Pharmacokinetics of Single-dose Ertugliflozin in Patients With Hepatic Impairment
| Autor: | Anne Hickman, Susan Zhou, Didier Saur, Steven G. Terra, David L. Cutler, Vaishali Sahasrabudhe, Kyle Matschke, Sangeeta Raje, Haihong Shi |
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| Rok vydání: | 2018 |
| Předmět: |
Male
medicine.medical_specialty Cmax 030209 endocrinology & metabolism 030226 pharmacology & pharmacy Gastroenterology Excretion 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Internal medicine Humans Medicine media_common.cataloged_instance Pharmacology (medical) Dosing European union Adverse effect Sodium-Glucose Transporter 2 Inhibitors media_common Pharmacology business.industry Liver Diseases Middle Aged Bridged Bicyclo Compounds Heterocyclic Diabetes Mellitus Type 2 Tolerability Area Under Curve Female business Body mass index |
| Zdroj: | Clinical Therapeutics. 40:1701-1710 |
| ISSN: | 0149-2918 |
| Popis: | Purpose Ertugliflozin, an oral, highly selective inhibitor of the sodium-glucose cotransporter 2, is approved in the United States and the European Union for the treatment of adults with type 2 diabetes mellitus. Hepatic impairment may affect, to varying degrees, the absorption, metabolism, and excretion of drugs and may be associated with a lower plasma protein binding compared with that in healthy individuals. This study was conducted to assess the effect of hepatic impairment on the pharmacokinetic (PK), safety, and tolerability profiles of ertugliflozin after administration of a single, 15-mg oral dose. Methods This was a Phase I, open-label, single-dose study in healthy individuals (n = 8) and those with moderate hepatic impairment (n = 8). Eligible participants were men or women aged 18 to 75 years with a body mass index of 18.0 to 40.5 kg/m2. Healthy individuals had normal hepatic function; patients with hepatic impairment had a Child-Pugh score of 7 to 9 points (moderate hepatic impairment). Blood samples were collected before dosing and during 96 hours after dosing for evaluation of PK parameters. Adverse events were monitored throughout the study. Findings The adjusted least squares geometric mean ratios for total ertugliflozin AUC0–∞ and Cmax in patients with moderate hepatic impairment compared with healthy individuals were 87.4% (90% CI, 68.1%–112.2%) and 78.7% (90% CI, 65.7%–94.2%), respectively. The AUC0–∞ and Cmax for unbound ertugliflozin were also similar between patients with moderate hepatic impairment and healthy individuals. Mean half-life estimates for ertugliflozin were similar (14.6 vs 13.8 hours) in patients with moderate hepatic impairment and healthy individuals. The number of participants with all-causality treatment-emergent adverse events was similar for both groups (2 of 8 patients with moderate hepatic impairment and 3 of 8 healthy individuals). Implications Moderate hepatic impairment had no clinically relevant effect on the PK and safety profiles of ertugliflozin. The results of this study support a recommendation for no dose adjustment of ertugliflozin in patients with mild or moderate hepatic impairment. Ertugliflozin was well tolerated when administered to healthy individuals and patients with moderate hepatic impairment. ClinicalTrials.gov identifier: NCT02115347. |
| Databáze: | OpenAIRE |
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