title: A Pharmacokinetic and Pharmacodynamic Study of Maraviroc as Acute Graft-versus-Host Disease Prophylaxis in Pediatric Allogeneic Stem Cell Transplant Recipients with Nonmalignant Diagnoses.
abstract: Maraviroc is an allosteric small molecule antagonist of chemokine receptor type 5 (CCR5) and has been used in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients to prevent acute graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract and liver. The goal of this study was to establish feasibility and pharmacokinetic and pharmacodynamic profiles of maraviroc in pediatric HSCT recipients. Children ages 2 to 12 years were enrolled and maraviroc was added to standard GVHD prophylaxis, which included a calcineurin inhibitor and either steroids or mycophenolate mofetil. Maraviroc was started on day -3 and administered at a dose of approximately 300 mg/m(2) orally twice daily until day +30 after stem cell infusion. On days 0 and day +10, samples for pharmacokinetic analysis were collected before the dose and 1, 2, 4, 6, 8, and 12 hours after maraviroc administration. Additional trough concentrations were collected on days +7, 14, and 21. Patients were followed until day +100 for acute GVHD. Functional blockade of CCR5 was assessed in a pharmacodynamic assay by flow cytometry. Thirteen patients, median age of 4 years (range, 2 to 11 years), were prospectively enrolled. Underlying diagnoses included a primary immune deficiency (n = 6), hemoglobinopathy (n = 4), metabolic disorder (n = 1), and bone marrow failure syndrome (n = 2). Patients received either a myeloablative preparative regimen (n = 7) or a reduced-intensity conditioning regimen (n = 6). Cyclosporine and methylprednisolone (n = 7) was the predominant GVHD prophylactic regimen, followed by tacrolimus and mycophenolate mofetil (n = 4) and tacrolimus and steroids (n = 2). Two formulations of maraviroc (150-mg tablets and 20-mg/mL solution) were used on study. Mean (± SD) area under the concentration-time curve from 0 to 12 hours was 4805 ± 3265 hour * ng/mL on day 0 and 5917 ± 4048 hour * ng/mL on day +10. Four patients developed grade 1 or 2 acute skin GVHD before day +100 and were successfully treated. Two patients developed grade 3 acute GI GVHD on days +23 and +24 after HSCT and both had discontinued maraviroc before development of GI GVHD. No adverse effects attributable to maraviroc were observed and administration by enteral tubes was well tolerated by children and accepted by parents. All evaluable patients demonstrated functional CCR5 blockade on day 0. Administration of maraviroc is feasible in most pediatric HSCT recipients with good safety and tolerability profile.
authors: Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: pooja.khandelwal@cchmc.org.
authors: Pooja
authors: P
authors: Khandelwal
authors: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Tsuyoshi
authors: T
authors: Fukuda
authors: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Kana
authors: K
authors: Mizuno
authors: Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Ashley
authors: A
authors: Teusink-Cross
authors: Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors: Parinda A
authors: PA
authors: Mehta
authors: Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors: Rebecca A
authors: RA
authors: Marsh
authors: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors: Angela D M
authors: ADM
authors: Kashuba
authors: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Alexander A
authors: AA
authors: Vinks
authors: Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors: Stella M
authors: SM
authors: Davies
mesh_terms: D000208:Acute Disease; D002648:Child; D002675:Child, Preschool; D003510:Cyclohexanes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D008297:Male; D000077592:Maraviroc; D011292:Premedication / Q000379:methods; D011446:Prospective Studies; D019713:Receptors, CCR5 / Q000187:drug effects; D019172:Transplantation Conditioning / Q000379:methods; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014781:Viscera / Q000473:pathology
chemical_list: C584933:CCR5 protein, human; D003510:Cyclohexanes; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc
keywords: CCR5 blockade; Chemokine receptor type 5 (CCR5) inhibition; Lymphocyte chemotaxis; Maraviroc