No abstract

Agasicles hygrophila was introduced into New Zealand in 1982 for the biological control of alligator weed, Alternanthera philoxeroides. The optimum temperature for A. hygrophila development was 27-30°C where development time was 19-20 days. Mortality was lowest (13-14%) at temperatures between 23-25°C. The estimated lower development threshold for A. hygrophila was 13.3°C. Adult beetles reared at 23-27°C were heavier than those reared at 15-20°C and 30°C, and females were heavier than males. There was significant mortality of adults during exposure to low temperatures. Mortality was 92% for adults exposed for four weeks at 10°C and 70% for adults exposed for 12 weeks at 15°C. The number of eggs laid subsequently decreased as the time adults were exposed to chilling was increased. Viability decreased as the temperature to which adults were exposed was lowered, and Received 10 March 1998; accepted 3 August 1998 with increased chilling time. Females survived longer than males when chilled at 10° and 15°C. All adults died when chilled for 13 h at -8°C; at 2° and -4°C there was high adult survival, but the viability of eggs laid was low. These results suggest the overwintering capacity of A. hygrophila is much reduced when exposed to temperatures of 15°C and below. Z98010

The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to support the rational testing and usage of innovative therapies in children with CNS tumors.

We previously investigated novel therapies for pediatric ependymoma and found 5‐fluorouracil (5‐FU) i.v. bolus increased survival in a representative mouse model. However, without a quantitative framework to derive clinical dosing recommendations, we devised a translational pharmacokinetic‐pharmacodynamic (PK‐PD) modeling and simulation approach. Results from our preclinical PK‐PD model suggested tumor concentrations exceeded the 1‐hour target exposure (in vitro IC90), leading to tumor growth delay and increased survival. Using an adult population PK model, we scaled our preclinical PK‐PD model to children. To select a 5‐FU dosage for our clinical trial in children with ependymoma, we simulated various 5‐FU dosages for tumor exposures and tumor growth inhibition, as well as considering tolerability to bolus 5‐FU administration. We developed a pediatric population PK model of bolus 5‐FU and simulated tumor exposures for our patients. Simulations for tumor concentrations indicated that all patients would be above the 1‐hour target exposure for antitumor effect.