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Population Pharmacokinetic Modeling of Canagliflozin in Healthy Volunteers and Patients with Type 2 Diabetes Mellitus

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Abstract

Background and Objectives

Canagliflozin is an orally active, reversible, selective sodium-glucose co-transporter-2 inhibitor. A population pharmacokinetic (popPK) model of canagliflozin, including relevant covariates as sources of inter-individual variability, was developed to describe phase I, II, and III data in healthy volunteers and in patients with type 2 diabetes mellitus (T2DM).

Methods

The final analysis included 9061 pharmacokinetic (PK) samples from 1616 volunteers enrolled in nine phase I, two phase II, and three phase III studies and was performed using NONMEM® 7.1. Inter-individual variability was evaluated using an exponential model and the residual error model was additive in the log domain. The first-order conditional estimation method with interaction was applied and the model was parameterized in terms of rate constants. Covariate effects were explored graphically on empirical Bayes estimates of PK parameters, as shrinkage was low. Clinical relevance of statistically significant covariates was evaluated. The predictive properties of the model were illustrated by prediction-corrected visual predictive checks.

Results

A two-compartment PK model with lag-time and sequential zero- and first-order absorption and first-order elimination best described the observed data. Sex, age, and weight on apparent volume of distribution of the central compartment, body mass index on first-order absorption rate constant, and body mass index and over-encapsulation on lag-time, and estimated glomerular filtration rate (eGFR, by MDRD equation), dose, and genetic polymorphism (carriers of UGT1A9*3 allele) on elimination rate constant were identified as statistically significant covariates. The prediction-corrected visual predictive checks revealed acceptable predictive performance of the model.

Conclusion

The popPK model adequately described canagliflozin PK in healthy volunteers and in patients with T2DM. Because of the small magnitude of statistically significant covariates, they were not considered clinically relevant. However, dosage adjustments are recommended for T2DM patients with renal impairment (eGFR ≥60 mL/min/1.73 m2: 100 or 300 mg/day; eGFR of 45 to <60 mL/min/1.73 m2: 100 mg/day).

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Acknowledgments

The authors are most grateful to the study volunteers for their contributions and to the investigational staff for the medical care. The authors acknowledge Hans Stieltjes for the skillful determination of plasma concentrations of canagliflozin, Nicole Vaccaro for her contribution to the protocol designs, Ashwini Patil (SIRO Clinpharm Pvt. Ltd.) for assistance in preparation of the manuscript (funded by Janssen Research and Development, LLC), and Bradford Challis (Janssen Research and Development, LLC) for additional editorial support. The research was funded entirely by Janssen Research and Development. All authors are employees of Janssen Research and Development and own stock and/or stock options in the company. Canagliflozin is being developed by Janssen Research and Development, LLC, in collaboration with the Mitsubishi Tanabe Pharma Corporation.

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Authors and Affiliations

  1. Model Based Drug Development, Quantitative Sciences, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse, 2340, Belgium

    Eef Hoeben, Willem De Winter, Martine Neyens, An Vermeulen & Adrian Dunne

  2. Clinical Pharmacology, Quantitative Sciences, Janssen Research and Development LLC, Raritan, NJ, USA

    Damayanthi Devineni

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  1. Eef Hoeben
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  2. Willem De Winter
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  3. Martine Neyens
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  4. Damayanthi Devineni
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  5. An Vermeulen
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  6. Adrian Dunne
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Correspondence to Eef Hoeben.

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Hoeben, E., De Winter, W., Neyens, M. et al. Population Pharmacokinetic Modeling of Canagliflozin in Healthy Volunteers and Patients with Type 2 Diabetes Mellitus. Clin Pharmacokinet 55, 209–223 (2016). https://doi.org/10.1007/s40262-015-0307-x

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