The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients

Abstract

BackgroundTacrolimus is an important immunosuppressive agent with high intra- and inter-individual pharmacokinetic variability and a narrow therapeutic index. As tacrolimus extensively accumulates in erythrocytes, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations. However, as hematocrit values in pediatric kidney transplant patients are highly variable after kidney transplantation, translating whole blood concentration targets without taking hematocrit into consideration is theoretically incorrect. The aim of this study is to evaluate the potential impact of hematocrit correction on tacrolimus target exposure in pediatric kidney transplant patients.MethodsData were obtained from 36 pediatric kidney transplant patients. Two hundred fifty-five tacrolimus whole blood samples were available, together responsible for 36 area under the concentration-time curves (AUCs) and trough concentrations. First, hematocrit corrected concentrations were derived using a formula describing the relationship between whole blood concentrations, hematocrit, and plasma concentrations. Subsequently, target exposure was evaluated using the converted plasma target concentrations. Ultimately, differences in interpretation of target exposure were identified and evaluated.ResultsIn total, 92% of our patients had lower hematocrit (median 0.29) than the reference value of adult kidney transplant patients. A different evaluation of target exposure for either trough level, AUC, or both was defined in 42% of our patients, when applying hematocrit corrected concentrations.ConclusionA critical role for hematocrit in therapeutic drug monitoring of tacrolimus in pediatric kidney transplant patients is suggested in this study. Therefore, we believe that hematocrit correction could be a step towards improvement of tacrolimus dose individualization.Electronic supplementary materialThe online version of this article (10.1007/s00467-018-4117-x) contains supplementary material, which is available to authorized users.

Unbound Plasma, Total Plasma, and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

“…This vulnerability to hemolysis makes analyses of plasma tacrolimus concentrations as a routine practice a major challenge. Our results concur with previous studies that suggest hematocritcorrected whole-blood concentrations could be of use for improved target exposure [11,24,33]. We assume that only correction to hematocrit is sufficient while protein levels will not have a large effect on the whole-blood concentrations because the majority of tacrolimus was associated with erythrocytes and plasma concentrations were < 1% of the whole-blood concentrations.…”

“…Tacrolimus extensively binds to red blood cells and blood proteins. As a consequence, tacrolimus whole-blood distribution is strongly affected by hematocrit and protein concentrations, e.g., albumin, lipoproteins, and α 1 -acid glycoprotein [7][8][9][10][11]. While wholeblood concentrations are commonly used for therapeutic drug monitoring, the unbound tacrolimus plasma concentrations might be better related to the toxicity and efficacy of tacrolimus [8,12,13].…”

Population pharmacokinetics and genetics of oral meltdose tacrolimus (Envarsus) in stable adult liver transplant recipients

“…Hematocrit was analyzed as covariate on CL and/or V1 based on literature. [26,27] Recipient and donor CYP3A4*22 and CYP3A5*3 genotype were analyzed on CL and F in an univariate analysis. In addition, using automated scm, donor, recipient and combined CYP3A4*22 and CYP3A5*3 genotype , together with IL-6, -10 and-18 genotype were analyzed on CL.…”

Clinical Pharmacokinetics and Impact of Hematocrit on Monitoring and Dosing of Tacrolimus Early After Heart and Lung Transplantation

“…Because of the large influence of hematocrit on wholeblood concentrations, hematocrit-corrected whole-blood concentrations may be suitable as a substitute for the prediction of clinical outcomes. Two studies showed that for clinically stable renal transplants, hematocrit standardized whole-blood concentrations improved the prediction of whole-blood concentrations [18,47]. Størset assumed that when hematocrit increases, the unbound concentration remains similar, which may be an incorrect assumption in patients with lower hematocrit fractions [18].…”