A Minimal Physiologically‐Based Pharmacokinetic Model for Tacrolimus in Living‐Donor Liver Transplantation: Perspectives Related to Liver Regeneration and the cytochrome P450 3A5 (CYP3A5) Genotype

Abstract

In adult patients after living‐donor liver transplantation, postoperative days and the cytochrome P450 3A5 (CYP3A5) genotype are known to affect tacrolimus pharmacokinetics. In this study, we constructed a physiologically‐based pharmacokinetic model adapted to the clinical data and evaluated the contribution of liver regeneration as well as hepatic and intestine CYP 3A5 genotypes on tacrolimus pharmacokinetics. As a result, liver function recovered immediately and affected the total body clearance of tacrolimus only during a limited period after living‐donor liver transplantation . The clearance was about 1.35‐fold higher in the recipients who had a liver with the CYP 3A5*1 allele than in those with the CYP 3A5*3/*3 genotype, whereas bioavailability was ~0.7‐fold higher in the recipients who had intestines with the CYP3A5*1 allele than those with CYP 3A5*3/*3 . In conclusion, the constructed physiologically‐based pharmacokinetic model clarified that the oral clearance of tacrolimus was affected by the CYP 3A5 genotypes in both the liver and intestine to the same extent.

Clinical significance of personalized tacrolimus dosing by adjusting to donor CYP3A‐status in liver transplant recipients

“…A number of clinical studies evaluated the impact of intestinal CYP3A5 polymorphism (recipient CYP3A5 genotype) on tacrolimus pharmacokinetics. Several trials involving mainly living donor liver transplant recipients demonstrated important consequences of recipients' CYP3A5 genotype on tacrolimus concentration/dose ratios and on dose requirements in the first postoperative month, 21,22,24,25 whereas other studies emphasized the contribution of the donor (hepatic) CYP3A5 polymorphism to the variations in tacrolimus dose requirement over recipient (intestinal) CYP3A5 genotype 8–10 . Our findings confirmed an important role of CYP3A5 expression (the presence of CYP3A5*1 allele) of the liver graft in tacrolimus concentrations normalized by the dose and bodyweight; however, recipients' CYP3A5 genotype was failed to significantly modify dose‐adjusted tacrolimus trough levels.…”

“…27 In the CYPtest group of the current study, the time for achieving target tacrolimus concentration was significantly reduced, confirming poten- A number of clinical studies evaluated the impact of intestinal CYP3A5 polymorphism (recipient CYP3A5 genotype) on tacrolimus pharmacokinetics. Several trials involving mainly living donor liver transplant recipients demonstrated important consequences of recipients' CYP3A5 genotype on tacrolimus concentration/dose ratios and on dose requirements in the first postoperative month, 21,22,24,25 whereas other studies emphasized the contribution of the donor to the control recipients on tacrolimus blood concentration guided dosing. Acute rejection has been demonstrated to be associated with low predose tacrolimus concentration (<10 ng mL −1 ) both in kidney and in liver transplant recipients.…”

“…16,27 For liver transplant recipients, the donor CYP3A-status (CYP3A5 genotype and CYP3A4 expression) was demonstrated to provide prognostic information regarding the initial tacrolimus dosing for therapeutic blood concentration. 27 In the on dose requirements in the first postoperative month, 21,22,24,25 whereas other studies emphasized the contribution of the donor to the control recipients on tacrolimus blood concentration guided dosing. Acute rejection has been demonstrated to be associated with low predose tacrolimus concentration (<10 ng mL −1 ) both in kidney and in liver transplant recipients.…”

“…12,20 In living-donor liver transplantation, due to the fact that the grafted liver regenerates its mass and tacrolimus clearance gradually increases with post-transplant time, the pharmacokinetics primarily affected by the intestinal (recipient) CYP3A5 genotype early after transplantation, and by the liver graft or by both the recipient and the donor genotypes at late postoperative time. [21][22][23][24][25] Conditions as a consequence of nonbalanced suboptimal immunosuppressive therapy can lead to allograft rejection episodes, whereas supraoptimal therapy can result in nephrotoxicity or increased susceptibility to infections. 6,26 One of the causes, associated with these conditions, is tacrolimusmetabolizing capacity of the graft; therefore, any factor that can modulate tacrolimus blood concentrations influences the outcome of transplantation.…”

“…In full‐size liver transplantation, tacrolimus concentration/dose ratios seem to be influenced by the donor CYP3A5 genotype rather than by the recipient in the early (<1 month after transplantation) and late postoperative period (> 1 month) 9,10,18,19 ; however, some authors have suggested that both the donor and the recipient CYP3A5 genotypes are of major impact on tacrolimus clearance 12,20 . In living‐donor liver transplantation, due to the fact that the grafted liver regenerates its mass and tacrolimus clearance gradually increases with post‐transplant time, the pharmacokinetics primarily affected by the intestinal (recipient) CYP3A5 genotype early after transplantation, and by the liver graft or by both the recipient and the donor genotypes at late postoperative time 21–25 . Conditions as a consequence of nonbalanced suboptimal immunosuppressive therapy can lead to allograft rejection episodes, whereas supraoptimal therapy can result in nephrotoxicity or increased susceptibility to infections 6,26 .…”