Understanding the variability in tacrolimus pharmacokinetics and toxicity in pediatric kidney transplant patients

Abstract

Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Up to 50% of the variability in tacrolimus exposure is explained by variants in the gene CYP3A5. Given equivalent doses, CYP3A5 expressers (*1 allele carriers) demonstrate faster tacrolimus metabolism than non-expressers. Trough concentration monitoring and dosing adjustments are used to reach a therapeutic range. Using CYP3A5-guided dosing immediately after transplant could decrease the time to the therapeutic dose and the number of dose adjustments. In chapter 1, we describe the effect of CYP3A5 gene, age, and concomitant fluconazole on the tacrolimus concentration. We hypothesize that CYP3A5 expressers will need more dose adjustments compared to CYP3A5 non-expressers in the 8 weeks following tacrolimus initiation. Our specific aim for this chapter is to study pediatric patients within the first 8 weeks after kidney transplant to examine the effect of CYP3A5 genotype and other clinical factors (i.e., age and fluconazole) on tacrolimus trough concentrations and TDM outcomes. We analyzed the electronic health records of 93 patients within the first 8 weeks after a kidney transplant. Banked DNA was collected, and genotyping was performed for CYP3A5 *1, *3, *6, *7, and *8 alleles using the MASSArray platform. Included patients received a kidney transplant between Jan 2010 to April 2021, with age ≤21 years at the time of the transplant. The tacrolimus target range was 10-15 ng/mL in the first four weeks and 7-10 ng/mL in the next four weeks. We found that CYP3A5 expressers (n=21) had fewer measurements in range than non-expressers (n=72) in the first 8 weeks (32.4% vs 39.6%, P=0.029). Expressers had more dose adjustments (8 vs 6, p=0.0234), and they needed more than 170% of the required daily dose compared to the non-expressers. The concentration/dose (C0/D) ratio was influenced by age and concomitant fluconazole (p=0.0003, P=0.034, respectively), and the average daily dose decreases with age in CYP3A5 non-expressers (p=0.001). In chapter 2, our specific aim is to study the association between tacrolimus concentration and toxicity in the first 8 weeks after tacrolimus initiation in pediatric kidney transplant. We hypothesize that the trough concentration of tacrolimus is associated with its toxicity. Adverse reactions to tacrolimus present as CNS toxicity (e.g., tremors, shaking, insomnia, headache, and dizziness), gastrointestinal toxicity (diarrhea, constipation, abdominal pain, nausea, and vomiting), and other toxicities like muscle cramps, edema, rashes, and hypertension. At Cincinnati Children’s, the target trough is 10-15 ng/mL in the first four weeks after transplant and 7-10 ng/mL in the following weeks while a global consensus report recommends that the target in pediatric kidney transplant patients be 10- 20 ng/mL during the first 2 months after transplantation and between 5 and 10 ng/mL thereafter. We investigated toxicity using a trough threshold of 15ng/mL because it is the upper limit of the target range at our center; we found that Patients who ever had troughs over 15 ng/mL were more likely to develop tremors and CNS toxicity compared to patients with troughs never over 15 ng/mL.