Background: Contemporary hypertension treatment has shifted toward intensive blood pressure targets and earlier use of fixed-dose combination therapy. The 2024 ESC guideline further emphasizes stricter systolic blood pressure (SBP) control and preferential use of single-pill fixed-dose combinations over multiple separately administered agents. Accordingly, treatment may progress from low-dose dual-combination therapy to low-dose triple-combination therapy, followed by escalation to a higher-dose triple combination when additional blood pressure reduction is required. Amoprel is a triple fixed-dose combination of amlodipine, losartan, and chlorthalidone, and its low-dose formulation is currently approved. However, prospective evidence directly comparing the planned high-dose formulation, amlodipine/losartan /chlorthalidone 3.34/33.34/8.34 mg, with the approved low-dose triple combination, conventional maintenance regimens, and component-based high-dose combination regimens is limited. This study aimed to predict the SBP-lowering effect of high-dose Amoprel using response-surface pharmacodynamic modeling based on pooled clinical trial data.
Methods: Pooled SBP data from 13 clinical trials evaluating amlodipine, losartan, and chlorthalidone as monotherapy, dual- or triple-combination therapy were analyzed. Because pharmacokinetic data were not consistently available across studies, a dose-based response-surface pharmacodynamic model was developed using administered dose as a surrogate for drug exposure. The administered dose of each component was normalized by its drug-specific ID50, representing the relative potency of each agent. The sum of the normalized doses was used as a common drug-intensity metric corresponding to exposure, while the mixture proportions of the normalized doses were used to characterize how the U50 and Imax components of the triple-drug sigmoid Imax model changed across dose combinations. This framework allowed the model to describe the contribution of each component and potential interactions across the overall combination-dose space. To account for between-study heterogeneity in baseline SBP, studies with similar baseline SBP distributions were grouped into higher and lower baseline SBP categories, and two corresponding baseline parameters (BASE1/BASE2) were estimated. Model-based simulations were performed for the high-dose triple combination, approved low-dose triple therapy, monotherapies, dual-combination regimens, and conventional maintenance regimens. Predicted SBP reductions were quantitatively compared between the high-dose triple combination and each comparator scenario. Fixed-parameter simulations were used to assess structural model-based predictions and treatment-effect ranking using the final parameter estimates. Bootstrap-based deterministic simulations were used to evaluate differences in population-average predicted responses across repeated virtual trials while incorporating parameter uncertainty. Bootstrap-based Monte-Carlo simulations further incorporated interindividual variability, allowing comparison of individual-level SBP reduction distributions across treatment scenarios.
Result: The estimated interaction terms suggested that both U50 and Imax varied according to dose combination. For U50, the amlodipine–losartan interaction indicated that the same SBP reduction could be achieved with a lower total potency unit, suggesting synergistic effect of this combination. For Imax, the amlodipine–losartan and losartan–chlorthalidone interactions reflected higher-than-additive maximal effect levels. Together, these findings indicate that the model captured both the relative contribution of each component and pairwise interaction effects across the combination-dose space. The BASE1/BASE2 structure accounted for between-study heterogeneity in baseline SBP, while predicted SBP reduction for the same dose combination remained generally consistent across baseline groups.
In fixed-parameter simulations, the high-dose triple combination produced the greatest mean SBP reduction among evaluated regimens. Monotherapies showed approximately 13–19 mmHg smaller mean SBP reduction, and most dual-combination regimens also showed lower predicted effects, although losartan/chlorthalidone 33.34/8.34 mg was the closest dual-combination comparator. The approved low-dose triple combination showed a smaller predicted effect, supporting a dose-dependent increase in SBP reduction within the same three-drug regimen. Among conventional maintenance regimens, amlodipine 10 mg showed the smallest mean difference from the high-dose triple combination, approximately 1.2 mmHg, suggesting comparable predicted efficacy. Bootstrap-based deterministic simulations preserved the overall treatment-effect ranking after accounting for fixed-effect parameter uncertainty. In bootstrap-based Monte-Carlo simulations, individual response distributions became wider and partially overlapped across some comparators; however, the high-dose triple combination maintained greater mean and median SBP reduction than most evaluated regimens, with a mean SBP reduction of −27.67 mmHg and a 95% percentile range of −36.77 to −21.03 mmHg.
Conclusion: The response-surface pharmacodynamic model provided quantitative model-informed evidence supporting the predicted SBP-lowering effect of high-dose amlodipine/losartan/chlorthalidone 3.34/33.34/8.34 mg. Across fixed-parameters, simulations for population prediction, and individual prediction, the high-dose triple combination consistently showed greater predicted SBP reduction than the approved low-dose triple therapy and high-dose mono- or dual-combination regimens. It also predicted overall greater SBP reduction than conventional maintenance regimens, although its effect was comparable to that of amlodipine 10 mg monotherapy. These findings suggest that the high-dose triple combination may serve as a model-informed candidate regimen that could substitute for conventional maintenance options and provide a rational next-step treatment option for patients requiring additional SBP reduction after low-dose triple therapy.