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Cancer Chemother Pharmacol. 2016 Feb;77(2):405-12. doi: 10.1007/s00280-015-2955-9. Epub 2016 Jan 20.

Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy.

Author information

1
Children's Hospital Los Angeles, University of Southern California, 4650 Sunset Blvd, Los Angeles, CA, 90027, USA. amarachelian@chla.usc.edu.
2
Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA, 19104, USA.
3
Vanderbilt University School of Medicine, 2200 Pierce Ave 397 PRB, Nashville, TN, 37232-6310, USA.
4
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University School of Medicine, 1405 Clifton Rd NE, Atlanta, GA, 30322, USA.
5
Duke University, DUMC 102382, Durham, NC, 27710, USA.
6
Arkansas Children's Hospital/University of Arkansas for Medical Sciences, 1 Children's Way; Slot 512-23, Little Rock, AR, 72202, USA.
7
Department of Pediatrics, The University of Chicago, 900 E 57th Street, KCBD, Rm 5100, Chicago, IL, 60637, USA.
8
School of Pharmacy, Wingate University, 515 N. Main Street, Wingate, NC, 28174, USA.
9
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA, 92010, USA.
10
United Therapeutics Corporation, 55 TW Alexander Drive, Research Triangle Park, NC, 27709, USA.
11
National Cancer Institute, 9609 Medical Center Dr, MSC 9739, Bethesda, MD, 20892-9739, USA.

Abstract

PURPOSE:

Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products.

METHODS:

In this randomized, two-sequence crossover study, 28 patients aged ≤8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m(2)/day (ch14.18-UTC) and 25 mg/m(2)/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3-5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM(®) version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (C max). All comparisons were based on a standardized single-dose regimen (17.5 mg/m(2) over 10 h).

RESULTS:

Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products' systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88-1.04) and C max (1.04; 90 % CI 0.98-1.11) within standard bioequivalence bounds (90 % CI 0.80-1.25). Products' adverse events were similar and consistent with those previously reported.

CONCLUSIONS:

Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences.

KEYWORDS:

Dinutuximab; Pharmacokinetics; Safety; Tolerability; Unituxin; ch14.18

PMID:
26791869
PMCID:
PMC4747995
DOI:
10.1007/s00280-015-2955-9
[Indexed for MEDLINE]
Free PMC Article

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