Population Pharmacokinetic Modeling of Cyclosporine Among Malaysian Renal Transplant Patients: An Evaluation of Methods to Handle Missing Doses in Conventional Drug‐Monitoring Data

Abstract

Cyclosporine is a primary drug in transplant immunosuppression regimens. It has a narrow therapeutic index and variable pharmacokinetic behavior. This study aimed to develop a population pharmacokinetic model of cyclosporine in Malaysian renal transplant recipients as well as to evaluate the performances of different methodsfor handling missing doses. A total of 2804 concentrationts predose and 2 hours after doses were collected retrospectively from 113 renal transplant patients on cyclosporine in Penang General Hospital. Model structure and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling software. Missing doses were handled using different methods to evaluate their performance. Covariate analysis was performed using stepwise forward addition (P < .05) followed by backward elimination (P < .001). Prediction-corrected visual predictive check and sampling-importance resampling methods were used to validate the final model. A 1-compartment model with first-order absorption and elimination best fitted the data. All methods to handle missing doses performed well with the missing dose method being superior to other methods and thus was applied in the final model. Cyclosporine clearance (CL/F) was estimated as 15.1 L/h, and volume of distribution (V/F) was 108 L. Postoperative time, sex, and calcium channel blockers were identified as significant covariates on CL/F, whereas sex and cholesterol level were identified as significant covariates on V/F. This is the first population pharmacokinetic model developed in Malaysian renal transplant patients using a large sample with an evaluation of different methods to handle missing doses in less informative conventional therapeutic drug-monitoring data.

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

“…Dose recommendations differ with time post-transplantation, even when using the same population values because of improved CsA clearance with weeks after transplantation. 12 CsA clearance was also found to be higher in male patients than female patients, possibly because of higher expression of P-glycoprotein (MDR1) in males. 12 Furthermore, concomitant administration of calcium channel blockers was associated with cytochrome P450 (CYP) 3A inhibition leading to slower clearance of CsA.…”

“…12 CsA clearance was also found to be higher in male patients than female patients, possibly because of higher expression of P-glycoprotein (MDR1) in males. 12 Furthermore, concomitant administration of calcium channel blockers was associated with cytochrome P450 (CYP) 3A inhibition leading to slower clearance of CsA. 12 These covariates can also be updated in the online tool when population clearance is used for estimation.…”

“…12 Furthermore, concomitant administration of calcium channel blockers was associated with cytochrome P450 (CYP) 3A inhibition leading to slower clearance of CsA. 12 These covariates can also be updated in the online tool when population clearance is used for estimation.…”

“…11 Several factors have been reported to affect the clearance of CsA in renal transplant patients, including postoperative time, sex, and concomitant calcium channel blockers. 12 However, to date, knowledge of the PKPD relationship in terms of renal graft function response to CsA exposure after transplantation is limited.…”

A Repeated Time-to-Positive Symptoms Improvement among Malaysian Patients with Schizophrenia Spectrum Disorders Treated with Clozapine

“…Furthermore, due to the limited sample population, all the patients’ data were utilized to develop the model; thus, external validation was not performed and can be a potential topic of future research. However, the internal validation, especially the visual predictive check, is also valuable to investigate the model performance and was utilized in several studies to describe the performance of the models when external validation was not performed [ 22 , 50 , 51 ]. Information about clozapine concentrations was not available for evaluation as another measure of exposure.…”