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Population pharmacokinetics and initial dosing regimen optimization of cyclosporin in pediatric hemophagocytic lymphohistiocytosis patients

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posted on 14.08.2019 by Dong-Dong Wang, Qiao-Feng Ye, Xiao Chen, Hong Xu, Zhi-Ping Li

Hemophagocytic lymphohistiocytosis (HLH) is induced by various triggers, including genetic factors, infections, autoimmune diseases, lymphoma or other malignancies. Cyclosporin is one of the clinical treatments for HLH. However, cyclosporin has considerable inter- and intra-individual variabilities in pharmacokinetics and also displays a narrow therapeutic window, making it difficult to define an optimal dose for HLH treatment. This study is aimed to establish cyclosporin population pharmacokinetic (PPK) model of pediatric HLH patients and formulate an initial dose regimen for personalized medicine.

Pediatric HLH patients between June 2014 and March 2019 from Children’s Hospital of Fudan University were analyzed using NONMEM. Dose recommended was investigated using Monte Carlo simulations.

The final cyclosporin PPK model was: CL/F = 91×(WT/70)0.75×(1+ Piperacillin–Tazobactam × θP–T); V/F = 4250×(WT/70), where WT, and θP–T were weight, and the coefficient of the Piperacillin–Tazobactam, respectively. Based on the simulation results of our model, new initial dosage suggestions were recommended. In conclusion, the first cyclosporin PPK model in pediatric HLH patients was established and the model could be used to predict individualized initial dosing regimens in children with HLH.

Hemophagocytic lymphohistiocytosis (HLH) is induced by various triggers, including genetic factors, infections, autoimmune diseases, lymphoma or other malignancies. Cyclosporin is one of the clinical treatments for HLH. However, cyclosporin has considerable inter- and intra-individual variabilities in pharmacokinetics and also displays a narrow therapeutic window, making it difficult to define an optimal dose for HLH treatment. This study is aimed to establish cyclosporin population pharmacokinetic (PPK) model of pediatric HLH patients and formulate an initial dose regimen for personalized medicine.

Pediatric HLH patients between June 2014 and March 2019 from Children’s Hospital of Fudan University were analyzed using NONMEM. Dose recommended was investigated using Monte Carlo simulations.

The final cyclosporin PPK model was: CL/F = 91×(WT/70)0.75×(1+ Piperacillin–Tazobactam × θP–T); V/F = 4250×(WT/70), where WT, and θP–T were weight, and the coefficient of the Piperacillin–Tazobactam, respectively. Based on the simulation results of our model, new initial dosage suggestions were recommended. In conclusion, the first cyclosporin PPK model in pediatric HLH patients was established and the model could be used to predict individualized initial dosing regimens in children with HLH.

Funding

This work was supported by Clinical Pharmacy Key Specialty Construction Project of Shanghai [No. YZ2017/5]. Important Weak Subject Construction Project of Shanghai [No. 2016ZB0305]. Scientific Research Project of Science and Technology Commission of Shanghai Municipality [No. 18DZ1910604]. Fudan University Hospital Management Construction Project [No. Fudan medical administration 2018]. The China Scholarship Council [No. 201906100164].

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