Modeling of blood pressure lowering effect for co-administration of valsartan and amlodipine

Background: The objective of this study was to develop a pharmacodynamic (PD) model for antihypertensive effect of amlodipine and valsartan combined therapy.

Methods: Pharmacokinetic (PK) modeling was first carried out for both drugs using data collected from 48 healthy volunteers receiving a combined formulation of 10mg amlodipine and 160mg valsartan as a single dose. Systolic (SBP) and diastolic blood pressure (DBP) data were also collected from combination therapy. BP data for monotherapies were gathered from literature search. Using constructed PK models, PD models for monotherapy of each drug and combination therapy were built with NONMEM 7.2 using the data collected from literature search and clinical trial respectively. Visual predictive check was performed for model evaluation.

Results: Two compartment model with zero order absorption best described the PK data of both drugs. For BP, monotherapy data for amlodipine was best fitted into a linear model and that for valsartan into linear (SBP) and Emax model (DBP). Combined therapy was best described with proportional interaction term, (ADDR*(1+ALPHA)) where ADDR refers to the sum of BP lowering effects from amlodipine and valsartan monotherapies, and ALPHA the efficacy of combined therapy. ALPHA for SBP and DBP were -0.707 and -0.380 respectively. When Minto model was implemented, consistent infra-additive effects of interaction terms were estimated, which was consistent with literature result about combination therapy of ARB and CCB.

Conclusion: The BP model developed successfully described the efficacy of combination treatment of amlodipine and valsartan in comparison to monotherapy of each drug.