Pharmacokinetic-pharmacodynamic (dipeptidyl peptidase-4 inhibition) model to support dose rationale in diabetes patients, including those with renal impairment, for once-weekly administered omarigliptin.
Br J Clin Pharmacol
; 85(12): 2759-2771, 2019 12.
Article
en En
| MEDLINE
| ID: mdl-31454094
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.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Piranos
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Diabetes Mellitus Tipo 2
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Insuficiencia Renal
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Inhibidores de la Dipeptidil-Peptidasa IV
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Compuestos Heterocíclicos con 2 Anillos
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Hipoglucemiantes
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Fallo Renal Crónico
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Modelos Biológicos
Tipo de estudio:
Guideline
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Prognostic_studies
Idioma:
En
Revista:
Br J Clin Pharmacol
Año:
2019
Tipo del documento:
Article