Population Pharmacokinetics of Cyclosporine in Chinese Pediatric Patients With Acquired Aplastic Anemia

Abstract

Cyclosporine (CsA) is a component of the first-line treatment for acquired aplastic anemia (acquired AA) in pediatric patients. This study aimed to develop a population pharmacokinetic (PK) model of CsA in Chinese pediatric patients with acquired AA to inform individual dosage regimens. A total of 681 CsA whole blood concentrations and laboratory data of 157 pediatric patients with acquired AA were retrospectively collected from two hospitals in Shanghai. A nonlinear mixed-effect model approach was used to build the population PK model. Potential covariate effects of age, body weight, and biochemical measurements (renal and liver functions) on CsA PK disposition were evaluated. Model fit was assessed using the basic goodness of fit and a visual predictive check. The CsA concentration data were accurately described using a two-compartment disposition model with first-order absorption and elimination. Body weight value was implemented as a fixed allometric function on all clearance and volume of distribution parameters. Total bilirubin level was identified as a significant covariate on apparent clearance (CL/F), with a 1.07% reduction per 1 nmol/L rise in total bilirubin level. The final estimates for CL/F and central volume (Vc/F) were 29.1 L/h and 325 L, respectively, for a typical 28 kg child. Other covariates (e.g., gender, age, albumin, hemoglobin, hematocrit, serum creatinine, and concomitant medication) did not significantly affect the PK properties of CsA. This population PK model, along with a maximum a posteriori Bayesian approach, could estimate individual PK parameters in pediatric patients with acquired AA to conduct individual CsA therapy.

Keywords: NONMEM; acquired aplastic anemia; cyclosporine; pediatric patients; population pharmacokinetics.

FIGURE 1

Basic goodness of fit of the final population pharmacokinetic model of cyclosporine A. (A) conditionally weighted residuals vs. population-predicted concentrations. (B) conditionally weighted residuals vs. time. (C) observed plasma concentrations vs. population-predicted concentrations. (D) observed plasma concentrations vs. individually predicted concentrations; solid red lines represent locally weighted least-squares regressions.

FIGURE 2

Visual predictive check of the final population pharmacokinetic model of cyclosporine A. The visual predictive check was based on 1,000 stochastic simulations. Open circles are the observations and solid lines represent the 5^th, 50^th, and 95^th percentiles of the observed data. The shaded areas represent 95% prediction intervals around the simulated 5^th, 50^th, and 95^th percentiles. The Cmax was slightly underestimated.

FIGURE 3

Impact of body weight and total bilirubin level on the pharmacokinetic exposure at steady state after the oral administration of cyclosporine A (5 mg/kg/d). The data of 1,000 children were used for the simulation for each body weight band. The simulation was stratified by different total bilirubin levels: (A) the normal level (<17.1 μmol/L). (B) and (C) 1.5 and 2 times the upper limits of the normal level (25.65 and 34.2 μmol/L), respectively. The total simulated exposure was presented as median values (25^th–75^th percentiles).