A PK/PD study comparing twice-daily to 
once-daily dosing regimens of ertugliflozin in healthy subjects

• Published in: International journal of clinical pharmacology and therapeutics Vol. 57; no. 4; pp. 207 - 216
• Main Authors: Dawra, Vikas Kumar, Liang, Yali, Shi, Haihong, Bass, Almasa, Hickman, Anne, Terra, Steven G., Zhou, Susan, Cutler, David, Sahasrabudhe, Vaishali
• Format: Journal Article
• Language: English
• Published: Germany Dustri - Verlag Dr. Karl Feistle GmbH & Co. KG 01.04.2019; Dustri-Verlag Dr. Karl Feistle
• Subjects: Adolescent; Adult; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Cross-Over Studies; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Drug dosages; FDA approval; Female; Food; Glucose; Healthy Volunteers; Humans; Male; Metformin; Middle Aged; Pharmacology; Sodium-Glucose Transporter 2 Inhibitors - administration & dosage; Sodium-Glucose Transporter 2 Inhibitors - pharmacokinetics; Studies; Urine; Young Adult
• ISSN: 0946-1965
• DOI: 10.5414/CP203343

Ertugliflozin is approved in the US and European Union as a stand-alone product for adults with type 2 diabetes mellitus as once daily (QD) dosing. The approved fixed-dose combination (FDC) of ertugliflozin and immediate-release metformin is dosed twice daily (BID). This study assessed steady-state pharmacokinetics (PK; area under the concentration-time curve over 24 hours (AUC )) and pharmacodynamics (PD; urinary glucose excretion over 24 hours (UGE )) for ertugliflozin 5 and 15 mg total daily doses administered BID or QD. In this open-label, two-cohort, randomized, multiple-dose, crossover study, healthy subjects received ertugliflozin 2.5 mg BID and 5 mg QD (n = 28) or ertugliflozin 7.5 mg BID and 15 mg QD (n = 22) for 6 days. Plasma and urine samples were collected for 24 hour post morning dose on day 6 in each period. The geometric mean ratio (GMR) (90% CI) of ertugliflozin AUC was 100.8% (98.8%, 102.8%) for 2.5 mg BID vs. 5 mg QD, and 99.7% (97.1%, 102.5%) for 7.5 mg BID vs. 15 mg QD. GMR (90% CI) of UGE for BID vs. QD administration was 110.2% (103.0%, 117.9%) at a total daily dose of 5 mg, and 102.8% (97.7%, 108.1%) at 15 mg. The 90% CIs of the GMR of AUC and UGE for BID vs. QD dosing were within the acceptance range for equivalence (80 - 125%) and the prespecified criterion for similarity (70 - 143%), respectively. All treatments were well tolerated. There are no clinically meaningful differences in steady-state PK or PD between ertugliflozin BID and QD regimens at total daily doses of 5 and 15 mg, supporting BID administration of ertugliflozin as a component of the ertugliflozin/metformin (immediate-release) FDC.