Abstract
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.
Highlights
Sepsis is an infection-initiated system inflammatory syndrome
Sequential Organ Failure Assessment (SOFA) score can be used as the biomarker of pharmacological effect in sepsis patients along with PK exposure to guide the development of novel drugs in clinical trial
The study was conducted in accordance with the ethical principles stated by the Declaration of Helsinki, International Conference on Harmonization Technical Requirements for the Registration of Pharmaceuticals for Human Use of Good Clinical Practice. All participants or their guardians were required to sign a subject information agreement and the protocols of the study were approved by the Peking Union Medical College Hospital (PUMCH) Investigational Review Board (IRB)
Summary
Sepsis is an infection-initiated system inflammatory syndrome. More than 25–30% of patients with sepsis die from the condition, and hospital mortality for septic shock approaches 40–60% (Annane et al, 2005; Lever and Mackenzie, 2007; Martin, 2012; Singer et al, 2016). The disease severity of sepsis was correlated with the degree of organ dysfunction. The Sequential Organ Failure Assessment (SOFA) score, used to codify the degree of organ dysfunction, is a simple and effective method to monitor patient condition and disease progression, and is widely used in ICUs to evaluate the severity and prognosis of patients with sepsis (Ferreira et al, 2001; Tan et al, 2018; Lambden et al, 2019). Sepsis is defined in the presence of an infection combined with an acute change of two or more points of the SOFA score (Raith et al, 2017). SOFA score can be used as the biomarker of pharmacological effect in sepsis patients along with PK exposure to guide the development of novel drugs in clinical trial. No exposure-response models using the SOFA score have been reported
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