Personalizing initial calcineurin inhibitor dosing by adjusting to donor CYP3A‐status in liver transplant patients

Abstract

Aims Inter‐individual variability in dose requirements of calcineurin inhibitors (CNI) has been linked to genetic polymorphisms of CYP3A enzymes. CYP3A5*3, CYP3A4*1B and CYP3A4*22 alleles of liver grafts may explain about one third of the inter‐individual differences in pharmacokinetics of ciclosporin and tacrolimus in recipients. However, non‐genetic factors, influencing CYP3A expression, can contribute to the variability of CYP3A function due to phenoconversion. The present study evaluated the association between CYP3A4 expression combined with CYP3A5 genotype of donor livers and recipients' CNI therapy after transplantation. Methods The contribution of donors' CYP3A5 genotype and CYP3A4 expression to the blood concentrations and dose requirements of CNIs was evaluated in 131 liver transplant recipients. Results The recipients with grafts from normal CYP3A4 expresser donors carrying CYP3A5*3/*3 required CNI maintenance doses more or less similar to the bodyweight‐controlled starting doses (9.1 mg kg−1 of ciclosporin and 0.1 mg kg−1 of tacrolimus). The patients transplanted with grafts from low CYP3A4 expressers required substantial reduction (by about 50%, 4.2 mg kg−1 of ciclosporin, 0.047 mg kg−1 of tacrolimus, P < 0.001), while the recipients with grafts from high expressers or with grafts carrying at least one copy of the functional CYP3A5*1 allele required an increase (by about 50% [12.8–13.8 mg kg−1] for ciclosporin and 100% [0.21 mg kg−1] for tacrolimus, P < 0.001) of the initial CNI dose for achieving target blood concentrations. Conclusions Donor livers' CYP3A‐status, taking both CYP3A5 allelic variations and CYP3A4 expression into account, can better identify the risk of CNI over‐ or underexposure, and may contribute to the avoidance of misdosing‐induced graft injury in the early post‐operative period.

Effect of diurnal variation,CYP2B6genotype and age on the pharmacokinetics of nevirapine in African children

“…Although not confirmed for nevirapine, systemic exposures of CYP3A substrates have been shown to be altered by SNPs rs35599367 ( CYP3A4 *22) 24,25 and rs776746 ( CYP3A5 *1). 26,27 Additionally, CYP3A activity exhibits diurnal variation, with nevirapine clearance rates increasing during the day and reducing at night. 28,29 Differences between morning (AM) and evening (PM) nevirapine trough concentrations ( C min ) have been previously reported 30 and may relate to diurnal variation in the CYP3A -mediated effects on pharmacokinetics.…”

Effect of CYP3A5*1 expression on tacrolimus required dose after liver transplantation: A systematic review and meta‐analysis

“…Two parameters were checked as confounders, and apart from five studies, others did not assess one or both of them. Appraisal of outcomes revealed that in 23 studies, outcomes of interest were not presented (eg, because of nonsignificant data) or presented improperly (eg, as median) which led to the exclusion of the study from the analyses or obligated us to estimate required data . Eight studies did not continue blood level measurement at specified time points for at least one month or did not mention the time of measurement clearly .…”

Metabolic Drug Interactions with Immunosuppressants

“…1c9-dihydroxy-ciclosporin, 1-carboxy-ciclosporin) are toxic contributing to the nephrotoxic and hepatotoxic properties of the parent compound [33,34]. Consequently, high CYP3A activity increases the rate of ciclosporin metabolism and decreases the immunosuppressive effect, which requires dose modification [35]. However, high CYP3A activity also increases the toxic metabolite formation and the risk of nephrotoxicity and hepatotoxicity.…”

“…(2) substantial interindividual differences in hepatic CYP3A activity result in great variability in the rate of tacrolimus metabolism, which requires continuous drug monitoring and dose modification primarily in the early postoperative period; (3) concomitant treatment with CYP3A inhibitors is the potential source of metabolic drug interactions; (4) genetic polymorphisms of CYP3A5 also contribute to the high interindividual variability. Since the relative contribution of CYP3A5 to tacrolimus biotransformation is significantly higher than that of CYP3A4 [40], the recipients carrying wild type CYP3A5*1 allele or transplanted with liver grafts carrying CYP3A5*1 are able to metabolize tacrolimus more rapidly than CYP3A5 nonexpressers [35,41].…”