Prediction of first-in-human dose for new composition bee venom based on allometric scaling and pharmacokinetic modeling approach.

Bee venom is a traditional remedy used to treat conditions related to the nervous and musculoskeletal systems, as well as autoimmune diseases. Recently, we developed a new composition bee venom (NCBV), a fortified content of bee venom phospholipase A2 (bvPLA2), which may be effective in the treatment of Alzheimer's disease. NCBV is currently preparing to conduct a phase 1 clinical trial, and this study aimed to predict the first-in-human (FIH) dose using a mechanistic approach. First, animal pharmacokinetic (PK) studies from three different species were explored and integrated to build a PK model using nonlinear mixed-effect modeling. The final models were described by two-compartment model with first order absorption and elimination, and were used to define the PK parameters for each species. To predict human PK parameters, simple, brain weight (BrW) or maximum lifespan potential (MLP) incorporated allometric scaling approaches were used, with the BrW method showing the highest correlation (R = 0.974). The initial FIH dose was back-calculated based on the area under the concentration-time curve of 0.397 μg·h/mL after the injection of an efficacious dose of 0.1 mg/kg in mice using the developed PK model. The predicted initial doses for a 70 kg human were 5.5, 1.3, and 3.5 mg, when using the simple, BrW, and MLP incorporated model, respectively. A subcutaneous FIH dose of 1.3 mg NCBV was ultimately recommended for a 70-kg human. Based on the no observed adverse effect level, the suggested FIH dose ranges for NCBV are 0.1 to 3 mg, which correspond with our proposed dose.