Background: Topotecan is a topoisomerase I inhibitor with activity against xenografts of childhood solid tumors and established clinical activity against neuroblastoma and rhabdomyosarcoma. We have studied the relationship between systemic exposure to and the antitumor activity of topotecan lactone (the active form of the drug) in the xenograft models. Furthermore, we determined whether the responses seen in these models occur at systemic exposure levels that are tolerable in children. Methods: Neuroblastoma xenografts derived from the tumors of six different patients were established subcutaneously in immune-deprived mice. Topotecan was administered by intravenous bolus injection 5 days a week for 2 consecutive weeks, repeated every 21 days for three cycles. The minimum daily doses that induced complete responses (CRs) and partial responses (PRs) were determined. Topotecan lactone pharmacokinetic studies were performed in both tumor-bearing and nontumor-bearing mice. Results: The minimum doses associated with CRs and PRs in four of the six neuroblastoma xenografts were 0.61 and 0.36 mg/kg body weight, respectively. The topotecan lactone single-day systemic exposures associated with these doses were 88 and 52 ng · hr/mL, respectively. There was an approximately sixfold difference in topotecan lactone systemic exposure (290 ng · hr/mL versus 52 ng · hr/mL) associated with achieving CRs in the least-sensitive and mostsensitive tumors, respectively. Conclusions: Neuroblastoma xenografts are highly sensitive to topotecan therapy, and responses in mice are achieved at systemic exposures similar to those that are clinically effective and tolerable in children. These results support the concept of deriving preclinical data relating systemic exposure to antitumor activity in xenograft models. Such data may be valuable in making informed decisions regarding the clinical development of new agents.

Purpose: To study the role of drug transporters in central nervous system (CNS) penetration and cellular accumulation of erlotinib and its metabolite, OSI-420. Experimental Design: After oral erlotinib administration to wild-type and ATP-binding cassette (ABC) transporter-knockout mice (Mdr1a/b^−/−, Abcg2^−/−, Mdr1a/b^−/−Abcg2^−/−, and Abcc4^−/−), plasma was collected and brain extracellular fluid (ECF) was sampled using intracerebral microdialysis. A pharmacokinetic model was fit to erlotinib and OSI-420 concentration–time data, and brain penetration (P_Brain) was estimated by the ratio of ECF-to-unbound plasma area under concentration–time curves. Intracellular accumulation of erlotinib was assessed in cells overexpressing human ABC transporters or SLC22A solute carriers. Results:P_Brain in wild-type mice was 0.27 ± 0.11 and 0.07 ± 0.02 (mean ± SD) for erlotinib and OSI-420, respectively. Erlotinib and OSI-420 P_Brain in Abcg2^−/− and Mdr1a/b^−/−Abcg2^−/− mice were significantly higher than in wild-type mice. Mdr1a/b^−/− mice showed similar brain ECF penetration as wild-type mice (0.49 ± 0.37 and 0.04 ± 0.02 for erlotinib and OSI-420, respectively). In vitro, erlotinib and OSI-420 accumulation was significantly lower in cells overexpressing breast cancer resistance protein (BCRP) than in control cells. Only OSI-420, not erlotinib, showed lower accumulation in cells overexpressing P-glycoprotein (P-gp) than in control cells. The P-gp/BCRP inhibitor elacridar increased erlotinib and OSI-420 accumulation in BCRP-overexpressing cells. Erlotinib uptake was higher in OAT3- and OCT2-transfected cells than in empty vector control cells. Conclusion: Abcg2 is the main efflux transporter preventing erlotinib and OSI-420 penetration in mouse brain. Erlotinib and OSI-420 are substrates for SLC22A family members OAT3 and OCT2. Our findings provide a mechanistic basis for erlotinib CNS penetration, cellular uptake, and efflux mechanisms. Clin Cancer Res; 17(1); 89–99. ©2010 AACR.

Numerous studies have documented that adolescents and young adults (AYAs) experience a significant cancer burden as well as significant cancer mortality compared with other age groups. The reasons for the disparate outcomes of AYAs and other age groups are not completely understood and are likely to be multifactorial, including a range of sociodemographic issues unique to these individuals as well as differences between adolescents, younger pediatric patients, and adults in the pharmacology of anticancer agents. Because adolescence is a period of transition from childhood to early adulthood, numerous physical, physiologic, cognitive, and behavioral changes occur during this time. In this review, we provide an overview of the unique developmental physiology of the adolescent and explain how these factors and the behavioral characteristics of adolescents may affect the pharmacology of anticancer agents in this patient population. Finally, we describe examples of studies that have assessed the relation between drug disposition and age, focusing on the AYA age group.