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.

Efficacy, safety and prognosis analysis of oral cyclosporine immunosuppressive regimen in children with acquired non-severe aplastic anemia: 13 years’ experience from a children’s hematology center of China

“…Although the initial dose of CsA in this study was recommended as 5 mg/kg/d according to the Chinese guidelines, but during dose titration, there was a 4.4 times difference between the maximum and minimum doses of CsA, which also con rmed that CsA was applied to children with large individual differences in PK. Not long ago, we also established the PK model of children's AA CsA to better guide the use of children's CsA with more clinical parameters [30].…”

Initial dosage optimisation of cyclosporine in Chinese paediatric patients undergoing allogeneic haematopoietic stem cell transplantation based on population pharmacokinetics: a retrospective study

“…Despite the fact that Pop-PK research on CsA for organ transplantation has been widely conducted in recent years, [12][13][14][15] there have been few studies in paediatric patients with haematological diseases. [16][17][18] According to studies, the PK parameters of CsA differ significantly between different organ transplantation types and populations (such as adults and children), resulting in high uncertainty in the safety and effectiveness of CsA PK extrapolation. 19 20 Currently, research aimed at CsA Pop-PK in Chinese children receiving allo-HSCT is severely lacking.…”