title: Basiliximab in pediatric liver transplantation: a pharmacokinetic-derived dosing algorithm.
abstract: The pharmacokinetics and immunodynamics of basiliximab were assessed in 37 pediatric de novo liver allograft recipients to rationally design a dose regimen for this age-group. In part one of the study, patients were given 12 mg/m2 basiliximab by bolus intravenous injection after organ perfusion and on day 4 after transplant. An interim pharmacokinetic evaluation supported a fixed-dose approach for part two of the study in which infants and children received two 10-mg doses of basiliximab and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for screening for anti-idiotype antibodies and analysis of basiliximab and soluble interleukin-2 receptor (IL-2R) concentrations. Basiliximab clearance in infants and children < 9 yr of age (n = 30) was reduced by approximately 50% compared with adults from a previous study and was independent of age to 9 yr, weight to 30 kg, and body surface area to 1.0 m2. Clearance in children and adolescents 9-14 yr of age (n = 7) approached or reached adult values. An average of 15% of the dose was eliminated via drained ascites fluid, and drug clearance via this route averaged 29% of total body clearance. Patients with > 5 L of ascites fluid drainage tended to have lower systemic exposure to basiliximab. CD25-saturating basiliximab concentrations were maintained for 27 +/- 9 days in part one of the study (mg/m2 dosing) with infants exhibiting the lowest durations. CD25 saturation lasted 37 +/- 11 days in part two of the study, based on the fixed-dose regimen (p = 0.004 vs. mg/mg2 dosing), but did not show the age-related bias observed in part one of the study. Anti-idiotype antibodies were detected in four patients, but this did not influence the clearance of basiliximab or duration of CD25 saturation. All 40 enrolled patients were included in the intent-to-treat clinical analysis. Episodes of acute rejection occurred in 22 patients (55%) during the first 12 months post-transplant. Three patients experienced loss of their graft as a result of technical complications, and six patients died during the 12-month study. Basiliximab was well tolerated by intravenous bolus injection, with no cytokine-release syndrome or other infusion-related adverse events. Hence, basiliximab was safe and well tolerated in pediatric patients undergoing orthotopic liver transplantation. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients < 35 kg in weight should receive two 10-mg doses and those > or = 35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose should be given within 6 h after organ perfusion and the second on day 4 after transplantation. A supplemental dose may be considered for patients with a large volume of drained ascites fluid relative to body size.
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland. john.kovarik@pharma.novartis.com
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Bruno G
authors.initials: BG
authors.lastname: Gridelli
authors.forename: Steven
authors.initials: S
authors.lastname: Martin
authors.forename: Burkhard
authors.initials: B
authors.lastname: Rodeck
authors.forename: Michael
authors.initials: M
authors.lastname: Melter
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Dunn
authors.forename: Robert M
authors.initials: RM
authors.lastname: Merion
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Tzakis
authors.forename: Estella
authors.initials: E
authors.lastname: Alonso
authors.forename: John
authors.initials: J
authors.lastname: Bucuvalas
authors.forename: Harvey
authors.initials: H
authors.lastname: Sharp
authors.forename: Christophe
authors.initials: C
authors.lastname: Gerbeau
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chodoff
authors.forename: Alexander
authors.initials: A
authors.lastname: Korn
authors.forename: Michael
authors.initials: M
authors.lastname: Hall
mesh_terms: D000293:Adolescent; D000465:Algorithms; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000077552:Basiliximab; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D007376:Interleukin-2 / Q000097:blood; D016031:Liver Transplantation; D008297:Male; D011446:Prospective Studies; D011993:Recombinant Fusion Proteins
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab