Aim:
Kukoamine B, a small molecule compound, is being developed for the treatment of
sepsis in a Phase II clinical trial. The objective of this study was to optimize dosing selection for a Phase IIb clinical trial using an exposure-response model. Methods: Data of 34
sepsis patients from a Phase IIa clinical trial were used in the model: 10
sepsis patients from the placebo group and a total of 24
sepsis patients from the 0.06 mg/kg, 0.12 mg/kg, and 0.24 mg/kg drug groups. Exposure-response relationship was constructed to model the impact of the standard care
therapy and area under curve (AUC) of
kukoamine B to the disease
biomarker (SOFA score). The model was evaluated by goodness of fit and visual predictive check. The simulation was performed 1,000 times based on the built model. Results: The data of the placebo and the drug groups were pooled and modeled by a nonlinear mixed-effect modeling approach in
sepsis. A latent-variable approach in conjunction with an inhibitory indirect response model was used to link the standard care
therapy effect and drug exposure to SOFA score. The maximum fraction of the standard care
therapy was estimated to 0.792. The eliminate rate constant of the SOFA score was 0.263/day for the standard care
therapy. The production rate of SOFA score (Kin) was estimated at 0.0569/day and the AUC at half the maximal drug effect (EAUC50) was estimated at 1,320 h*ng/mL. Model evaluation showed that the built model could well describe the observed SOFA score. Model-based simulations showed that the SOFA score on day 7 decreased to a plateau when AUC increased to 1,500 h*ng/mL. Conclusion: We built an exposure-response model characterizing the pharmacological effect of
kukoamine B from the standard care
therapy in
sepsis patients. A dose regimen of 0.24 mg/kg was finally recommended for the Phase IIb clinical trial of
kukoamine B based on modeling and simulation results.