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Pharmacokinetic-pharmacodynamic (dipeptidyl peptidase-4 inhibition) model to support dose rationale in diabetes patients, including those with renal impairment, for once-weekly administered omarigliptin.

ABSTRACT: AIMS:To characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of the once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin in healthy subjects and patients with type 2 diabetes mellitus, and use these models to support the dosing recommendation for patient labelling including patients with renal impairment. METHODS:PK and PD were assessed from a total of 9827 omarigliptin concentrations collected from 1387 healthy subjects and patients participating in Phase 1, 2 and 3 studies examining single- or multiple-dose weekly administration of omarigliptin at doses ranging from 0.25 to 400 mg. Population PK and PD analyses were performed using nonlinear mixed effect modelling. RESULTS:A semi-mechanistic 2-compartment model with linear unbound clearance and concentration-dependent binding of omarigliptin to the DPP-4 enzyme in both the central and peripheral compartments adequately described omarigliptin PK. Key covariates on omarigliptin PK included reduced unbound clearance with renal impairment. A direct effect sigmoid maximum inhibitory efficacy model adequately described the relationship between omarigliptin plasma concentrations and DPP-4 inhibition. These models supported the current Japan label instructions that the approved omarigliptin 25-mg once-weekly dose be halved in patients with severe renal impairment and in those with end-stage renal disease. Also, if patients missed a dose, the next dose of omarigliptin should be taken as soon as remembered up to and including the day before the next scheduled dose. No other clinically important covariates were identified. CONCLUSION:The models in the present analysis adequately described PK and PD characteristics of omarigliptin and supported the dosing and administration section of the omarigliptin label.

SUBMITTER: Jain L

PROVIDER: S-EPMC6955405 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Pharmacokinetic-pharmacodynamic (dipeptidyl peptidase-4 inhibition) model to support dose rationale in diabetes patients, including those with renal impairment, for once-weekly administered omarigliptin.

Jain Lokesh L Chain Anne S Y ASY Tatosian Daniel A DA Hing Jeremy J Passarell Julie A JA Kauh Eunkyung A EA Lai Eseng E

British journal of clinical pharmacology 20191209 12

<h4>Aims</h4>To characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of the once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin in healthy subjects and patients with type 2 diabetes mellitus, and use these models to support the dosing recommendation for patient labelling including patients with renal impairment.<h4>Methods</h4>PK and PD were assessed from a total of 9827 omarigliptin concentrations collected from 1387 healthy subjects and patients participati ...[more]

PMID: 31454094

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Project description:IntroductionDipeptidyl peptidase-4 (DPP-4) inhibitors are an established treatment in type 2 diabetes mellitus (T2DM). The objective of this study was to investigate differences in quality of life (QOL) and treatment satisfaction among treatment-naïve T2DM patients receiving once-weekly trelagliptin or a daily DPP-4 inhibitor.MethodsIn this multicenter, randomized, open-label, parallel-group, phase IV study conducted in Japan, 218 patients were randomized to trelagliptin 100 mg once weekly or a once- or twice-daily DPP-4 inhibitor for 12 weeks (NCT03014479; JapicCTI-173482). QOL and treatment satisfaction were assessed using the Diabetes Therapy-Related QOL (DTR-QOL) Questionnaire and Diabetes Treatment Satisfaction Questionnaire (DTSQ), respectively. The primary endpoint was change from baseline in DTR-QOL total score at week 12. Secondary endpoints included further analysis of the DTR-QOL and DTSQ components. Other endpoints included glycemic control, treatment adherence, and safety.ResultsThe between-group difference in the change from baseline to week 12 in DTR-QOL total score was 2.418 (95% confidence interval - 1.546, 6.382; P = 0.2305). Analysis of the DTR-QOL and DTSQ results by subscales and stratification generally showed a numerical improvement with trelagliptin over daily DPP-4 inhibitors. QOL and treatment satisfaction improved with a reduction in frequency of concurrent and study drug dosing. Treatment adherence was > 97% for both groups. The effect of trelagliptin on glycemic control was similar to that seen with daily DPP-4 inhibitors. Trelagliptin and daily DPP-4 inhibitors were well-tolerated and demonstrated similar safety profiles.ConclusionsOnce-weekly trelagliptin 100 mg administered for 12 weeks resulted in a numerically, but not statistically, greater improvement in QOL and treatment satisfaction versus daily DPP-4 inhibitors. The decision to administer once-weekly or daily DPP-4 inhibitor treatment is likely to depend on patient preferences and the treatment policies of physicians.Trial registrationClinicalTrials.gov (NCT03014479) and JAPIC (JapicCTI-173482).FundingTakeda Pharmaceutical Company Ltd.

Dataset Information

Pharmacokinetic-pharmacodynamic (dipeptidyl peptidase-4 inhibition) model to support dose rationale in diabetes patients, including those with renal impairment, for once-weekly administered omarigliptin.

Publications

Pharmacokinetic-pharmacodynamic (dipeptidyl peptidase-4 inhibition) model to support dose rationale in diabetes patients, including those with renal impairment, for once-weekly administered omarigliptin.

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