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Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
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Tacrolimus dose requirements in paediatric renal allograft recipients are characterized by a biphasic course

Noël Knops1,2, Jean Herman1, Maria van Dyck1

  • 1Dept. of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.

British Journal of Clinical Pharmacology
|December 15, 2016
PubMed

Insights

Children

Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Pediatric Nephrology
  • Immunosuppression Therapy

Background:

  • Age-dependent differences in drug disposition are known in children, but mechanisms and precise course remain unclear.
  • Tacrolimus dosing in pediatric kidney transplant recipients requires optimization due to variable drug handling.

Purpose of the Study:

  • To determine the course and determinants of individual relative dose requirements for tacrolimus in children during long-term follow-up.
  • To evaluate the impact of age and pharmacogenetics on tacrolimus disposition in pediatric renal allograft recipients.

Main Methods:

  • A cohort study involving 43 pediatric renal allograft recipients (≤19 years) with standardized annual pharmacokinetic (PK) follow-up.
  • Evaluation of tacrolimus exposure (AUC0-12hr) corrected for dose per kg and per m², using mixed models.
  • Determination of pharmacogenetic variants (CYP3A4, CYP3A5, CYP3A7) and their association with dose requirements.

Main Results:

  • Tacrolimus exposure corrected for dose per kg showed a biphasic course: a 4.4% annual increase until age ±14, then a 13.4% increase.
  • Exposure corrected for dose per m² was stable until age ±14 (+0.8% annually), followed by a significant increase (≥14 years, +11%).
  • Bone maturation (TW2: 800) correlated with tacrolimus disposition changes, and genetic variations in CYP3A4/5/7 affected dose requirements independently of age.

Conclusions:

  • Pediatric tacrolimus disposition follows a biphasic course, with altered drug clearance around pubertal development (age ±14 years).
  • Pharmacogenetic variations influence tacrolimus dose requirements independent of age or puberty.
  • Current pediatric dosing algorithms for tacrolimus and similar drugs warrant re-evaluation based on these findings.
Abstract

Keywords:
childrendrug dispositionontogenypharmacokineticstacrolimus

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