TY - JOUR
TI - Dose individualization of intravenous busulfan in pediatric patients undergoing bone marrow transplantation: Impact and in vitro evaluation of infusion lag-time
AU - Neroutsos, E.
AU - Athanasiadou, I.
AU - Paisiou, A.
AU - Zisaki, K.
AU - Goussetis, E.
AU - Archontaki, H.
AU - Tsirigotis, P.
AU - Kitra, M.
AU - Grafakos, S.
AU - Spyridonidis, A.
AU - Dokoumetzidis, A.
AU - Valsami, G.
JO - The Journal of pharmacy and pharmacology
PY - 2021
VL - 73
TODO - 10
SP - 1340-1350
PB - Oxford University Press
SN - null
TODO - 10.1093/jpp/rgab087
TODO - busulfan;  busulfan;  immunosuppressive agent, adolescent;  adult;  area under the curve;  Article;  blood sampling;  body weight;  bone marrow transplantation;  child;  dose individualization;  drug blood level;  drug monitoring;  female;  groups by age;  high performance liquid chromatography;  human;  in vitro study;  in vivo study;  individualization;  infant;  major clinical study;  male;  maximum concentration;  retrospective study;  age;  blood;  dose response;  drug monitoring;  intravenous drug administration;  pediatrics;  preschool child;  procedures;  young adult, Administration, Intravenous;  Adolescent;  Adult;  Age Factors;  Area Under Curve;  Body Weight;  Bone Marrow Transplantation;  Busulfan;  Child;  Child, Preschool;  Dose-Response Relationship, Drug;  Drug Monitoring;  Female;  Humans;  Immunosuppressive Agents;  Infant;  Infusions, Intravenous;  Male;  Pediatrics;  Young Adult
TODO - Objectives: To apply therapeutic drug monitoring and dose-individualization of intravenous Busulfan to paediatric patients and evaluate the impact of syringe-pump induced Busulfan infusion lag-time after in vitro estimation. Methods: 76 children and adolescents were administered 2 h intravenous Busulfan infusion every 6 h (16 doses). Busulfan plasma levels, withdrawn by an optimized sampling scheme and measured by a validated HPLC-PDA method, were used to estimate basic PK parameters, AUC, Cmax, kel, t1/2, applying Non-Compartmental Analysis. In vivo infusion lag-time was simulated in vitro and used to evaluate its impact on AUC estimation. Key findings: Mean (%CV) Busulfan AUC, Cmax, clearance and t1/2 for pediatric population were found 962.3 μm × min (33.1), 0.95 mg/L (41.4), 0.27 L/h/kg (33.3), 2.2 h (27.8), respectively. TDM applied to 76 children revealed 6 (7.9%) being above and 25 (32.9%) below therapeutic-range (AUC: 900-1350 μm × min). After dose correction, all patients were measured below toxic levels (AUC < 1500 μm × min), no patient below 900 μm × min. Incorporation of infusion lag-time revealed lower AUCs with 17.1% more patients and 23.1% more younger patients, with body weight <16 kg, being below the therapeutic-range. Conclusions: TDM, applied successfully to 76 children, confirmed the need for Busulfan dose-individualization in paediatric patients. Infusion lag-time was proved clinically significant for younger, low body-weight patients and those close to the lower therapeutic-range limit. © The Author(s) 2021.
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