title: Pharmacokinetic-pharmacodynamic modeling of the antihypertensive interaction between azilsartan medoxomil and chlorthalidone in spontaneously hypertensive rats.
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.
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.|Academy of Scientific and Innovative Research, New Delhi, 110001, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar Puttrevu
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.|Academy of Scientific and Innovative Research, New Delhi, 110001, India.
authors.forename: Rachumallu
authors.initials: R
authors.lastname: Ramakrishna
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.|Academy of Scientific and Innovative Research, New Delhi, 110001, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Bhateria
authors.affiliation: Academy of Scientific and Innovative Research, New Delhi, 110001, India.|Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Moon
authors.initials: M
authors.lastname: Jain
authors.affiliation: Academy of Scientific and Innovative Research, New Delhi, 110001, India.|Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors.forename: Kashif
authors.initials: K
authors.lastname: Hanif
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. rabi_bhatta@cdri.res.in.|Academy of Scientific and Innovative Research, New Delhi, 110001, India. rabi_bhatta@cdri.res.in.
authors.forename: Rabi Sankar
authors.initials: RS
authors.lastname: Bhatta
mesh_terms: D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects*; D002752:Chlorthalidone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D003198:Computer Simulation; D004195:Disease Models, Animal; D016903:Drug Monitoring / Q000379:methods; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D008954:Models, Biological; D010069:Oxadiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011918:Rats, Inbred SHR; D049993:Sodium Chloride Symporter Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D010069:Oxadiazoles; D049993:Sodium Chloride Symporter Inhibitors; C557413:azilsartan medoxomil; D002752:Chlorthalidone
keywords: Indirect response models; Noncompetitive interaction; PK-PD model; Pharmacodynamics; Pharmacokinetics; Synergism