Background. It is known that voriconazole (VCZ) plasma levels (PL) are highly variable. Dose recommendation changed in 2012 for paediatric patients between 2 and 12 years old (yo). Little data on therapeutic drug monitoring (TDM) after these new recommendations is available. We aim to evaluate TDM of VCZ in paediatric patients with invasive fungal infection (IFI) and its relationship with safety and effectiveness._x000D_ _x000D_ Methods. Prospective observational single-centre study from January 2014 to August 2018. All consecutive patients aged 2-12 yo receiving VCZ were included. TDM was performed weekly and doses were changed according to local protocol. IFI were categorized as possible/probable/proven according to EORTC/MSG group criteria, response to treatment was evaluated according to same group criteria and adverse events were recorded following the Common Terminology Criteria for Adverse Events. Factors potentially influencing PL were analysed. _x000D_ _x000D_ Results. We obtained 229 PL from 28 IFI episodes (18 probable/proven). Duration of treatment in proven/probable episodes was 83.5 days (5-896). 64.2% of PL were therapeutic (1-5.5 mg/L), but more than one-third of them weren’t: 27.5% below; 8.3% above. After dose modification according with our protocol, 75% therapeutic PL were achieved. In the first week of treatment there were more infratherapeutic PL (43.5%) than the rest of the period (25.9%) (p=0.07). Dose to achieve therapeutic PL in patients below 8 yo (21mg/kg/day) was higher than recommended and higher than in older patients. In these patients, a linear relationship between dose and PL value was observed (p=0.01). Severe hypoalbuminemia (p=0,02) and marked elevation of C-reactive protein (CRP) (p=0,03) were associated with worse PL adequacy. The effectiveness of treatment was 60% in the early evaluation and 53.3% in the late evaluation. Survival at 6 months was 80%, with no deaths attributed to IFI. Non-infratherapeutic PL were associated with better treatment response at late evaluation, and supratherapeutic PL were associated with liver (p=0,02) and renal dysfunction (p=0,03). _x000D_ _x000D_ Conclusions. VCZ PL variability remains high despite current updated recommendations and it’s influenced by severe hypoalbuminemia and increased CRP. Therefore, additional efforts to control inflammation in children with IFI should be encouraged. Our dose modification recommendation appears to be effective. Treatment with the new dosage is effective and safe, but alterations in liver enzymes are common. Therapeutic VCZ PL are related to treatment effectiveness and safety; thus, TDM of VCZ is mandatory. Higher doses should be considered in patients below 8 yo. It’s necessary to consider protocolizing the dose modification based on the value of the PL.
Variabilitat, efectivitat i seguretat del voriconazole en la infecció fúngica invasiva a pediatria
VALLE T FIGUERAS, J. M. (Author). 10 Jul 2020
Student thesis: Doctoral thesis
Student thesis: Doctoral thesis