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Hyun Chul Kim,1,2 Sangmi Lee,1,2 Siyoung Sung,3 Eunjin Kim,3 In-Jin Jang,1 Jae-Yong Chung4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea; 3Dong-A ST Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of KoreaCorrespondence: Jae-Yong Chung, Seoul National University College of Medicine and Bundang Hospital, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea, Tel +82-31-787-3955, Fax +82-31-787-4045, Email jychung@snubh.orgBackground: Dapagliflozin formate (DAP-FOR, DA-2811), an ester prodrug of dapagliflozin, was developed to improve the stability and pharmaceutical manufacturing process of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor.Purpose: This study aimed to evaluate the pharmacokinetics (PKs) and safety of dapagliflozin for DAP-FOR compared to those for dapagliflozin propanediol monohydrate (DAP-PDH, Forxiga) in healthy subjects.Methods: This was an open-label, randomized, single-dose, two-period, two-sequence crossover study. The subjects received a single dose of DAP-FOR or DAP-PDH 10 mg in each period, with a 7-day washout. Serial blood samples for PK analysis were collected up to 48 hours after a single administration to determine plasma concentrations of DAP-FOR and dapagliflozin. PK parameters were calculated using a non-compartmental method and compared between the two drugs.Results: In total, 28 subjects completed the study. DAP-FOR plasma concentrations were not detected in all of the blood sampling time points except for one time point in one subject, and the corresponding DAP-FOR plasma concentration in the subject was close to the lower limit of quantification. The mean plasma concentration–time profiles of dapagliflozin were comparable between the two drugs. The geometric mean ratios and its 90% confidence intervals of the maximum plasma concentration and area under the plasma concentration–time curve of dapagliflozin for DAP-FOR to DAP-PDH were within the conventional bioequivalence range of 0.80– 1.25. Both drugs were well-tolerated, with a similar incidence of adverse drug reactions.Conclusion: The rapid conversion of DAP-FOR into dapagliflozin led to the extremely low exposure of DAP-FOR and comparable PK profiles of dapagliflozin between DAP-FOR and DAP-PDH. The safety profiles were also similar between the two drugs. These results suggest that DAP-FOR can be used as an alternative to DAP-PDH.Keywords: prodrugs, dapagliflozin, pharmacokinetics, clinical trial, phase I |
