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

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 Busulfan plasma levels, withdrawn by an optimized sampling scheme and measured by a validated HPLC-PDA method, were used to estimate basic PK parameters, AUC, Cmax, kel, t1/2, applying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

Pharmacokinetics of doripenem in CSF of patients with non-inflamed meninges.

OBJECTIVES: To investigate intact blood-brain barrier (BBB) penetration by doripenem and characterize doripenem pharmacokinetics in CSF using a pharmacokinetic model. PATIENTS AND METHODS: Thirty-eight neurological patients with no active neurological disease or CNS infection received a single 500 mg doripenem dose before pump implantation surgery, or lumbar puncture, for intrathecal baclofen administration. In most cases single CSF and blood samples were collected per patient and analysed for doripenem with HPLC. A two-stage pharmacokinetic analysis was performed to estimate: (i) empirical Bayesian estimates (EBEs) of individual doripenem plasma pharmacokinetic parameters, using plasma doripenem concentrations and literature population priors for a two-compartment model; and (ii) doripenem CSF pharmacokinetic parameters using simulated plasma concentrations from stage (i) as a forcing function. The mean values of the structural model parameters, k(CSF) (distribution rate constant) and PC (CSF/plasma partition coefficient), and the residual variability were estimated. RESULTS: The mean estimates of the parameters were k(CSF)= 0.105 h(-1) and PC= 0.053, corresponding to mean steady-state doripenem CSF concentrations of 0.20 mg/L and 0.40 mg/L for regimens of 3 × 500 mg daily and 3 × 1000 mg daily, respectively, and a mean equilibrium half-life of 6.6 h. The model was validated internally using a visual predictive check (VPC) and bootstrap. Simulating two dosing scenarios gave doripenem levels in the CSF above or close to the literature MIC values. CONCLUSIONS: The present NONMEM software analysis shows that doripenem crosses intact BBB significantly and suggests that the drug should be further evaluated as a candidate to treat certain CNS infections, since drug penetration through BBB is enhanced by meningeal inflammation.