Exposure-Response Modeling to Support Dosing Selection for Phase IIb Development of Kukoamine B in Sepsis Patients

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.

Safety, Tolerability, and Pharmacokinetics of Kukoamine B in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Phase I Study

“…The results of our study showed that the multiple intravenous infusion of KB in healthy volunteers for the dose range of 0.06-0.24 mg/kg was safe. These findings are comparable to those of Wang et al, who reported no major AEs associated with a 0.24 mg/kg dose regimen in patients with sepsis and so recommended it for further clinical trials [17]. Additionally, hypertriglyceridemia was the most frequently reported AE in both the KB group (4, 22.22%) and the placebo group (2, 33.33%) during the trial.…”

“…Hence, they are not particularly efficient at combating sepsis as both aforementioned molecules are usually involved during sepsis. Therefore, LPS and CpG DNA could be used as co-targets for sepsis drugs in the development of novel sepsis therapies such as kukoamine B (KB) [17].…”

Fixed dosing of kukoamine B in sepsis patients: Results from population pharmacokinetic modelling and simulation

“…The predicted concentrations vs time (0–8 h) on the two dosing regimens are plotted in Figure 6. The exposure (AUC) of the fixed dose was approximately the target AUC 1500 ng*h/mL 21 …”

Research Progress on Natural Small-Molecule Compounds for the Prevention and Treatment of Sepsis

“…As shown in Figure 13 , kukoamine B (CAS: 164991-67-7), as a novel dual inhibitor of LPS and CpG DNA, regulates the downstream signal pathway by directly binding and neutralizing LPS and CpG DNA, thus significantly inhibiting the inflammatory response in LPS-induced septic mice [ 79 ]. Wang et al [ 80 ] used an exposure-response model to optimize dose selection in phase IIb clinical trials and recommended a 0.24 mg/kg regimen. A randomized, double-masked, placebo-controlled, multi-dose phase I study also demonstrated that single and multiple intravenous infusions of 0.06–0.24 mg/kg were safe and tolerable in healthy volunteers [ 81 ].…”