Effect of developmental changes on pharmacokinetics of drugs used in the treatment of infant acute lymphoblastic leukaemia-A comprehensive review.
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While the event-free survival (EFS) of children treated for acute lymphoblastic leukaemia (ALL) has improved greatly in the last decades, the EFS for patients diagnosed with ALL before the age of one is still under 50%. This outcome further decreases when infants have a rearrangement in the gene encoding histone-lysine N-methyltransferase 2A (KMT2A), whose EFS is under 40%. To improve the EFS of infants treated for ALL, it is crucial to implement optimal dosing guidelines tailored to this population. The pharmacokinetics (PK) of chemotherapeutics in infants is complex due to rapid physiological development in the first year of life. Current dosing guidelines are often extrapolated from paediatric or adult standards using body surface area or age-based adjustments. This may not adequately account for the unique PK-characteristics of infants since developmental changes will influence the absorption, distribution, metabolism, and elimination of chemotherapeutics. In this review, we will provide a comprehensive overview of how developmental changes could affect the PK of chemotherapeutics used in the treatment of ALL. Key factors we evaluated are renal maturation, body composition, blood composition and ontogeny of drug-metabolizing enzymes and transporters. Understanding the influence of developmental processes taking place in the first year of life on the PK of chemotherapeutics will aid the eventual application of evidence-based dosing guidelines tailored specifically to infants treated for ALL, making it possible to determine more appropriate starting doses for each stage of development. These tailored dosing guidelines will enhance the precision and safety of chemotherapy in this vulnerable population.