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Dose Optimization Based on Population Pharmacokinetic Modeling of High-Dose Cyclosporine, a P-glycoprotein Inhibitor, in Combination with Systemic Chemotherapy in Pediatric Patients with Retinoblastoma

 Yoon sun Ree  ;  Hyun-moon Back  ;  Hwi-yeol Yun  ;  Ji Hyun Ahn  ;  Eun Sun Son  ;  Jung Woo Han  ;  Chuhl Joo Lyu  ;  Sandy Jeong Rhie 
 Journal of Ocular Pharmacology and Therapeutics, Vol.34(9) : 647-655, 2018 
Journal Title
 Journal of Ocular Pharmacology and Therapeutics 
Issue Date
P-glycoprotein inhibitor ; cyclosporine ; pediatrics ; population pharmacokinetics ; retinoblastoma
PURPOSE: Retinoblastoma is a childhood malignancy of the retina. To increase the exposures of systemic chemotherapy, high-dose cyclosporine, as a P-glycoprotein modulating agent, has been combined with a standard chemotherapy. However, the effective and safe dose of cyclosporine has not been well evaluated. This study is to optimize cyclosporine dose using population pharmacokinetic modeling. METHODS: Clinical data were obtained from 161 systemic chemotherapy cycles of 34 pediatric retinoblastoma patients between December 2006 and April 2015. Total 15 scenarios were simulated by 5 different doses (12, 14, 15, 17, and 20 mg/kg) of cyclosporine in 3 different weight groups (5-10, 10-15, and 15-20 kg). Numerical success ratio was obtained after assessing the simulated target cyclosporine concentration in the range of 2,000-2,500 ng/mL using NONMEM version 7.3 software. RESULTS: A final model was built based on a 1-compartment model with weight-normalized allometric scaling to minimize the variability of pediatric size. In simulations, numeric success ratio with 15 mg/kg/day and the above were higher than that of traditional doses in all of the scenario groups. No significant adverse responses were reported. Conclusion and Relevance: High-dose cyclosporine regimen as a P-gp modulator is required to improve the efficacy of systemic chemotherapy with caution in pediatric patients with retinoblastoma. Clearance, volume of distribution, and body weight are important parameters to consider in selecting adequate dosing regimen.
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1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
Yonsei Authors
안지현(Ahn, Ji Hyun)
유철주(Lyu, Chuhl Joo) ORCID logo https://orcid.org/0000-0001-7124-7818
이윤선(Ree, Yoon Sun)
한정우(Han, Jung Woo) ORCID logo https://orcid.org/0000-0001-8936-1205
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