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Population Pharmacokinetic-Pharmacodynamic Modelling of 24-h Diastolic Ambulatory Blood Pressure Changes Mediated by Axitinib in Patients with Metastatic Renal Cell Carcinoma

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Abstract

Background

Increased blood pressure (BP) is commonly observed in patients treated with vascular endothelial growth factor pathway inhibitors, including axitinib. Ambulatory BP monitoring (ABPM) and pharmacokinetic data were collected in a randomised, double-blind phase II study of axitinib with or without dose titration in previously untreated patients with metastatic renal cell carcinoma.

Objective

Aims of these analyses were to (1) develop a population pharmacokinetic-pharmacodynamic model for describing the relationship between axitinib exposure and changes in diastolic BP (dBP) and (2) simulate changes in dBP with different axitinib dosing regimens.

Methods

We employed a three-stage modelling approach, which included development of (1) a baseline 24-h ABPM model, (2) a pharmacokinetic model from serial and sparse pharmacokinetic data, and (3) an indirect-response, maximum-effect (E max) model to evaluate the exposure-driven effect of axitinib on dBP. Simulations (N = 1,000) were performed using the final pharmacokinetic-pharmacodynamic model to evaluate dBP changes on days 4 and 15 of treatment with different axitinib doses.

Results

Baseline ABPM data from 62 patients were best described by 24-h mean dBP and two cosine terms. The final indirect-response E max model showed good agreement between observed 24-h ABPM data and population and individual predictions. The maximum increase in dBP was 20.8 %, and the axitinib concentration at which 50 % of the maximal increase in dBP was reached was 12.4 ng/mL.

Conclusion

Our model adequately describes the relationship between axitinib exposure and dBP increases. Results from these analyses may potentially be applied to infer dBP changes in patients administered axitinib at nonstandard doses.

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Acknowledgments

This study was sponsored by Pfizer Inc. The study sponsor was involved in trial design, and the collection and analysis of data. Medical writing support was provided by Joanna Bloom, PhD, and Helen Jones, PhD, of Engage Scientific Solutions, and was funded by Pfizer Inc. We thank Ana Ruiz, PharmD, PhD, of Pfizer Inc. and Jing Wang, PhD, and Vaishnavi Ganti, PhD, for their contribution to the development of the pharmacokinetic-pharmacodynamic analyses.

Conflict of interest disclosures

YC, AHB, GMM and YKP are employees of and own stock in Pfizer Inc. BIR has served as an advisor for and received research funding from Pfizer Inc. The authors have full control of the primary data and agree to allow the journal to review their data if required.

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Authors and Affiliations

  1. Pfizer Oncology, Clinical Pharmacology, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA

    Ying Chen, Angel H. Bair, Ganesh M. Mugundu & Yazdi K. Pithavala

  2. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA

    Brian I. Rini

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  1. Ying Chen
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  2. Brian I. Rini
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Correspondence to Ying Chen.

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Chen, Y., Rini, B.I., Bair, A.H. et al. Population Pharmacokinetic-Pharmacodynamic Modelling of 24-h Diastolic Ambulatory Blood Pressure Changes Mediated by Axitinib in Patients with Metastatic Renal Cell Carcinoma. Clin Pharmacokinet 54, 397–407 (2015). https://doi.org/10.1007/s40262-014-0207-5

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  • DOI: https://doi.org/10.1007/s40262-014-0207-5

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