rifampin and dapagliflozin

This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin.

Topics: Administration, Oral; Adolescent; Antibiotics, Antitubercular; Area Under Curve; Benzhydryl Compounds; Child; Child, Preschool; Computer Simulation; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Female; Glucosides; Glucuronosyltransferase; Healthy Volunteers; Hepatic Insufficiency; Humans; Infant; Infant, Newborn; Male; Mefenamic Acid; Models, Biological; Predictive Value of Tests; Renal Insufficiency; Rifampin; Sodium-Glucose Transporter 2 Inhibitors; UDP-Glucuronosyltransferase 1A9

Dapagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that decreases serum glucose by reducing renal glucose reabsorption, thereby promoting urinary glucose excretion. Dapagliflozin is primarily metabolized via the uridine diphosphate-glucuronosyltransferase (UGT)1A9 pathway to its major inactive metabolite, dapagliflozin 3-O-glucuronide. The aim of this study was to evaluate the potential for drug-drug interaction between dapagliflozin and two potential UGT1A9 modulators.. The results of two open-label, non-randomized, single-sequence studies are reported in which the effects of rifampin (a pleiotropic drug-metabolizing enzyme inducer; study 1) and mefenamic acid (a strong UGT1A9 inhibitor; study 2) were evaluated on the pharmacokinetics and pharmacodynamics (assessed by urinary glucose excretion [UGE]) of dapagliflozin in healthy subjects. In study 1, 14 subjects received single doses of dapagliflozin 10 mg alone and in the presence of rifampin 600 mg QD (6 days). In study 2, 16 subjects received single doses of dapagliflozin 10 mg alone and in the presence of mefenamic acid 250 mg q6h (5 days).. Rifampin reduced total exposure (area under the concentration-time curve from time 0 to infinity [AUC0-inf]) to dapagliflozin by 22% and mefenamic acid increased dapagliflozin AUC0-inf by 51%. No clinically meaningful effect of rifampin or mefenamic acid on the pharmacokinetics of dapagliflozin or on dapagliflozin-mediated urinary glucose excretion was observed.. Modest changes in dapagliflozin exposure were seen with rifampin and mefenamic acid with minor changes in UGE, none of which were considered clinically meaningful.

Topics: Adolescent; Adult; Benzhydryl Compounds; Body Mass Index; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Female; Glucosides; Glucuronosyltransferase; Humans; Hypoglycemic Agents; Male; Mefenamic Acid; Middle Aged; Rifampin; Signal Transduction; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; UDP-Glucuronosyltransferase 1A9