Changes in Rosuvastatin Pharmacokinetics During Postnatal Ontogenesis in Rats

Purpose: Statin therapy should be considered in children with familial hypercholesterolemia and sustained high LDL-C levels. There are no data on rosuvastatin exposure in patients <6 years and efficacy/safety can only be derived from case reports. Our aim was to examine developmental changes in pharmacokinetics of rosuvastatin in rats in vivo as a basis for clinical development of formulations for patients < 6 years. Methods: Rosuvastatin pharmacokinetics was examined in rats aged 1, 4, 7, 10, 14, 21, 28, 35 and 42 days (from birth to sexual maturity). After intraperitoneal dose of 5 mg/kg, blood samples to determine serum rosuvastatin levels were taken at 0.5, 3 and 5 hours. Pharmacokinetic parameters (Vd, CL, AUClast, AUC0-∞) were calculated using pharmacokinecic simulations. Results: Both rosuvastatin CL and Vd started to increase systematically between 2 - 3 weeks of age, which was reflected by decreased total drug exposure. The AUC was up to 13 times higher in the age groups ≤14 days compared with the value at 42 days. Conclusions: Based on interspecies scaling, a dose reduction could be a feasible way, how to develop appropriate dosing schedule and formulations for children aged 2 - 6 years. However, confirmation in clinical development studies will be needed.

Extrapolating acute bee sensitivity to insecticides using a phylogenetically informed interspecies scaling framework

Plant protection products, including insecticides, are important for global food production. Historically, research of the adverse effects of insecticides on bees has focused on the honeybee (Apis mellifera), while non-Apis bee species remained understudied. Consequently, sensitivity assessment of insecticides for the majority of bees is lacking, which in turn hinders accurate risk characterization and consequently bee protection. Interspecies sensitivity extrapolation based on body weight offers a potential solution to this problem, but in the past such approaches have often ignored the phylogenetic background and consequently non independence of species used in such models. Using published data on the sensitivity of different bee species to commonly used insecticides, their body weight and phylogenetic background I build interspecies scaling models (ISMs) applying a phylogenetically informed framework. In addition, I compared, the relative sensitivity of the standard test species Apis mellifera to other bee species to evaluate their protectiveness when used as standards screening bee species in the risk assessment process. I found that overall 1) body weight is a predictor of bee sensitivity to insecticides for a range of insecticide classes and 2) A. mellifera is the most sensitive standard test species currently available and consequently a suitable surrogate species for ecotoxicological risk assessment.