Transl Clin Pharmacol.  2019 Sep;27(3):107-114. 10.12793/tcp.2019.27.3.107.

Development of a physiologically-based pharmacokinetic model for cyclosporine in Asian children with renal impairment

• Yoon S
• Yi S
• Rhee SJ
• Lee HA
• Kim Y
• Yu KS
• Chung JY

• KMID: 2458950
• DOI: http://doi.org/10.12793/tcp.2019.27.3.107

Abstract

This study aimed to assess the pharmacokinetics of cyclosporine A (CsA) in Asian children with renal impairment (RI) by developing a physiologically-based pharmacokinetic (PBPK) model with Simcyp Simulator. The PBPK model of Asian children with RI was developed by modifying the physiological parameters of the built-in population libraries in Simcyp Simulator. The ratio of healthy and RI populations was obtained for each parameter showing a difference between the populations. Each ratio was multiplied by the corresponding parameter in healthy Asian children. The model verification was performed with published data of Korean children with kidney disease given multiple CsA administrations. Simulations were performed with different combinations of ethnicity, age, and renal function to identify the net impact of each factor. The simulated results suggested that the effect of RI was higher in children than adults for both Caucasian and Asian. In conclusion, the constructed model adequately characterized CsA pharmacokinetics in Korean children with RI. Simulations with populations categorized by ethnicity, age, and renal function enabled to assess the net impact of each factor on specific populations.

Keyword

Cyclosporine; Ethnicity; PBPK; Pediatrics; Renal impairment

MeSH Terms

Adult
Asian Continental Ancestry Group*
Child*
Cyclosporine*
Humans
Kidney Diseases
Pediatrics
Pharmacokinetics
Cyclosporine

Figure

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  Figure 1 Overlay of observed (circles) blood concentration and simulated (lines) steady-state plasma concentration-time profile of cyclosporine A. Dotted lines indicate a healthy population. Dashed lines indicate a population with moderate renal impairment. Solid lines indicate a population with severe renal impairment. Black lines indicate the overall mean for the virtual populations. The gray lines indicate the 5–95% confidence intervals.

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  Figure 2 Comparison of simulated (A) Cmax,ss and (B) AUCτ,ss of CsA in three populations: healthy Asian children, Asian children with moderate renal impairment and Asian children with severe renal impairment.

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  Figure 3 Comparison of PBPK model simulated steady-state plasma concentration-time profiles of cyclosporine A in (A) Caucasian adults and (B) children and (C) Asian adults and (D) children. Dotted lines indicate a healthy population. Dashed lines indicate a population with moderate renal impairment. Solid lines indicate a population with severe renal impairment.

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