Exogenous and Endogenous Biomarkers of CYP2D6 and CYP3A4 Variability in Pediatrics

This proposal represents a continuation of previous and ongoing longitudinal studies to characterize the relative contribution of pharmacogenetics and ontogeny to variability in CYP2D6 and CYP3A4 activity between birth and adolescence. Specifically, the overall goal of the research program is to test the hypothesis that genetic variability, rather than ontogeny, is the primary source of variability in CYP2D6 and CYP3A4 activity during adolescence. This study will extend our current series of longitudinal phenotyping studies and will be a cross-sectional study in children aged 7-15 years, studied on seven occasions, 6 months apart.

Children will be recruited from Children's Mercy Hospitals and Clinics, The Children's Mercy Hospital Northland Campus, and The Children's Mercy South Campus.

Subjects participating in this study will consist of a total of 220 children and adolescents from 7 to 15 years of age with a gender and ethnic distribution representative of the patient population served by Children's Mercy Hospital (CMH; from a representative 12 month period) as follows: White, 59.6%; African-American, 31.9%; Hispanic, 4.9%; Asian, 0.6%;Native American, 0.1%; Other, 2.9%. The gender distribution is 44.4% female and 55.6% male. An equal number of pediatric patients who meet the DSM-IV criteria for a primary diagnosis of ADHD or ADD (~33%) and age- and sex-matched controls (~67%) will be recruited. The patients represent a population of children who can reasonably expect to be treated with a medication that is primarily dependent upon CYP2D6 for its elimination from the body. An example is atomoxetine, also known as Strattera®. Each patient will be asked to invite a friend to participate in the phenotyping study with them, providing a non-ADHD population as a reference. Additional phenotyping visits will occur every six months (totaling 7 visits). Justification: Assuming a 10% attrition rate for the second visit, the sample size is expected to provide approximately 25 patients and 25 controls (50 subjects total) in each initial 2-year age bin: 7.0 to 9.0 y, 9.1 to 11.0 y, 11.1 to 13.0 y, and 13.1 to 15.0 y.

Subjects will be enrolled via informed permission/assent and will be studied as outpatients utilizing resources provided by the Pediatric Clinical Research Unit located in the Division of Clinical Pharmacology and Medical Toxicology at Children's Mercy Hospital. For the ADHD group, patients being treated with atomoxetine at the time of study enrollment will be allowed to participate. Although in vitro studies indicate that atomoxetine inhibits CYP2D6 activity by ~50%, there does not appear to be any effect in vivo as single dose pharmacokinetics of the CYP2D6 substrate, desipramine, were unaffected by four days of atomoxetine 60 mg b.i.d. Thus, we do not expect any substantial effect on DM biotransformation. Furthermore, if during the six month interval between phenotyping visits ADHD patients are prescribed medications that are known CYP2D6 inhibitors, they will be allowed to continue in the study; the dose and start date of these medications will be recorded and the effect of the inhibitor on CYP2D6 phenotype (urinary metabolite ratio and endogenous biomarker) will be determined. These data points will be excluded from the ontogeny and genotype-phenotype correlation analysis

Pre-study visit. (about 1 hour long) On a screening visit, prospective subjects (and their parents) will be provided with a description of the proposed study. After all their questions have been answered, they will be given a copy of the permission/assent form to review and sign Subjects will then have their medical history and use of medications reviewed, including the use of non-prescription and herbal remedies. All subjects will be given a complete physical examination by a physician, including vital signs (blood pressure, heart rate, breathing rate, temperature, height and weight) and an assessment of pubertal development by Tanner stage. Breast development will be assessed by visual inspection. Pubic hair will be assessed by visual inspection. Testicular volume will be measured by direct comparison to orchidometer beads. Tanner Staging will be assessed by a gender appropriate physician. Blood will be drawn by needle stick for serum chemistries, liver function tests and a hematology panel; a portion will also be retained for DNA testing (approximately 2 teaspoons of blood total). Urine will be collected for a Urinalysis with Micro. Numbing cream may be applied to the site to minimize discomfort. A urine pregnancy test will be performed for females of child bearing age.