Initial dosage optimization of tacrolimus in Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics

ABSTRACT

Background

The purpose of our research was to recommend the initial tacrolimus dosage for Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics.

Methods

Demographic data, laboratory results, drug combinations, and pharmacogenetics from Chinese pediatric patients undergoing kidney transplantation were analyzed using non-linear mixed-effects modeling. A Monte Carlo simulation was performed to evaluate the optimal initial dose of tacrolimus.

Results

Body weight and post-transplant days, combined with wuzhi-capsule (WZ, extracted from schisandra sphenanthera, whose primary efficient constituents are schisantherin A, schisandrol B, schisandrin, etc., and often used to treat drug-induced hepatitis in Chinese organ transplant patients) and CYP3A5 polymorphisms, influenced the clearance of tacrolimus in these patients. With same weight and post-transplant days, tacrolimus clearance rates from patients carrying CYP3A5*3/*3 and without WZ, carrying CYP3A5*1 allele and without WZ, carrying CYP3A5*3/*3 and with WZ, carrying CYP3A5*1 allele and with WZ were 1, 1.6, 0.72, and 1.152, respectively. In addition, the initial dose for each condition is recommended.

Conclusions

The initial dosage recommendations in the tacrolimus instructions were not individualized, and we have developed more accurate initial doses based on weight and the CYP3A5 genotype. In addition, lower initial doses are recommended with concurrent use of WZ.

KEYWORDS:

• Pediatric kidney transplantation
• initial dosage optimization
• pharmacogenetics
• population pharmacokinetics
• tacrolimus

Article highlights

• The study will firstly recommend the initial dosing regimen optimization of tacrolimus in Chinese pediatric kidney transplantation patients based on population pharmacokinetics and pharmacogenetics.

• Body weight and post-transplant days, combined with wuzhi-capsule (WZ) and CYP3A5 polymorphisms, influenced the clearance of tacrolimus.

• With same weight and post-transplant days, tacrolimus clearance rates from patients carrying CYP3A5*3/*3 and without WZ, carrying CYP3A5*1 allele and without WZ, carrying CYP3A5*3/*3 and with WZ, carrying CYP3A5*1 allele and with WZ were 1, 1.6, 0.72, and 1.152, respectively.

• The initial dosage recommendation in the tacrolimus instructions were not individualized and we have developed more accurate initial doses based on weight and CYP3A5 genotype.

Lower initial doses are recommended with concurrent use of WZ.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer declarations

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

ZL and HX conceived and designed the study. XC and DW collected the data, built the model and evaluated the data. XC wrote the manuscript. DW reviewed and edited the manuscript. All authors read and approved the manuscript.

Additional information

Funding

This work was supported by Scientific Research Project of Science and Technology Commission of Shanghai Municipality (grant no. 18DZ1910604/19DZ1910703), Shanghai Science and Techonology Commission (grant no. 19XD1400900), The China Scholarship Council (grant no. 201906100164).