193: Microdosed Yohimbine as CYP2D6 Probe Drug in Pediatric Heart Patients Aged 6 Months to 6 Years

Statement of Purpose: A safe and effective drug therapy for children requires a fundamental understanding of the role of ontogeny in pharmacokinetics (PK) and pharmacodynamics. The maturation of CYP2D6 during early infancy has been described by being present at 1 week of age, increasing to 20% of adult activity by the age of 1 month, and reaching adult capacity by 3-5 years of age. In addition, genetic polymorphisms can contribute to variations in the expression of CYP2D6 activity, thus suitable probe drugs are evaluated for phenotyping. Yohimbine is a plant-derived indole alkaloid and alpha-2 receptor antagonist. It is metabolized to 11-OH-yohimbine by CYP2D6. The purpose of this study was to characterize CYP2D6 activity by means of a yohimbine microdose in young children.

Description of Methods & Materials: A single-center, open label, fixed-sequence clinical trial primarily evaluating a microdosed anticoagulant cocktail (EudraCT 2019-001759-38) was conducted in children aged 6 months-6 years (body weight >7 kg) after congenital heart surgery. Yohimbine (25 µg p.o.) was used as probe drug to determine CYP2D6 activity. Plasma concentrations over 12 h were quantified by UHPLC-MS/MS.

Data & Results: The mean age of the 14 children (6m/8f) was 1.9 (0.5–4.9) years and mean body weight was 10.9 (7.2 –18.2) kg. All patients received concomitant treatment per standard of care after heart surgery. Oral clearance was 167 (95% CI 147-326) mL/min, Volume of distribution was 16.8 (95% CI 13.4-31.9) L. T_1/2 was 1.2 (95%-CI 1.0-1.4) h. C_max was 2757 (95% CI 2,028-5,249) pg/mL. AUC_0-inf was 2,500 (95% CI 53-10,100) h*pg/mL. No adverse events related to the study drugs occurred.

Interpretation, Conclusion or Significance: This small cohort delivers first, preliminary information on the PK of Yohimbine in young children up to 6 years of age. The application of a 25 µg microdose together with highly sensitive analytical methods is a safe and effective methodology to assess CYP2D6 activity in vulnerable pediatric populations. Yohimbine seems to be a suitable candidate as probe drug for CYP2D6 phenotyping in children, which should be evaluated in a larger cohort.

Disclosures: Nothing to disclose by any of the authors.