Dose individualization of intravenous busulfan in pediatric patients undergoing bone marrow transplantation: impact and in vitro evaluation of infusion lag-time

J Pharm Pharmacol. 2021 Sep 7;73(10):1340-1350. doi: 10.1093/jpp/rgab087.


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 Busulfan plasma levels, withdrawn by an optimized sampling scheme and measured by a validated HPLC-PDA method, were used to estimate basic PK parameters, AUC, Cmax, kel, t1/2, applying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.

Keywords: busulfan; infusion lag-time; pediatric population; pharmacokinetics; precision dosing; therapeutic drug monitoring.

MeSH terms

  • Administration, Intravenous
  • Adolescent
  • Adult
  • Age Factors
  • Area Under Curve
  • Body Weight
  • Bone Marrow Transplantation*
  • Busulfan / administration & dosage*
  • Busulfan / blood
  • Busulfan / pharmacokinetics
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Drug Monitoring*
  • Female
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / blood
  • Immunosuppressive Agents / pharmacokinetics
  • Infant
  • Infusions, Intravenous / methods*
  • Male
  • Pediatrics
  • Young Adult


  • Immunosuppressive Agents
  • Busulfan