Cyclophosphamide is an alkylating agent used in the treatment of solid and haematological malignancies and as an immunosuppressive agent. As a prodrug, it is dependent on bioactivation to the active phosphoramide mustard metabolite to elicit its therapeutic effect. This focused review will highlight the evidence for the role of germline pharmacogenetic variation in both plasma pharmacokinetics and clinical outcomes. There is a substantial indication from 13 pharmacokinetic and 17 therapeutic outcome studies, in contexts as diverse as haematological malignancy, breast cancer, systemic lupus erythematosus and myeloablation, that pharmacogenetic variation in both CYP2C19 and CYP2B6 influence the bioactivation of cyclophosphamide. An additional role for pharmacogenetic variation in ALDH1A1 has also been reported. Future studies should comprehensively assess these 3 pharmacogenes and undertake appropriate statistical analysis of gene–gene interactions to confirm these findings and may allow personalised treatment regimens.
Inter-individual differences in DNA adduct formation and repair influence the response to melphalan treatment, however, further clinical investigation of this variability requires a logistically feasible and reproducible bioassay. Our improved fluorescence-based QPCR-block assay is robust, has good precision, and improved throughput. It also incorporates direct PCR amplification from melphalan exposed PBMC using commercially available blood tubes and extraction kits to maximise the utility of this assay for future clinical studies. Using this assay we have demonstrated reproducible inter-individual differences in melphalan-induced QPCR-block across individual PBMC donors. As proof-of-principle we assessed nine healthy donors and found a 7.8 fold range in sensitivity following exposure of PBMC ex vivo. This likely reflects differences in melphalan transport into cells as well as differences in DNA adduct repair proficiency. This improved bioassay may be useful for assessment of these processes in patients about to receive melphalan treatment.
BackgroundMontelukast, a potent orally selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma.Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed significant inter-individual variability on pharmacokinetics.None of pharmacokinetic study has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of this study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1on Montelukast pharmacokinetics in Chinese paediatric patients.MethodsAfter oral administration with montelukast, opportunistic samples were collected from asthma children and plasma concentrations were determined by high performance liquid chromatography coupled with fluorescence detector (HPLC-FLD) method. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped.ResultsFifty patients (age range 0.7–10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in subjects with SLCO2B1 c.935GA and c.935AAgenotype compared withSLCO2B1 c.935GGsubjects (0.94±0.26 versus 0.77±0.21, p=0.020). Weight was also found to be significantly corrected with montelukast clearance (p 0.0001).ConclusionsThe developmental pharmacogenetics of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype showed independently significant impacts on theclearanceofmontelukast.Disclosure(s)Nothing to disclose.
BackgroundAlthough the understanding of CYP2D6 developmental pharmacogenetics in children has made great progress, the current findings are mainly focused on Caucasian children. Given the clear ethnicity difference of CYP2D6 pharmacogenetic profile, there are still unmet needs in understanding developmental pharmacogenetics in inter-ethnic population. We sought to use loratadine as a probe drug to evaluate the effects of ontogeny and pharmacogenetics on the developmental pattern of CYP2D6 in Chinese paediatric patients.MethodsChinese children receiving loratadine treatment were enrolled in the present study. The metabolic ratio (MR) of loratadine converted to desloratadine [desloratadine concentrations/loratadine concentrations] of trough concentrations samples at steady-state condition was used as a surrogate of CYP2D6 activity. Loratadine and desloratadine were determined by LC/MS/MS method and variants of CYP2D6 were genotyped.ResultsA total of 40 patients were available for final analysis. The mean age was 4.6 (range 0.5–9.0) years and the mean weight was 19.9 (range 9.0- 42.0) kg. The MR was significantly higher in homozygous wild-type subjects compared with CYP2D6*10 subjects (16.94±14.12 versus 9.37±7.54, p = 0.028). Weight was also found to be significantly corrected with MR (p = 0.030).ConclusionsThe developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a probe drug. Weight and CYP2D6 genotype showed independently significant impacts on MR.Disclosure(s)Nothing to disclose.
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