Population Pharmacokinetic-Pharmacodynamic modeling of furosemide for anti-hypertensive effect
Mahendra Shukla (1,2) Moon Jain (2,3) Swati Jaiswal (1,2) Abhisheak Sharma (1,2) Kashif Hanif (2,3) and Jawahar Lal (1,2)
(1) Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, India (2) Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India (3) Academy of Scientific and Innovative Research, New Delhi, India
Objectives: Despite its long term use as an established diuretic, the anti-hypertensive effect of furosemide has not been well characterized. The previous PK-PD studies of furosemide mainly modeled its diuretic effect [1]. The reports pertaining to the use of furosemide in treating different forms of hypertension are limited. Also the multiple dose studies for the anti-hypertensive effect of furosemide are lacking. Therefore, the present study aims at bridging this void by providing a comparative PK-PD analysis for the blood pressure lowering effect of furosemide after multiple dosing in spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats), the commonly employed animal models for human primary and secondary hypertension respectively.
Methods: Multiple dose oral (40 and 80 mg/kg dose daily for 3 weeks at 24 h interval) PK-PD study of furosemide was carried out in SHR and DOCA-salt rats. Blood samples were withdrawn up to three weeks post treatment and harvested serum samples were analysed using LC-MS/MS method [2]. For PD study, BP was monitored using noninvasive blood pressure monitoring in conscious rats using tail cuff method at various predefined time points. A simultaneous PK-PD model was developed to allow the estimation of PK as well as PD parameters in a single fit. Analysis was conducted using FOCE I in NONMEM 7.3. Xpose and PsN were used for graphical evaluation and model diagnostics.
Results: A 2-compartment model provided the best fit to the PK data. V1 of furosemide was found to be higher in DOCA-salt rats as compared to SHR at similar dose. A nonlinear behaviour of clearance (2.3-fold increment) was observed in SHR at higher dose owing to the saturable metabolism of furosemide, whereas in DOCA-salt rats, it was found to be dose-independent. The PD parameter estimates from the best fitted Emax model with the effect compartment indicated the higher efficacy of furosemide as an anti-hypertensive in DOCA-salt rats as compared to SHR that is shown by the lower EC50 values predicted by our finalized PK-PD model. The tolerance was found to be much higher (2-fold) in DOCA-salt model as compared to SHR. Even at the highest dose used in our study, the EC50 values were found to be higher as compared to achieved serum concentration.
Conclusions: The final PK-PD model described the data well and provides detailed insights into the use of furosemide as an anti-hypertensive agent.
References:
[1] MM Hammarlund, B Odlind, LK Paalzow. Acute tolerance to furosemide diuresis in humans: Pharmacokinetic-pharmacodynamic modeling. J Pharmacol Exp Therap 1985; 233(2): 447-53.
[2] ME Abdel-Hamid. High-performance liquid chromatography-mass spectrometric analysis of furosemide in plasma and its use in pharmacokinetic studies. Farmaco 2000; 55(6-7): 448-54.
