Purpose: The investigate and model the pharmacokinetic/pharmacodynamic (PK/PD) interaction of irbesartan (IRB) and hydrochlorothiazide (HCT) in normal volunteers.
Methods: The study used three-way crossover experimental design. Each volunteer (n=12) received a single oral dose of IRB 300mg alone, HCT 25mg alone, and IRB /HCT 300mg/25mg on three separate occasions with washout periods of two weeks between treatments. Serial blood samples were obtained and the drug effects on systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate were monitored simultaneously. An effect compartment PK/PD model was developed to describe the PK/PD behavior of IRB when administered alone and in combination with HCT.
Results: After a single administration, HCT alone did not cause significant decrease in blood pressure, while IRB reduced both systolic and diastolic blood pressure with IRB plus HCT had greater BP lowering effect compared to IRB alone (Figure 1). The average IRB Cmax, tmax, AUC, and CLT/F were 5.61 ng/ml, 2 hr, 33.2 ng-hr/ml, and 10.3 L/hr, respectively after IRB alone and 5.9 ng/ml, 2 hr, 32.9 ng-hr/ml, and 10.5 L/hr, respectively after IRB plus HCT. While the average HCT Cmax, tmax, AUC, and CLT/F concentration were 129 ng/ml, 3 hr, 1352 ng-hr/ml, and 19.6 L/hr, respectively after HCT alone and 127 ng/ml, 2.5 hr, 1084 ng-hr/ml, and 25.6 L/hr, respectively after IRB+HCT. IRB pharmacokinetic parameters were not changed by HCT coadministration, however IRB decreased the AUC of HCT by approximately 25% and increased its apparent total body clearance by 25% in the study volunteers (Figure 2). The effect of IRB on HCT pharmacokinetics is unlikely to have any clinical significance since HCT had no BP lowering effect after a single dose. A plot of IRB plasma concentration and its effects in chronological order showed an anticlockwise hysteresis (Figure 3). The relationship of IRB plasma concentration and its antihypertensive effect was described by a PK/PD model consisting of a two-compartment pharmacokinetic model, an effect compartment linked to the central compartment, and a sigmoid Emax pharmacodynamics model. The model predicted parameters for the effect of IRB on SBP, when administered with HCT were significantly different from their values when IRB was administered alone. There were 25% increase in Emax, 40% decrease in EC50 and 100% increase in ke0, which all suggest synergistic blood pressure lowering effect for IRB and HCT combination. While parameter estimates for the effect of IRB on DBP were also changed by HCT coadministration, however the differences were not significant.
Conclusion: IRB (300mg) administered alone or in combination with HCT (25mg) was well tolerated in healthy volunteers. A limited potential for synergistic interactions between IRB and HCT at the given doses were observed which warrant close monitoring of the therapeutic effect.