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Pediatr Transplant. 2018 Nov;22(7):e13285. doi: 10.1111/petr.13285. Epub 2018 Sep 3.

A randomized clinical trial of age and genotype-guided tacrolimus dosing after pediatric solid organ transplantation.

Author information

1
Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
2
Department of Pharmacy, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
3
Department of Cardiac Critical Care Medicine, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
4
Transplant and Regenerative Medicine Centre, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
5
Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, Ontario, Canada.
6
Child Health Evaluative Sciences Program, SickKids Research Institute, Toronto, Ontario, Canada.
7
Cardiovascular Data Management Centre (CVDMC) Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Abstract

BACKGROUND:

Tacrolimus pharmacokinetics are influenced by age and CYP3A5 genotype with CYP3A5 expressors (CYP3A5*1/*1 or *1/*3) being fast metabolizers. However, the benefit of genotype-guided dosing in pediatric solid organ transplantation has been understudied.

OBJECTIVE:

To determine whether age and CYP3A5 genotype-guided starting dose of tacrolimus result in earlier attainment of therapeutic drug concentrations.

SETTING:

Single hospital-based transplant center.

METHODS:

This was a randomized, semi-blinded, 30-day pilot trial. Between 2012 and 2016, pediatric patients listed for solid organ transplant were consented and enrolled into the study. Participants were categorized as expressors, CYP3A5*1/*1 or CYP3A5*1/*3, and nonexpressors, CYP3A5*3/*3. Patients were stratified by age (≤ or > 6 years) and randomized (2:1) after transplant to receive genotype-guided (n = 35) or standard (n = 18) starting dose of tacrolimus for 36-48 hours and were followed for 30 days.

RESULTS:

Median age at transplant in the randomized cohort was 2.1 (0.75-8.0) years; 24 (45%) were male. Participants in the genotype-guided arm achieved therapeutic concentrations earlier at a median (IQR) of 3.4 (2.5-6.6) days compared to those in the standard dosing arm of 4.7 (3.5-8.6) days (P = 0.049), and had fewer out-of-range concentrations [OR (95% CI) = 0.60 (0.44, 0.83), P = 0.002] compared to standard dosing, with no difference in frequency of adverse events between the two groups.

CONCLUSIONS:

CYP3A5 genotype-guided dosing stratified by age resulted in earlier attainment of therapeutic tacrolimus concentrations and fewer out-of-range concentrations.

KEYWORDS:

genetics; immunosuppression; pediatric transplantation; solid organ; tacrolimus; therapeutic drug monitoring; transplantation

PMID:
30178515
DOI:
10.1111/petr.13285
[Indexed for MEDLINE]

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