Influence of pharmacogenetic variability on the pharmacokinetics and toxicity of the aurora kinase inhibitor danusertib

Objectives Danusertib is a serine/threonine kinase inhibitor of multiple kinases, including aurora-A, B, and C. This explorative study aims to identify possible relationships between single nucleotide polymorphisms in genes coding for drug metabolizing enzymes and transporter proteins and clearance of danusertib, to clarify the interpatient variability in exposure. In addition, this study explores the relationship between target receptor polymorphisms and toxicity of danusertib. Methods For associations with clearance, 48 cancer patients treated in a phase I study were analyzed for ABCB1, ABCG2 and FMO3 polymorphisms. Association analyses between neutropenia and drug target receptors, including KDR, RET, FLT3, FLT4, AURKB and AURKA, were performed in 30 patients treated at recommended phase II dose-levels in three danusertib phase I or phase II trials. Results No relationships between danusertib clearance and drug metabolizing enzymes and transporter protein polymorphisms were found. Only, for the one patient with FMO3 18281AA polymorphism, a significantly higher clearance was noticed, compared to patients carrying at least 1 wild type allele. No effect of target receptor genotypes or haplotypes on neutropenia was observed. Conclusions As we did not find any major correlations between pharmacogenetic variability in the studied enzymes and transporters and pharmacokinetics nor toxicity, it is unlikely that danusertib is highly susceptible for pharmacogenetic variation. Therefore, no dosing alterations of danusertib are expected in the future, based on the polymorphisms studied. However, the relationship between FMO3 polymorphisms and clearance of danusertib warrants further research, as we could study only a small group of patients

Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study

Purpose: Response to anticancer therapy is believed to be directly related to the concentration of the anticancer drug in the tumor itself. Assessment of intra-tumor drug pharmacokinetics can be helpful to gain more insight into mechanisms involved in the (in)sensitivity of tumors to anticancer therapy. We explored the pharmacokinetics of 5-fluorouracil in both plasma and tumor tissue during a 5-day continuous infusion of 5-fluorouracil in patients with cancer. Sampling for measurement of 5-fluorouracil in tumor tissue was performed using microdialysis. Experimental design: In seven patients with an accessible (sub)cutaneous tumor treated with a continuous 5-fluorouracil infusion, plasma and microdialysate samples from tumor and normal adipose tissue were collected over a period of 5 days. Results: For six patients, drug concentrations in both tumor tissue and plasma were available. Concentration-time curves of unbound 5-fluorouracil were lower in tumor tissue compared to the curves in plasma, but exposure ratios of tumor tissue versus plasma increased during the 5-day infusion period. The presence of circadian rhythmicity of 5-fluorouracil pharmacokinetics in the tumor itself was demonstrated as 5-fluorouracil concentrations in tumor extracellular fluid were higher during the night than during daytime. Conclusion: Microdialysis was successfully employed in patients with cancer during a continuous 5-day 5-fluorouracil infusion. Plasma and tumor pharmacokinetics of 5-fluorouracil differed substantially with increasing 5-fluorouracil concentrations in tumor over time, possibly resulting from a lowered interstitial fluid pressure by 5-fluorouracil itself. This microdialysis 5-fluorouracil model might be useful to monitor the effect of drug delivery modulating strategies in future studies

Determinants of quality of life in children with psychiatric disorders

Objective: To assess factors that, in addition to childhood psychopathology, are associated with Quality of Life (QoL) in children with psychiatric problems. Methods: In a referred sample of 252 8 to 18-year-olds, information concerning QoL, psychopathology and a broad range of child, parent, and family/ social network factors was obtained from children, parents, teachers and clinicians. Results: Poor child, parent, and clinician reported QoL was associated with child psychopathology, but given the presence of psychopathology, also with child factors, such as low self-esteem, and poor social skills, and family/social network factors, such as poor family functioning, and poor social support. In multiple linear regression analyses the importance of parent factors, such as parenting stress, was almost negligible. Conclusion: To increase QoL of children with psychiatric problems, treatment of symptoms is important, but outcome might improve if treatment is also focussed on other factors that may affect QoL. Results are discussed in relation to current treatment programs. © Springer 2005