drug), against co-administration of Olmesartan/Amlodipine 40/10mg tablet and Rosuvastatin 20mg tablet (reference drug).
In the DDI study, the 90% CIs (confidence interval) of the geometric mean ratio of AUC and Cmax for the co-administration of reference drugs to the mono-administration of each drug were within the bioequivalent criteria (80 - 125%).
The FDC tablet finally selected and phase I study for its BE with co-administered Olmesartan/Amlodipine and Rosuvastatin single tablets as reference drugs was performed.
Through dissolution studies of various formulations, it was found that bioequivalence can be achieved when Olmesartan/Amlodipine and Rosuvastatin were formulated into a combination dosage form using a conventional method.
The results of the BE study proved that the FDC is equivalent to the reference drugs in 54 subjects. Furthermore, there was no significant difference in the prevalence of Adverse events between the reference and test drugs.
When Olmesartan/Amlodipine and Rosuvastatin were co-administered, the pharmacokinetic exposure of 3 drugs was not significantly influenced by the other as determined by the comparative bioavailability range. Through appropriate control of dissolution rates of drug substances, development of the FDC tablet displaying pharmacokinetic profiles comparable to that of reference drugs could be achieved.
Bohoon Kim– Formulation research team, Daewoong Pharmaceutical Corporation, Yongin-si, Kyonggi-do
Hyunryung Kim– Formulation resarch team, Daewoong Pharmaceutical Corporation, Yongin-si, Kyonggi-do
Ji Yeon Kim– Formulation Research, Daewoong Pharmaceutical Co.Ltd, Yongin-si