Characterization and Pharmacokinetic Evaluation of Oxaliplatin Long-Circulating Liposomes

The clinical efficacy of Oxaliplatin (L-OHP) is potentially limited by dose-dependent neurotoxicity and high partitioning to erythrocytes in vivo. Long-circulating liposomes could improve the pharmacokinetic profile of L-OHP and thus enhance its therapeutic efficacy and reduce its toxicity. The purpose of this study was to prepare L-OHP long-circulating liposomes (L-OHP PEG lip) by reverse-phase evaporation method (REV) and investigate their pharmacokinetic behavior based on total platinum in rat plasma using atomic absorption spectrometry (AAS). A simple and a sensitive AAS method was developed and validated to determine the total platinum originated from L-OHP liposomes in plasma. Furthermore, long-circulating liposomes were fully characterized in vitro and showed great stability when stored at 4°C for one month. The results showed that the total platinum in plasma of L-OHP long-circulating liposomes displayed a biexponential pharmacokinetic profile with five folds higher bioavailability and longer distribution half-life compared to L-OHP solution. Thus, long-circulating liposomes prolonged L-OHP circulation time and may present a potential candidate for its tumor delivery. Conclusively, the developed AAS method could serve as a reference to investigate the pharmacokinetic behavior of total platinum in biological matrices for other L-OHP delivery systems.

The Main Anorthosite Layer of the West-Pana Intrusion, Kola Region: Geology and U-Pb Age Dating

The West-Pana intrusion belongs to the Paleoproterozoic Fedorova-Pana Complex of the Kola Region in NW Russia, which represents one of Europe’s most significant layered complexes in terms of total platinum group element (PGE) endowment. Numerous studies on the age of the West-Pana intrusion have been carried out in the past; however, all published U-Pb isotope ages were determined using multi-grain ID-TIMS. In this study, the mineralized Main Anorthosite Layer from the upper portion of the intrusion was dated using SHRIMP-II for the first time. High Th/U (0.9–3.7) zircons gave an upper intercept age of 2509.4 ± 6.2 Ma (2σ), whereas the lower portion of the intrusion was previously dated at 2501.5 ± 1.7 Ma, which suggests an out-of-sequence emplacement of the West-Pana intrusion. Furthermore, high-grade PGE mineralization hosted by the anorthosite layer, known as “South Reef”, can be attributed to (1) downward percolation of PGE-enriched sulfide liquid from the overlying gabbronoritic magma or (2) secondary redistribution of PGEs, which may coincide with a post-magmatic alteration event recorded by low Th/U (0.1–0.9) zircon and baddeleyite at 2476 ± 13 Ma (upper intercept).

Geochemistry of the Madawara Igneous Complex, Bundelkhand Craton, Central India: Implications for PGE Metallogeny

The southern part of the Bundelkhand craton contains a series of a E-W trending mafic and ultramafic rocks, about 40 km in length and 2–4 km wide, that occur as intrusions within the Bundelkhand Gneissic Complex (BnGC). They are confined between the Madawara- Karitoran and Sonrai-Girar shear zones. Dunite, harzburgite, lherzolite and websterite are the commonly occurring ultramafic rocks that have high MgO, Ni, Cr, PGE and low Al2O3, CaO, K2O, TiO2 and V contents, and shows peridotitic affinity. A distinct trend of crystallization from peridotite to komatiitic basalt has been inferred from geochemical plots, which also indicates the occurrence of at least two varieties among the ultramafic suite of the Madawara ultramafic complex, namely, Group I comprising dunite, spinel peridotite, harzburgite and lherzolite, and Group II consisting of pyroxenite, websterite and olivine websterite. In several places, the rocks of Group II have an intrusive relationship with Group I, and are relatively enriched in total platinum group elements (PGE ~ 300 ppb). The discrimination diagrams suggest that the PGE are enriched in low sulphur-fugacity source magma at moderate to deeper depths by high degree of partial melting of the mantle.

Phase I study of combination chemotherapy consisting of capecitabine plus fractional cisplatin for unresectable gastric cancer in an outpatient setting.

