Initial dose optimization of tacrolimus for children with systemic lupus erythematosus based on theCYP3A5polymorphism and coadministration with Wuzhi capsule

Abstract

What is known and objectives Tacrolimus, an immunosuppressant, has been used to treat paediatric systemic lupus erythematosus, but the optimal initial regimen is not clear. The purpose of this study was to explore the optimal initial dose of tacrolimus for children with systemic lupus erythematosus using population pharmacokinetics and pharmacogenomics. Methods Clinical information, tacrolimus concentrations and related genetic polymorphisms were incorporated into a model using non‐linear mixed‐effects modelling (NONMEM) analysis. Results and discussion The results showed that weight, the CYP3A5 genotype and combined treatment with Wuzhi capsule can affect tacrolimus clearance in children with systemic lupus erythematosus. Furthermore, at the same weight, the ratios of tacrolimus clearance were 1:2.49:0.57:1.4193 from people who were CYP3A5*3/*3 and did not take Wuzhi capsule, people who had the CYP3A5*1 allele and did not take Wuzhi capsule, people who were CYP3A5*3/*3 and took Wuzhi capsule, and people who had the CYP3A5*1 allele and took Wuzhi capsule, respectively. In addition, we found that 0.10 mg/kg split into two doses was suitable for people with weights from 10 to 60 kg who were CYP3A5*3/*3 and did not take Wuzhi capsule, who were CYP3A5*3/*3 and took Wuzhi capsule, and who had the CYP3A5*1 allele and took Wuzhi capsule. In people who had the CYP3A5*1 allele and did not take Wuzhi capsule, 0.15 mg/kg split into two doses was appropriate for those with weights from 10 to 40 kg and 0.10 mg/kg split into two doses was appropriate for those with weights from 40 to 60 kg. What is new and conclusion This study is the first study to recommend an optimal initial regimen of tacrolimus for children with systemic lupus erythematosus based on the CYP3A5 polymorphism and coadministration of Wuzhi capsule.

Population pharmacokinetics model and initial dose optimization of tacrolimus in children and adolescents with lupus nephritis based on real‑world data

“…The clinical information of 32 pediatric and adolescent patients with LN (5 males and 27 females) was collected for the present study and was used for population modelling. The clinical information of certain patients was collected in previous studies (13,14). Table I presents patient characteristics and drug combinations.…”

“…The clinical information was collected from the hospital's information system and tacrolimus whole-blood levels were acquired from a therapeutic drug detection system. Partial basic clinical information data with partial overlap were collected from certain patients in previous studies (13,14). The present study was approved by the Research Ethics Committee of the Children's Hospital of Fudan University [ethical approval code: (2019)020].…”

“…VPC, prediction-corrected visual predictive check. Partial concentration values were collected based on previous studies(13,14).…”

Analysis of time course and dose effect of tacrolimus on proteinuria in lupus nephritis patients

“…Tacrolimus is a first‐line immunosuppressant that has been widely used for liver, 18 kidney, 19 haematopoietic stem cell transplantations, 20 systemic lupus erythematosus, 21 lupus nephritis 22 and other diseases. The use of tacrolimus for the treatment of lupus nephritis, especially proteinuria, can be significantly reduced 23‐32 .…”

“…Since there is no significant dose‐response relationship, clinical efficacy is rarely measured by tacrolimus dose; instead, the drug concentration is controlled within a certain range. Many studies have reported that the clinical use of tacrolimus in transplantation, 51 nephrotic syndrome 52 and SLE 21 was also based on maintaining the concentration within a certain range using therapeutic drug monitoring. In fact, many drugs in combination can affect the metabolism of tacrolimus, and the advantage of using the tacrolimus window in this study is that we can adjust its flexible dose to keep the concentration within the window through routine therapeutic drug monitoring, simplifying the complex clinical problems.…”