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Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, on the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects.
Clin Drug Investig. 2019 Oct; 39(10):967-978.CD

Abstract

BACKGROUND

Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice.

OBJECTIVE

To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults.

METHODS

We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated.

RESULTS

In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs.

CONCLUSIONS

Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS.

GOV IDENTIFIER

NCT03699774.

JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER

JapicCTI-152878.

Authors+Show Affiliations

Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan. maekawa.yutaro.jb@daiichisankyo.co.jp.Osaka Pharmacology Clinical Research Hospital, Medical Corporation Heishinkai, Osaka, Japan.Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.Worldwide Clinical Trials, San Antonio, TX, USA.Daiichi Sankyo Inc., Basking Ridge, NJ, USA.Daiichi Sankyo Inc., Basking Ridge, NJ, USA. Janssen Research and Development, Raritan, NJ, USA.Daiichi Sankyo Inc., Basking Ridge, NJ, USA. Phase 1 Solutions, LLC, Union, NJ, USA.Daiichi Sankyo Inc., Basking Ridge, NJ, USA.Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.

Pub Type(s)

Clinical Trial
Journal Article

Language

eng

PubMed ID

31321631

Citation

Maekawa, Yutaro, et al. "Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, On the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects." Clinical Drug Investigation, vol. 39, no. 10, 2019, pp. 967-978.
Maekawa Y, Furuie H, Kato M, et al. Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, on the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects. Clin Drug Investig. 2019;39(10):967-978.
Maekawa, Y., Furuie, H., Kato, M., Myobatake, Y., Kamiyama, E., Watanabe, A., Shiosakai, K., Taguchi, T., Bass, R., Zhou, J., Dishy, V., Warren, V., Vashi, V., & Ishizuka, H. (2019). Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, on the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects. Clinical Drug Investigation, 39(10), 967-978. https://doi.org/10.1007/s40261-019-00825-1
Maekawa Y, et al. Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, On the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects. Clin Drug Investig. 2019;39(10):967-978. PubMed PMID: 31321631.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, on the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects. AU - Maekawa,Yutaro, AU - Furuie,Hidetoshi, AU - Kato,Manabu, AU - Myobatake,Yusuke, AU - Kamiyama,Emi, AU - Watanabe,Akiko, AU - Shiosakai,Kazuhito, AU - Taguchi,Takashi, AU - Bass,Robert, AU - Zhou,Jin, AU - Dishy,Victor, AU - Warren,Vance, AU - Vashi,Vijay, AU - Ishizuka,Hitoshi, PY - 2019/7/20/pubmed PY - 2019/12/24/medline PY - 2019/7/20/entrez SP - 967 EP - 978 JF - Clinical drug investigation JO - Clin Drug Investig VL - 39 IS - 10 N2 - BACKGROUND: Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. OBJECTIVE: To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. METHODS: We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. RESULTS: In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. CONCLUSIONS: Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS. GOV IDENTIFIER: NCT03699774. JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER: JapicCTI-152878. SN - 1179-1918 UR - https://www.unboundmedicine.com/medline/citation/31321631/Effect_of_DS_8500a_a_Novel_G_Protein_Coupled_Receptor_119_Agonist_on_the_Pharmacokinetics_of_Rosuvastatin_and_Atorvastatin_in_Healthy_Subjects_ L2 - https://dx.doi.org/10.1007/s40261-019-00825-1 DB - PRIME DP - Unbound Medicine ER -