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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:Background and objectiveBrensocatib is an investigational, first-in-class, selective, and reversible dipeptidyl peptidase 1 inhibitor that blocks activation of neutrophil serine proteases (NSPs). The NSPs neutrophil elastase, cathepsin G, and proteinase 3 are believed to be central to the pathogenesis of several chronic inflammatory diseases, including bronchiectasis. In a phase II study, oral brensocatib 10 mg and 25 mg reduced sputum neutrophil elastase activity and prolonged the time to pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis (NCFBE). A population pharmacokinetic (PPK) model was developed to characterize brensocatib exposure, determine potential relationships between brensocatib exposure and efficacy and safety measures, and inform dose selection in clinical studies.MethodsPharmacokinetic (PK) data pooled from a phase I study of once-daily brensocatib (10, 25, and 40 mg) in healthy adults and a phase II study of once-daily brensocatib (10 mg and 25 mg) in adults with NCFBE were used to develop a PPK model and to evaluate potential covariate effects on brensocatib pharmacokinetics. PK-efficacy relationships for sputum neutrophil elastase below the level of quantification (BLQ) and reduction in pulmonary exacerbation and PK-safety relationships for adverse events of special interest (AESIs; periodontal disease, hyperkeratosis, and infections other than pulmonary infections) were evaluated based on model-predicted brensocatib exposure. A total of 1284 steady-state brensocatib concentrations from 225 individuals were included in the PPK data set; 241 patients with NCFBE from the phase II study were included in the pharmacodynamic (PD) population for the PK/PD analyses.ResultsThe PPK model that best described the observed data consisted of two distributional compartments and linear clearance. Two significant covariates were found: age on volume of distribution and renal function on apparent oral clearance. PK-efficacy analysis revealed a threshold brensocatib exposure (area under the concentration-time curve) effect for attaining sputum neutrophil elastase BLQ and a strong relationship between sputum neutrophil elastase BLQ and reduction in pulmonary exacerbations. A PK-safety evaluation showed no noticeable trends between brensocatib exposure and the incidence of AESIs. Based on the predicted likelihood of clinical outcomes for sputum neutrophil elastase BLQ and pulmonary exacerbations, brensocatib doses of 10 mg and 25 mg once daily were selected for a phase III clinical trial in patients with NCFBE (ClinicalTrials.gov identifier: NCT04594369).ConclusionsPPK results revealed that age and renal function have a moderate effect on brensocatib exposure. However, this finding does not warrant dose adjustments based on age or in those with mild or moderate renal impairment. The PK/PD evaluation demonstrated the clinically meaningful relationship between suppression of neutrophil elastase activity and reduction in exacerbations in brensocatib-treated patients with NCFBE, supporting further development of brensocatib for bronchiectasis.

Project description:IntroductionLong-term effectiveness and durability of glucose-lowering medications are important considerations in managing type 2 diabetes (T2D). This study aimed to compare durability of treatment efficacy of once-weekly (OW) semaglutide for T2D with that of the dipeptidyl peptidase 4 inhibitor (DPP-4i) class.MethodsThis observational cohort study used 2017-2022 data from the Optum® Clinformatics® Data Mart to compare long-term clinical outcomes associated with semaglutide or DPP-4i in US adults with T2D. The primary outcomes were HbA1c at 2-year follow-up, change in HbA1c from baseline, and the odds of achieving HbA1c targets. BMI at 2-year follow-up, change in BMI from baseline, odds of reducing BMI category, and the need for treatment augmentation were exploratory outcomes. Bivariate and multivariate analyses were conducted using inverse probability of treatment weighting (IPTW) weighted descriptive statistics.ResultsWeighted HbA1c and BMI cohorts included 865 and 642 semaglutide users and 779 and 537 DPP-4i users, respectively. In the weighted HbA1c cohort, semaglutide and DPP-4i users had an average age of 60 years and similar baseline characteristics including HbA1c level and comorbidity status. Two-year follow-up HbA1c with semaglutide was 0.56% lower than with DPP-4i; reduction in HbA1c from baseline was 0.61% greater. Odds of achieving HbA1c level < 7% were 2.16 times greater after covariate adjustment (all, p < 0.001). Semaglutide was associated with 1.03 kg/m2 greater reduction in BMI and 2.27 times greater odds of reducing BMI category vs DPP-4i (p < 0.001). Semaglutide users were less likely to add new glucose-lowering treatment (hazard ratio [HR] 0.57; p < 0.001) or initiate insulin (HR 0.49; p < 0.001) vs DPP-4i users.ConclusionCompared with DPP-4i, semaglutide was associated with lower follow-up HbA1c and BMI, greater reduction in HbA1c and BMI from baseline, and reduced likelihood of requiring treatment augmentation or insulin initiation to manage T2D in US adults, suggesting better durability of semaglutide vs DPP-4i. INFOGRAPHIC.

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.

Similar Datasets

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