Time-Dissociated Pharmacokinetic Pharmacodynamic Model of Cyclosporine Among Malaysian Renal Transplant Recipients

Background: Cyclosporine is an essential component of many immunosuppressive regimens. However, its pharmacokinetic and pharmacodynamic (PKPD) modeling has not been widely investigated. This study aims to develop a time-dissociated PKPD model of cyclosporine in renal transplant patients. Methods: Medical records of renal transplant patients at Penang General Hospital were retrospectively analyzed. A time-dissociated PKPD model with covariate effects was developed using NONMEM to evaluate renal graft function response, quantified as estimated glomerular filtration rate (eGFR), toward the cyclosporine cumulative exposure (area under the concentration-time curve). The final model was integrated into a tool to predict the potential outcome. Individual eGFR predictions were evaluated based on the clinical response recorded as acute rejection/nephrotoxicity events. Results: A total of 1256 eGFR readings with 2473 drug concentrations were obtained from 107 renal transplant patients receiving cyclosporine. An E-max drug effect with a linear drug toxicity model best described the data. The baseline renal graft level (E-0), maximum effect (E-max), area under the concentration-time curve achieving 50% of the maximum effect, and nephrotoxicity slope were estimated as 12.9 mL center dot min(-1)center dot 1.73 m(-2), 50.7 mL center dot min(-1)center dot 1.73 m(-2), 1740 ng center dot h center dot mL(-1), and 0.00033, respectively. The hemoglobin level was identified as a significant covariate affecting the E-0. The model discerned acute rejection from nephrotoxicity in 19/24 cases. Conclusions: A time-dissociated PKPD model successfully described a large number of observations and was used to develop an online tool to predict renal graft response. This may help discern early rejection from nephrotoxicity, especially for patients unwilling to undergo a biopsy or those waiting for biopsy results.