Effect of pharmacogenetic markers of vitamin D pathway on deferasirox pharmacokinetics in children

ObjectivesPatients with -thalassemia major have extremely low vitamin D levels, owing to reduced intestinal absorption, subicteric tint, and/or iron-induced higher pigmentation. We investigated whether some polymorphisms within the VDR, CYP24A1, CYP27B1, and GC genes could play a role in deferasirox pharmacokinetics in a cohort of pediatric patients.Patients and methodsEighteen children with -thalassemia were enrolled. Drug plasma concentrations at the end of dosing interval (C-trough) and after 0, 2, 4, 6, and 24h of drug administration were measured by a HPLC-UV method. Allelic discrimination for VDR (TaqI, FokI, BsmI, Cdx2, and ApaI), CYP24A1 (22776, 3999 and 8620), CYP27B1 (2838 and -1260), and GC (1296) single nucleotide polymorphisms was performed by real-time PCR.ResultsCYP24A1 8620 AG/GG group negatively predicted C-trough in regression analysis (P=0.012). ApaI AA genotype resulted as a negative predictor of C-trough (P=0.025) and area under the concentration curve (P=0.007); FoKI CC genotype remained as area under the concentration curve positive predictor (P=0.008) and TC/CC group as half-life (t(1/2)) (P=0.003) and volume of distribution (V-d) (P=0.011) negative one; TaqI TC/CC was retained as a negative predictor of drug maximum concentration (C-max) (P=0.004). Moreover, GC 1296 TG/GG seemed able to predict lower time to reach drug maximum concentration (T-max) (P=0.033).ConclusionOur preliminary experience suggested the potential usefulness of vitamin D pharmacogenetic to better understand deferasirox interindividual variability, also in pediatric patients.