@article{3020190,
    title = "Dose individualization of intravenous busulfan in pediatric patients undergoing bone marrow transplantation: Impact and in vitro evaluation of infusion lag-time",
    author = "Neroutsos, E. and Athanasiadou, I. and Paisiou, A. and Zisaki, K. and Goussetis, E. and Archontaki, H. and Tsirigotis, P. and Kitra, M. and Grafakos, S. and Spyridonidis, A. and Dokoumetzidis, A. and Valsami, G.",
    journal = "The Journal of pharmacy and pharmacology",
    year = "2021",
    volume = "73",
    number = "10",
    pages = "1340-1350",
    publisher = "Oxford University Press",
    doi = "10.1093/jpp/rgab087",
    keywords = "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",
    abstract = "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 Busulfan plasma levels, withdrawn by an optimized sampling scheme and measured by a validated HPLC-PDA method, were used to estimate basic PK parameters, AUC, Cmax, kel, t1/2, applying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."
}