Six-month, prospective, longitudinal, open-label caffeine and dextromethorphan phenotyping study in children with growth hormone deficiency receiving recombinant human growth hormone replacement.
BACKGROUND
Recombinant human growth hormone (r-hGH) is increasingly being used in children. Although growth hormone (GH) may alter the clearance of concomitantly administered medications, its effects on individual drug-metabolizing enzymes in children have not been characterized.


OBJECTIVE
The goal of this study was to assess the activities of cytochrome P450 (CYP) 1A2, N-acetyltransferase 2, xanthine oxidase, and CYP2D6 in children with isolated idiopathic GH deficiency before and 3 and 6 months after initiation of r-hGH treatment.


METHODS
This 6-month, prospective, longitudinal, open-label phenotyping study was conducted at 4 academic tertiary care centers within the Pediatric Pharmacology Research Unit network. Prepubertal or early pubertal children (4-14 years) with short stature and isolated idiopathic GH deficiency were enrolled. Patients were given 4 ounces of a cola beverage and 0.5 mg/kg of dextromethorphan (DM) before and 3 and 6 months after initiation of r-hGH treatment. Urine was collected for 8 hours after probe substrate administration, and enzyme activity was assessed using validatedcaffeine/metaboliteandDM/metabolitemolar ratios. Patients with a DM/dextrorphan molar ratio > or =0.3 were classified as poor metabolizers, and those with a ratio <0.3 were classified as extensive metabolizers. Anthropometric and biochemical responses were assessed at each visit. Blood was also obtained for determination of serum insulinlike growth factor-1 (IGF-1) levels and CYP2D6 genotype.


RESULTS
Fourteen patients (mean [SD] age, 11.5 [2.6] years [age range, 4.5-14.6 years]; 11 males, 3 females; 100% white; median height and weight, 131.8 cm and 29.2 kg, respectively) completed the 3 study visits. However, data from 2 patients were excluded from analysis due to procedural violations. In all patients, growth velocity and serum IGF-1 concentrations were significantly higher (P < 0.001) after r-hGH treatment (mean doses, 0.32 and 0.33 mg/kg per week at 3 and 6 months, respectively). However, molar ratio values did not significantly change after initiation of r-hGH.


CONCLUSIONS
In this study population of children with isolated idiopathic GH deficiency, no significant differences in caffeine/metabolite and DM/metabolite molar ratios were observed after initiation of r-hGH treatment.
Kennedy
Mary Jayne
MJ
Kosair Charities Pediatric Clinical Research Unit, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, Kentucky 40202, USA. mjkenn07@louisville.edu
Davis
Daniel A
DA
Smith
Ned
N
Gaedigk
Andrea
A
Pearce
Robin E
RE
Kearns
Gregory L
GL
D000293:Adolescent; D001191:Arylamine N-Acetyltransferase / Q000187:drug effects / Q000378:metabolism; D002110:Caffeine / Q000378:metabolism / Q000652:urine*; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000652:urine*; D002648:Child; D002675:Child, Preschool; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects / Q000378:metabolism; D003915:Dextromethorphan / Q000378:metabolism / Q000652:urine*; D004393:Dwarfism, Pituitary / Q000188:drug therapy; D005260:Female; D006130:Growth Disorders / Q000097:blood / Q000188:drug therapy*; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008137:Longitudinal Studies; D008297:Male; D010641:Phenotype; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014969:Xanthine Oxidase / Q000187:drug effects / Q000378:metabolism
D000697:Central Nervous System Stimulants; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D002110:Caffeine; D007334:Insulin-Like Growth Factor I; D003915:Dextromethorphan; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D014969:Xanthine Oxidase; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human