Population Pharmacokinetic and Pharmacodynamic Analysis of Voriconazole‐Induced Liver Injury in Chinese Lung Transplant Patients

Background Voriconazole (VCZ) served as primary therapy for invasive aspergillosis in lung transplant recipients. However, VCZ‐induced hepatotoxicity emerged as a frequent adverse effect that critically compromised postoperative management and complication prevention in this vulnerable population. Methods We performed population pharmacokinetic/pharmacodynamic (PK/PD) modeling using nonlinear mixed‐effects methodology. The analysis included a one‐compartment PK model with alkaline phosphatase (ALP) as the primary hepatotoxicity biomarker. Monte Carlo simulations assessed the effects of dosing regimens on ALP dynamics across various covariate scenarios. Results The final PK/PD model indicated an apparent systemic clearance of 3.09 L/h and a central volume of 80.31 L. The exposure–response relationship was described using an indirect response model, with the pharmacological effect linked to increases in ALP levels. The maximum drug effect (E max ) was 188.78. The rate constant for psoriatic plaque production (K in ) was 0.31/day, while the rate for plaque loss (K out ) was 0.53/day. Creatinine clearance (CrCL) was identified as a key covariate for apparent clearance, while weight and tacrolimus (TAC) trough level were significant for Emax. The average probability of target attainment for optimized regimens reached 50.2% across all covariate combinations. Clinical simulations identified 100 mg twice daily (bid) as the optimal maintenance dose for hepatotoxicity prevention. Weight‐based dose reduction was recommended for recipients below 50 kg, with stringent therapeutic drug monitoring of TAC concentrations. Conclusion Our population PK/PD model provides clinically actionable guidance for VCZ dose optimization, particularly for underweight lung transplant recipients on maintenance therapy. The model effectively predicts and prevents VCZ‐induced hepatotoxicity while maintaining therapeutic efficacy.