title: Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose fingolimod (FTY720) in adolescents with stable renal transplants.
abstract: Oral fingolimod signals the sphingosine 1-phosphate receptor and this in turn mediates immunomodulatory activity. No data of fingolimod in any pediatric population existed before this study. We put our study results in perspective against data from adult renal transplant patients. We investigated pharmacokinetics and pharmacodynamics of single-dose fingolimod (0.07 mg/kg) and its effects on lymphocytes and heart rate in seven adolescents (14.1 ± 1.6 yr) with stable renal transplants. Blood samples for pharmacokinetics and lymphocytes were collected at screening, baseline, and up to 28 days post-dosing. Cardiac monitoring included 12-lead ECG, 24-h Holter monitoring, and echocardiography. A fingolimod dose of 0.07 mg/kg resulted in mean AUC of 731 ± 240 ng·h/mL and C(max) of 3.6 ± 0.6 ng/mL. Drug exposure was nearly identical to adults receiving the same dose. Absolute lymphocyte count decreased 85% from baseline; average nadir occurred by six h post-dose. Heart rate decreased from 74 bpm (predose mean) to 53 bpm (nadir) three h post-dose. Mean heart rates recovered by Day 14 (75 bpm). Weight-adjusted doses of fingolimod in adolescents resulted in drug exposure similar to adults. Adolescents and adults shared comparable negative chronotropic effects and decreased lymphocyte count. Recovery trajectories of these parameters back to baseline were similar between age groups.
authors.affiliation: Division of Pediatric Nephrology, Mattel Children's Hospital UCLA, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095-1752, USA. rettenger@mednet.ucla.edu
authors.forename: R
authors.initials: R
authors.lastname: Ettenger
authors.forename: R
authors.initials: R
authors.lastname: Schmouder
authors.forename: J M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: M C
authors.initials: MC
authors.lastname: Bastien
authors.forename: P F
authors.initials: PF
authors.lastname: Hoyer
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004562:Electrocardiography; D015716:Electrocardiography, Ambulatory / Q000379:methods; D005260:Female; D000068876:Fingolimod Hydrochloride; D005500:Follow-Up Studies; D006085:Graft Survival; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008991:Monitoring, Physiologic / Q000379:methods; D011182:Postoperative Care / Q000379:methods; D011409:Propylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011446:Prospective Studies; D018570:Risk Assessment; D013110:Sphingosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016176:T-Lymphocyte Subsets / Q000187:drug effects
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine