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

Vikas Kumar Dawra, Yali Liang, Haihong Shi, Almasa Bass, Anne Hickman, Steven G Terra, Susan Zhou, David Cutler, Vaishali Sahasrabudhe, Vikas Kumar Dawra, Yali Liang, Haihong Shi, Almasa Bass, Anne Hickman, Steven G Terra, Susan Zhou, David Cutler, Vaishali Sahasrabudhe

Abstract

Objective: 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 (AUC24)) and pharmacodynamics (PD; urinary glucose excretion over 24 hours (UGE24)) for ertugliflozin 5 and 15 mg total daily doses administered BID or QD.

Materials and methods: 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.

Results: The geometric mean ratio (GMR) (90% CI) of ertugliflozin AUC24 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 UGE24 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 AUC24 and UGE24 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.

Conclusion: 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.

Figures

Figure 1.. Median plasma ertugliflozin concentration-time profiles…
Figure 1.. Median plasma ertugliflozin concentration-time profiles on day 6 after multiple QD or BID oral doses. A: Ertugliflozin 2.5 mg BID/5 mg QD. B: Ertugliflozin 7.5 mg BID/15 mg QD. BID = twice daily; QD = once daily.
Figure 2.. Mean ± SD UGE vs.…
Figure 2.. Mean ± SD UGE vs. time intervals for (A) ertugliflozin 2.5 mg BID/5 mg QD and (B) ertugliflozin 7.5 mg BID/15 mg QD. BID = twice daily; QD = once daily; SD = standard deviation; UGE = urinary glucose excretion.

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Source: PubMed

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