Abstract: AIM: To apply the weighted modification model with the nonlinear mixed effect model (NONMEM) to quantitatively assess the optimal combination of allantoin (X₁), metronidazole (X₂), and dexamethasone (X₃) for anti-inflammatory effects in mice. METHODS: The activity of t-PA in peritoneum was taken as index for the analysis in Kunming mice. The weighted modification model was selected as basic model and NONMEM was used to build final model with drug interaction as fixed effect and random effects. RESULTS: The weighted modification model was built with X₁X₂ as fixed effect successfully (P<0.001). In the final model, the combination of X₁ and X₃ had a strong synergism, the both components were main effective ones, and the optimal dose ratio of X₁, X₂ and X₃ was 400∶131∶8.0 (mg/kg, i.p.). CONCLUSION: The weighted modification model can provide more information for a combination design in using NONMEM, and the interactions among components and variability of inter-subject and intra-subject can be fully evaluated.

Key words: Weighted modification method, Drug interactions, Nonlinear mixed effect model, Formula optimization