Application of pharmacometric approaches to evaluate effect of weight and renal function on pharmacokinetics of alogliptin

Dec 1, 2015British journal of clinical pharmacology

Using drug analysis methods to study how body weight and kidney function affect alogliptin levels in the body

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Abstract

A two-compartment model predicts a 17% to 339% increase in systemic exposure of alogliptin in patients with renal impairment compared to healthy subjects.

Creatinine clearance significantly affects the oral clearance of alogliptin.
Subjects with mild, moderate, and severe renal impairment had lower alogliptin clearance of 17%, 35%, and 80%, respectively.
Systemic exposure to alogliptin increased by 56%, 89%, and 339% in subjects with mild, moderate, and severe renal impairment.
Weight was found to have no clinically relevant impact on alogliptin clearance.
Simulations support the approved doses of 12.5 mg and 6.25 mg for patients with moderate and severe renal impairment, respectively.

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AIMS: The aims of the study were to characterize the pharmacokinetics (PK) of alogliptin in healthy and type 2 diabetes mellitus (T2DM) subjects using a population PK approach and to assess the influence of various covariates on alogliptin exposure.

METHODS: Plasma concentration data collected from two phase 1 studies and one phase 3 study following administration of alogliptin (12.5-400 mg) were used for the PK model development. One- and two-compartment models were evaluated as base structural PK models. The impact of selected covariates was assessed using stepwise forward selection and backward elimination procedures. The predictability and robustness of the final model was evaluated using visual predictive check and bootstrap analyses. The final model was used to perform simulations and guide appropriate dose adjustments.

RESULTS: A two-compartment model with first-order absorption and elimination best described the alogliptin concentration vs. time profiles. Creatinine clearance and weight had a statistically significant effect on the oral clearance (CL/F) of alogliptin. The model predicted a lower CL/F (17%, 35%, 80%) and a higher systemic exposure (56%, 89%, 339%) for subjects with mild, moderate and severe renal impairment, respectively, compared with healthy subjects. Effect of weight on CL/F was not considered clinically relevant. Simulations at different doses of alogliptin support the approved doses of 12.5 mg and 6.25 mg for patients with moderate and severe renal impairment, respectively.

CONCLUSIONS: The PK of alogliptin was well characterized by the model. The analysis suggested an alogliptin dose adjustment for subjects with moderate-to-severe renal impairment and no dose adjustments based on weight.

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Application of pharmacometric approaches to evaluate effect of weight and renal function on pharmacokinetics of alogliptin

Abstract

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