Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease.

Autor:	Kanter J; Division of Hematology and Oncology, University of Alabama, Birmingham, AL., Brown RC; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA., Norris C; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA., Nair SM; Mid Florida Hematology and Oncology Center, Orange City, FL., Kutlar A; Sickle Cell Center, Medical College of Georgia, Augusta University, Augusta, GA., Manwani D; Department of Pediatrics, Albert Einstein College of Medicine, Children's Hospital at Montefiore, Bronx, NY., Shah N; Department of Medicine, Duke University, Durham, NC., Tanaka C; Novartis Pharmaceuticals Corporation, East Hanover, NJ., Bodla S; GCE Solutions, Manchester, United Kingdom., Sanchez-Olle G; Novartis Pharma AG, Basel, Switzerland., Albers U; Novartis Pharma AG, Basel, Switzerland., Liles D; Division of Hematology-Oncology, East Carolina University, Greenville, NC.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2023 Mar 28; Vol. 7 (6), pp. 943-952.
DOI:	10.1182/bloodadvances.2022008209
Abstrakt:	Crizanlizumab is an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, nonrandomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of crizanlizumab 5.0 mg/kg (N = 45) and 7.5 mg/kg (N = 12) in patients with SCD with a history of VOCs. The median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion, and near complete and sustained ex vivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only 1 event was deemed treatment-related (7.5 mg/kg group). No treatment-related serious AEs occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 "pain during infusion"), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug-related. No treatment-related bleeding events were reported. No patients developed immunogenicity. The median (range) absolute reduction from baseline in the annualized rate of VOCs leading to a health care visit was -0.88 (-14.7 to 13.3) and -0.93 (-2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in patients with SCD and the potential sustained efficacy and long-term safety of the drug after >12 months' treatment. This trial was registered at www.clinicaltrials.gov as #NCT03264989. (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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