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Pharmacokinetic-pharmacodynamic modeling of the antihypertensive interaction between azilsartan medoxomil and chlorthalidone in spontaneously hypertensive rats

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Abstract

A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of blood pressure following oral administration of azilsartan medoxomil (AZM) and/or chlorthalidone (CLT) in spontaneously hypertensive (SH) rats. The drug concentration and pharmacological effects, including systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tail-cuff manometry, respectively. Sequential PK-PD analysis was performed, wherein the plasma concentration-time data was modeled by one compartmental analysis. Subsequently PD parameters were calculated to describe the time-concentration-response relationship using indirect response (IDR) PK-PD model. The combination of AZ and CLT had greater BP lowering effect compared to AZ or CLT alone, despite of no pharmacokinetic interaction between two drugs. These findings suggest synergistic antihypertensive pharmacodynamic interaction between AZ and CLT noncompetitively, which was simulated by inhibitory function of AZ and stimulatory function of CLT after concomitant administration of the two drugs. The present model was able to capture the turnover of blood pressure adequately at different time points at two different dose levels. The current PK-PD model was successfully utilized in the simulation of PD effect at a dose combination of 0.5 and 2.5 mg/kg for AZ and CLT, respectively. The developed preclinical PK-PD model may provide guidance in the optimization of dose ratio of individual drugs in the combined pharmacotherapy of AZ and CLT at clinical situations.

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Acknowledgements

The authors are thankful to the Director, CDRI, for providing facilities and infrastructure for the study. Authors SKP, RR, MB, and MJ are also thankful to the Council of Scientific and Industrial Research (CSIR) for providing fellowship and CSIR research grant through THUNDER project (BSC-1012). CSIR-CDRI communication number for this manuscript is: 9418.

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Authors and Affiliations

  1. Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India

    Santosh Kumar Puttrevu, Rachumallu Ramakrishna, Manisha Bhateria & Rabi Sankar Bhatta

  2. Academy of Scientific and Innovative Research, New Delhi, 110001, India

    Santosh Kumar Puttrevu, Rachumallu Ramakrishna, Manisha Bhateria, Moon Jain, Kashif Hanif & Rabi Sankar Bhatta

  3. Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    Moon Jain & Kashif Hanif

Authors
  1. Santosh Kumar Puttrevu
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  2. Rachumallu Ramakrishna
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  3. Manisha Bhateria
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  4. Moon Jain
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  5. Kashif Hanif
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  6. Rabi Sankar Bhatta
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Corresponding author

Correspondence to Rabi Sankar Bhatta.

Ethics declarations

All the experimental procedures were approved by the Institutional Animal Ethics Committee (IAEC) of CSIR-CDRI [IAEC approval no. IAEC/2011/21/Renew-4 (102/15)]. All the animal experiments were performed according to IAEC approved guidelines and regulations.

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The authors declare that they have no conflict of interest.

Additional information

Santosh Kumar Puttrevu, Rachumallu Ramakrishna, and Manisha Bhateria contributed equally to this work.

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Kumar Puttrevu, S., Ramakrishna, R., Bhateria, M. et al. Pharmacokinetic-pharmacodynamic modeling of the antihypertensive interaction between azilsartan medoxomil and chlorthalidone in spontaneously hypertensive rats. Naunyn-Schmiedeberg's Arch Pharmacol 390, 457–470 (2017). https://doi.org/10.1007/s00210-017-1339-6

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  • DOI: https://doi.org/10.1007/s00210-017-1339-6

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