Pharmacokinetics and Safety of DS-8500a, an Antidiabetic Drug, in Japanese Subjects with Hepatic or Renal Impairment: A Single-Center, Open-Label, Single-Dose Study
- 59 Downloads
The pharmacokinetics, safety, and tolerability of DS-8500a (a G protein receptor 119 agonist) up to 100 mg have been investigated in healthy Japanese adults. The objective of this study was to evaluate the effects of hepatic or renal impairment on the pharmacokinetics of a single 25-mg oral dose of DS-8500a.
This single-center, open-label study enrolled subjects into eight groups according to hepatic function (normal; mild or moderate impairment) and renal function [normal; mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]. Drug concentrations were measured by liquid-chromatography tandem mass spectrometry. Pharmacokinetic parameters were evaluated by non-compartmental analysis. Adverse events (AEs) were evaluated for safety.
The hepatic and renal groups enrolled 15 and 30 subjects, respectively. Pharmacokinetic parameters of DS-8500a were comparable between the normal hepatic function and mild hepatic impairment groups, but the mean area under the concentration–time curve (AUC) was 1.37-fold higher, and the half-life was longer in the moderate hepatic impairment group compared with the normal hepatic function group. The maximum concentration (Cmax) and AUC values were 0.704- and 0.609-fold lower, respectively, in the ESRD group compared with the values in the other renal impairment groups; no clear differences in AUC and time to Cmax were observed in the normal function and mild, moderate, and severe renal impairment groups. There was no relationship between apparent total body clearance and estimated glomerular filtration rate. The incidence of AEs was similar among all groups.
DS-8500a exposure in the mild hepatic impairment and mild to severe renal impairment groups was similar to that in the corresponding normal hepatic and renal function groups, but dose adjustments may be required in those with moderate hepatic impairment and ESRD.
Japic CTI-No. 163135.
Daiichi Sankyo Co. Ltd., Tokyo, Japan.
KeywordsDiabetes DS-8500a Hepatic impairment Pharmacokinetics Renal impairment Safety
The authors wish to thank the participants of the study. The authors also wish to thank Tsunenori Nakazawa for providing support with the bioanalysis of this study; and Yoshitake Furuta, Yoko Urasaki, and Nobuaki Watanabe, PhD, for assisting with the plasma protein binding ratio analysis of DS-8500a.
Sponsorship for this study and article processing charges were funded by Daiichi Sankyo Co. Ltd., Tokyo, Japan. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Medical Writing and Editorial Assistance
The authors wish to thank Michelle Belanger, MD, of Edanz Medical Writing for providing medical writing assistance, which was funded by Daiichi Sankyo Co., Ltd.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Manabu Kato was responsible for conception and design of the work and acquisition and interpretation of data. Hitoshi Ishizuka was responsible for conception and design of the work and interpretation of data. Takashi Taguchi was responsible for conception of the work and interpretation of data. Kazuhito Shiosakai and Emi Kamiyama were responsible for design of the work and analysis and interpretation of data. Michio Sata and Takafumi Yoshida were responsible for acquisition of data.
Manabu Kato is an employee of Daiichi Sankyo Co., Ltd. Hitoshi Ishizuka is an employee of Daiichi Sankyo Co., Ltd. Takashi Taguchi is an employee of Daiichi Sankyo Co., Ltd. Kazuhito Shiosakai is an employee of Daiichi Sankyo Co., Ltd. Emi Kamiyama is an employee of Daiichi Sankyo Co., Ltd. Michio Sata and Takafumi Yoshida have nothing to disclose.
Compliance with Ethics Guidelines
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. The study received institutional review board approval and all participants provided written informed consent.
The datasets generated during and/or analyzed during the current study are not publicly available, because the sponsor has the rights to the data generated in this study. However, datasets are available from the corresponding author on reasonable request.
- 1.Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol (Lausanne). 2013;4:37.Google Scholar
- 8.U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for industry pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. 2003. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072123.pdf. Accessed Feb 6, 2018.
- 9.U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling. 2010. https://www.fda.gov/downloads/drugs/guidances/ucm204959.pdf. Accessed Feb 6, 2018.
- 11.European Medicines Agency. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function. 2015. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/02/WC500200841.pdf. Accessed May 30, 2018.
- 15.Dreisbacha AW, Flessner MF. Drug metabolism and chronic kidney disease. In: Kimmel PL, Rosenberg ME, editors. Chronic renal disease. California: Academic; 2015. p. 674–81. https://doi.org/10.1016/B978-0-12-411602-3.00055-X.