Two grams of cefazolin at induction of anesthesia with a repeat dose after initiation of CPB ensures adequate drug levels to target a majority of pathogens of surgical site infections. Pharmacokinetic modeling demonstrated a significant influence of CPB on the volume of distribution and elimination of cefazolin. Other influences on pharmacokinetic parameters were albumin, protein, and creatinine clearance.

IntroductionFluconazole is an important antifungal in the prevention and treatment of invasive Candida infections in neonates, even though its use in preterm infants is still off-label. Here, we performed a population pharmacokinetic study on fluconazole in preterm neonates in order to optimise dosing through the identified predictive patient characteristics.MethodsFluconazole concentrations obtained from preterm infants from two studies were pooled and analysed using NONMEM V.7.3. The developed model was used to evaluate current dosing practice. A therapeutic dosing strategy aiming to reach a minimum target exposure of 400 and 200 mg×hour/L per 24 hours for fluconazole-susceptible C. albicans meningitis and other systemic infections, respectively, was developed.ResultsIn 41 preterm neonates with median (range) gestational age 25.3 (24.0–35.1) weeks and median postnatal age (PNA) at treatment initiation 1.4 (0.2–32.5) days, 146 plasma samples were collected. A one-compartment model described the data best, with an estimated clearance of 0.0147 L/hour for a typical infant of 0.87 kg with a serum creatinine concentration of 60 µmol/L and volume of distribution of 0.844 L. Clearance was found to increase with 16% per 100 g increase in actual body weight, and to decrease with 12% per 10 µmol/L increase in creatinine concentration once PNA was above 1 week. Dose adjustments based on serum creatinine and daily dosing are required for therapeutic target attainment.ConclusionIn preterm neonates, fluconazole clearance is best predicted by actual body weight and serum creatinine concentration. Therefore, fluconazole dosing should not only be based on body weight but also on creatinine concentration to achieve optimal exposure in all infants.Ethics statementThe Erasmus MC ethics review board approved the protocol of the DINO Study (MEC-2014-067) and the Radboud UMC ethics review board waived the need for informed consent for cohort 2 (CMO-2021-8302). Written informed consent from parents/legal guardians was obtained prior to study initiation.

Doxorubicin is a key component of a number of treatment regimens used in paediatric oncology, despite the very limited pharmacology data on which current dosing regimens are based. We conducted a multicentre, multinational phase II pharmacokinetic study investigating age-dependency in the clearance of doxorubicin in children with solid tumours and leukaemia. The study was funded under the Framework Program 7 of the European Commission. 101 patients treated with doxorubicin according to a tumour-specific national or European therapeutic trial were recruited to the study, with a particular focus on children less than 3 years. Absolute doses of doxorubicin ranged from 2.4 to 57 mg, administered, with infusion durations ranging from 0.25 to 24 hours. Samples were collected after 2 administrations, with 5 samples collected in children <3yrs and 8 samples in children ≥3yrs. Doxorubicin and its major metabolite doxorubicinol were measured in plasma using a validated HPLC-fluorescence assay with a limit of quantification of 2 μg/L for each analyte. Markers such as troponin T and natriuretic peptides were measured to evaluate as clinical indicators of cardiotoxicity. Data were analysed using a population pharmacokinetic approach, including pharmacogenetic covariates. Data were available from all but 5 patients, with samples lost due to withdrawn consent, analytical issues or sample stability related to sample transport. A three compartment model was sufficient to characterize the pharmacokinetics of doxorubicin, with a further compartment to describe those of the major metabolite doxorubicinol. All parameters of the population model were scaled to body surface area. Age dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a lower clearance (21.1±5.8 l/h/m2) than older children (26.6±6.7 l/h/m2) (p=0.0004), even after correcting for body weight. No other patient-related covariate, including liver function, was found to influence the parameters of the model. While the model provided a good fit to the doxorubicinol data, no covariate was identified which influenced the parameters of the metabolite model. Pharmacogenetic variants, including those in transporters and drug metabolizing enzymes, had little influence on pharmacokinetic parameters. Likewise, pharmacokinetics had only limited impact on markers of cardiotoxicity such as troponins or on measured cardiac function. This study yields new pharmacokinetic data on doxorubicin pharmacokinetics in very young patients, suggesting that lower doses may be appropriate in children less than 3 years. The data presented her may be useful for refining dosage regimens in this patient group. Citation Format: Alan V. Boddy, Nicolas Andre, Gianni Bisogno, Joachim Boos, Maurizio D'Incalci, Nina Kontny, Miriam Krischke, Swantje Voeller, Georg Hempel. Age dependence of doxorubicin pharmacokinetics in pediatric cancer patients; results of an FP7-funded clinical study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4625. doi:10.1158/1538-7445.AM2014-4625