Dynamic population pharmacokinetic-pharmacodynamic modelling and simulation supports similar efficacy in glycosylated haemoglobin response with once or twice-daily dosing of canagliflozin.
Br J Clin Pharmacol
; 83(5): 1072-1081, 2017 05.
Article
em En
| MEDLINE
| ID: mdl-28138980
ABSTRACT
AIM:
Canagliflozin is an SGLT2 inhibitor approved for the treatment of type-2 diabetes. A dynamic population pharmacokinetic-pharmacodynamic (PK/PD) model relating 24-h canagliflozin exposure profiles to effects on glycosylated haemoglobin was developed to compare the efficacy of once-daily and twice-daily dosing.METHODS:
Data from two clinical studies, one with once-daily, and the other with twice-daily dosing of canagliflozin as add-on to metformin were used (n = 1347). An established population PK model was used to predict full 24-h profiles from measured trough concentrations and/or baseline covariates. The dynamic PK/PD model incorporated an Emax relationship between 24-h canagliflozin exposure and HbA1c-lowering with baseline HbA1c affecting the efficacy.RESULTS:
Internal and external model validation demonstrated that the model adequately predicted HbA1c-lowering for canagliflozin once-daily and twice-daily dosing regimens. The differences in HbA1c reduction between the twice-daily and daily mean profiles were minimal (at most 0.023% for 100 mg total daily dose [TDD] and 0.011% for 300 mg TDD, up to week 26, increasing with time and decreasing with TDD) and not considered clinically meaningful.CONCLUSIONS:
Simulations using this model demonstrated the absence of clinically meaningful between-regimen differences in efficacy, supported the regulatory approval of a canagliflozin-metformin immediate release fixed-dose combination tablet and alleviated the need for an additional clinical study.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus Tipo 2
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Canagliflozina
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Hipoglicemiantes
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Modelos Biológicos
Tipo de estudo:
Clinical_trials
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Prognostic_studies
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article