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2564 Background: Gimatecan (Gim), a new potent oral topoisomerase I inhibitor is a lipophilic 7-oxyiminomethyl derivative of camptothecin. Its in vitro cytoxicity is more sustained than CPT-11 and topotecan, it has excellent anti-tumor activity in mouse xenografts, and shown good tolerability with Ph I activity. The study aim was to profile its disposition in cancer patients. Methods: 4 patients with advanced cancer received a single oral 1.5 mg dose of [14C] Gim (60 μCi) followed by standard Gim treatment on Day 15. Whole blood, plasma, urine, and feces were collected over 7 days with spot fecal collections up to Day 19. Total radioactivity was measured by liquid scintillation counting. Gim and metabolite concentrations in plasma and excreta were measured by LC- MS/MS and HPLC with radiometric detection. Results: Gim showed a rapid first-order absorption and a long elimination phase and was well tolerated. The median (range) Tmax for Gim was 1 h (0.5 to 3 h) and mean t1/2 and oral clearance values were 91 h and 0.6 L/h, respectively. Gim was the major moiety and its active metabolite LCF775 (t-butyl-mono-hydroxy Gim) was the main metabolite (albeit minor, 2–9%) in plasma. Trace glucuronide and sulfate metabolites were also detected in plasma. Mean recovery of radioactivity in urine (0-Day 7) and feces (0-Day 11) was 70.5 % (56.2–80.0%) of the dose. Incomplete recovery is attributed to opiates use in 2 patients and incomplete (sporadic) fecal sampling at later timepoints. Fecal excretion (0-Day 11) was prolonged and major in 3/4 patients (46- 73% of the dose, of which 14–23% is the unchanged Gim suggesting the drug is well absorbed). An additional 1.3–3.5% was recovered in spot collections (Days 14, 15 and 19). Urine excretion (0-Day 7) was 7.2–10.3% of the dose in 3 patients, one patient (cachectic, on opiates) excreted only 21% in feces and 46% in urine. Gim and several Gim metabolites (and glucuronide conjugates thereof) were the major components in excreta. Conclusions: Gim and its minor metabolite, LCF775 were the principal pharmacologically active components in plasma. Fecal excretion is the main elimination pathway in most patients. A long half-life (90hr) of Gim, uncomplicated metabolism, and good oral absorption make Gim an attractive candidate for Ph II development. [Table: see text]

To date, relatively little scholarly attention has been devoted to studying the above trends in a Latin American context. For this reason, several leading institutions organized a conference on "Offshore services in global value chains: New drivers of structural change in Latin America and the Caribbean?" on 18-19 October 2012 in Santiago.