Sandar Min1, Tanya Papaz1, Myriam Lafreniere-Roula1, Nadya Nalli2, Hartmut Grasemann1, Steven M Schwartz3, Binita M Kamath1, Vicky Ng4, Rulan S Parekh1,5,6, Cedric Manlhiot7, Seema Mital1. 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 receivegenotype-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.
RCT Entities:
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.
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