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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

Title
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
Authors
Ree, Yoon SunBack, Hyun-moonYun, Hwi-yeolAhn, Ji HyunSon, Eun SunHan, Jung WooLyu, Chuhl JooRhie, Sandy Jeong
Ewha Authors
이정연
SCOPUS Author ID
이정연scopus
Issue Date
2018
Journal Title
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS
ISSN
1080-7683JCR Link

1557-7732JCR Link
Citation
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS vol. 34, no. 9, pp. 647 - 655
Keywords
retinoblastomapopulation pharmacokineticspediatricscyclosporineP-glycoprotein inhibitor
Publisher
MARY ANN LIEBERT, INC
Indexed
SCIE; SCOPUS WOS
Document Type
Article
Abstract
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 20mg/kg) of cyclosporine in 3 different weight groups (5-10, 10-15, and 15-20kg). Numerical success ratio was obtained after assessing the simulated target cyclosporine concentration in the range of 2,000-2,500ng/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 15mg/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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DOI
10.1089/jop.2018.0041
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약학대학 > 약학과 > Journal papers
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