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

Min, Sandar; Papaz, Tanya; Lafrenière-Roula, Myriam; Nalli, Nadya; Grasemann, Hartmut; Kamath, Binita M.; Ng, Vicky L.; Parekh, Rulan S.; Manlhiot, Cedric; Mital, Seema

doi:10.1111/petr.13285

Cited by 34 publications

(32 citation statements)

References 30 publications

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“…Our findings suggest that it may be of advantage stratifying genotype-guided dosing by the graft size (GRWR) instead of the recipient age 17 . We reported in Fig.…”

Section: Discussionmentioning

confidence: 87%

Early impact of donor CYP3A5 genotype and Graft-to-Recipient Weight Ratio on tacrolimus pharmacokinetics in pediatric liver transplant patients

Pinon

Nicolò

Pizzol

et al. 2021

Sci Rep

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Tacrolimus (TAC) pharmacokinetics is influenced by the donor CYP3A5 genotype and the age of pediatric liver recipients. However, an optimization of a genotype-based algorithm for determining TAC starting is needed to earlier achieve stable target levels. As the graft itself is responsible for its metabolism, the Graft-to-Recipient Weight Ratio (GRWR) might play a role in TAC dose requirements. A single-center study was carried out in a cohort of 49 pediatric recipients to analyse the impact of patient and graft characteristics on TAC pharmacokinetics during the first 15 post-transplant days. Children < 2 years received grafts with a significantly higher GRWR (4.2%) than children between 2–8 (2.6%) and over 8 (2.7%). TAC concentration/weight-adjusted dose ratio was significantly lower in recipients from CYP3A5*1/*3 donors or with extra-large (GRWR > 5%) or large (GRWR 3–5%) grafts. The donor CYP3A5 genotype and GRWR were the only significant predictors of the TAC weight adjusted doses. Patients with a GRWR > 4% had a higher risk of acute rejection, observed in 20/49 (41%) patients. In conclusion, TAC starting dose could be guided according to the donor CYP3A5 genotype and GRWR, allowing for a quicker achievement of target concentrations and eventually reducing the risk of rejection.

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“…Our findings suggest that it may be of advantage stratifying genotype-guided dosing by the graft size (GRWR) instead of the recipient age 17 . We reported in Fig.…”

Section: Discussionmentioning

confidence: 87%

Early impact of donor CYP3A5 genotype and Graft-to-Recipient Weight Ratio on tacrolimus pharmacokinetics in pediatric liver transplant patients

Pinon

Nicolò

Pizzol

et al. 2021

Sci Rep

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“…There is compelling evidence that CYP3A5 expressers require a 1.5-to 2-fold higher tacrolimus dose than nonexpressers [15,[17][18][19][30][31][32][33][34][35][36]. A randomized clinical trial of age-and genotype-guided tacrolimus dosing in children concluded that CYP3A5 genotype-guided dosing stratified by age resulted in earlier attainment of therapeutic tacrolimus concentrations and fewer out-of-range concentrations [37]. Clinical outcomes were not studied.…”

Section: Discussionmentioning

confidence: 99%

A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement

et al. 2019

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Background and Objective Bodyweight-based dosing of tacrolimus is considered standard care. Currently, at first steady state, a third of pediatric kidney transplant recipients has a tacrolimus pre-dose concentration within the target range. We investigated whether adaptation of the starting dose according to a validated dosing algorithm could increase this proportion. Methods This was a multi-center, single-arm, prospective trial with a planned interim analysis after 16 patients, in which the tacrolimus starting dose was based on bodyweight, cytochrome P450 3A5 genotype, and donor status (living vs. deceased donor). Results At the interim analysis, 31% of children had a tacrolimus pre-dose concentration within the target range. As the original dosing algorithm was poorly predictive of tacrolimus exposure, the clinical trial was terminated prematurely. Next, the original model was improved by including the data of the children included in this trial, thereby doubling the number of children in the model building cohort. Data were best described with a two-compartment model with inter-individual variability, allometric scaling, and inter-occasion variability on clearance. Cytochrome P450 3A5 genotype, hematocrit, and creatinine influenced the tacrolimus clearance. A new starting dose model was developed in which the cytochrome P450 3A5 genotype was incorporated. Both models were successfully internally and externally validated. Conclusions The weight-normalized starting dose of tacrolimus should be higher in patients with a lower bodyweight and in those who are cytochrome P450 3A5 expressers. Key Points A validated dosing algorithm could poorly predict the individual starting dose of tacrolimus following renal transplantation in cytochrome P450 3A5 expressers receiving a kidney from a deceased donor. The dosing algorithm was improved and the weightnormalized starting dose of tacrolimus should be higher in patients with lower bodyweight and in those who are cytochrome P450 3A5 expressers. This study demonstrates that even though a model is validated on paper, it is not necessarily effective in clinical practice. Dosing algorithms should first be tested in prospective studies.

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“…9 A randomized clinical trial in pediatrics showed that CYP3A5 genotypeguided dosing based on age resulted in earlier attainment of target concentrations. 15 There are little to no data in the dosing of sirolimus, an immunosuppressant frequently prescribed off-label in the pediatric population, for infants and newborns. In the last 5 years, clinical pharmacology research has led to the development of population pharmacokinetic models in this young population, and model-informed precision dosing has been used to achieve therapeutic response in children with vascular anomalies.…”

Section: Researchmentioning

confidence: 99%

Partnering with Clinical Pharmacologists to Improve Medication Use in Children

Miyagi

Lam

Girdwood

2020

The Journal of Pediatrics

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A merican children receive on average 3.5 prescriptions annually, with 62%-85% used off-label. 1,2 Lack of formulations suitable for children is a major reason for off-label and unlicensed use of medications. 3 Although this practice does not imply improper, illegal, contraindicated, or investigational use, it often lacks substantial evidence of effectiveness and/or safety from adequate and well-controlled studies. The passage of legislation (Best Pharmaceuticals for Children Act in 2002, the Pediatric Research Equity Act in 2003, the Food and Drug Administration Safety and Innovation Act in 2012; and the Food and Drug Administration Reauthorization Act in 2017) has helped to change >500 labels to include pediatric indications, yet 59% of drug labels still do not contain pediatric information. 2 Furthermore, clinical data for preterm and full-term neonates, infants, children <2 years of age, in addition to children with chronic or rare diseases, are lacking. 2,4 The lack of pediatric clinical data can lead to subtherapeutic effects owing to underdosing or toxicity related to overexposure. Furthermore, children are also inherently predisposed to adverse drug events owing to developmental pharmacology, the age-dependent changes that affect response to and elimination of drugs. 1,2,4-6 It is also unethical to deny children the benefit of medications that are otherwise approved for adults just because they are a vulnerable population and the conduct of pediatric trials is difficult. Thus, it is necessary to conduct pediatric drug trials under conditions that optimize protection for children as participants in research.

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

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

Cited by 34 publications

References 30 publications

Early impact of donor CYP3A5 genotype and Graft-to-Recipient Weight Ratio on tacrolimus pharmacokinetics in pediatric liver transplant patients

Early impact of donor CYP3A5 genotype and Graft-to-Recipient Weight Ratio on tacrolimus pharmacokinetics in pediatric liver transplant patients

A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement

Partnering with Clinical Pharmacologists to Improve Medication Use in Children

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