173 Background: The combination chemotherapy of capecitabine and cisplatin is one of the standard regimen for unresectable gastric cancer. However, the high dose of cisplatin could cause the nephrotoxicity and require the adequate hydration to avoid the damage of renal during the administration. For that reason, the hospitalization is recommended for the patients to receive the chemotherapy including high dose of cisplatin. The present study aimed to establish the proper dose of fractional cisplatin in the combination with capecitabine in an outpatient setting. Methods: Capecitabine was administered orally every day from the evening of day 1 to the morning of 15. Cisplatin were infused on days 1, 8 and 15 for 60 minutes without hydration. The starting dose of cisplatin was 15 mg/m2 as level 1. The following cisplatin dose could be given to subsequent cohorts of patients depending on safety findings observed in the previous cohort: level 2, 20 mg/m2 and level 3, 25 mg/m2, respectively. Serum concentration of total platinum was analyzed before the administration of cisplatin on days 1, 8 and 15. Results: A total of 9 patients were recruited. The median age was 64 years and there were 8 males and one female. Histological types included intestinal (n=5) and diffuse (n=4). Eight patients had multiple metastatic sites, including lymph nodes (n=8), peritoneum (n=5), liver (n=3), lung (n=2) and bone (n=1). The major toxicities were thrombocytopenia (67%), leukopenia (56%) and neutropenia (22%). However, no dose-limiting toxicity was observed in each level. Therefore, the recommended dose of cisplatin was 25 mg/m2. Of the 9 patients, 6 patients had measurable lesions and 5 patients had partial responses, resulting in an overall response rate of 83%. The median administered course was four. In patients at level 3, the mean concentration of total platinum on days 8 and 15 were 0.25μg/ml and 0.42μg/ml, respectively. Conclusions: The recommend dose of cisplatin was confirmed with 25 mg/m2 weekly. Although its safety and feasibility should be evaluated in further clinical trial, this regimen could be expected as an outpatient treatment for unresectable gastric cancer. Clinical trial information: 000005708.

A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases (ILM) from colorectal cancer (CRC).

283 Background: IHP is a proven approach for regional delivery of chemotherapy in patients with unresectable ILM. This study sought to determine safety and MTD of administering 5FU in combination with fixed dose oxaliplatin via IHP. Methods: Prospective Phase I dose escalation with standard 3x3 dosing. Subjects with unresectable ILM from CRC scheduled to receive an HAI pump were eligible. IHP employed fixed dose oxaliplatin (previously established)with escalating doses of 5FU. 1 endpoint was to determine MTD for this combination. 2 endpoints were response to IHP alone, PFS, and OS for IHP + HAI-FUDR. Systemic and IHP plasma PK of 5FU, anabolites, total, and free platinum were determined by validated assays. Results: Between Aug 2007 - Mar 2011, 11 subjects were enrolled. All patients received at least one line of pre-IHP systemic chemotherapy. There were 4 Grade 3 SAE (36.3%) and no grade 4 events. 2 DLTs occurred in the second dose cohort of 300mg/m2. Dose escalation was terminated and 200mg/m2 5FU was determined to be the MTD. There was 1 DLT in the dose de-escalating phase of 200mg/m2. At first follow-up, 9 pts (82%) had a partial response, while 2 (18%) had stable disease. 64% of pts had a >50% decrease in CEA level. Actuarial 1 and 2 year survival was 100% and 75% respectively, with median follow-up of 23 mos. IHP exposures (AUC0-60min) were 10.9±4.5 µgPt·h/mL (platinum), 49.3±30.7 µg·h/mL 5FU (DL1) and 70.5±35.5 µg·h/mL 5FU (DL2). Free platinum represented 82±14% of total platinum. Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both total platinum (1.1±1.5%) and 5FU (0.09±0.10%). IHP exposure to metabolites relative to 5FU was 4.9±2.5% for FUrd and 0.23±0.14% for FdUrd, respectively. Conclusions: MTD for IHP with 5FU and oxaliplatin is 200 mg/m2 and 40mg/m2 respectively. Systemic exposure to the agents was minimal. The response and survival observed in this dose escalation study warrants assessment in a larger phase II trial. [Table: see text]