Purpose: This study explored factors affecting the pharmacokinetic variability of imatinib and CGP 74588, and the pharmacokinetic-pharmacodynamic correlations in patients with advanced gastrointestinal stromal tumors. Experimental Design: Thirty-five patients with advanced gastrointestinal stromal tumors received 400 mg of imatinib daily. Six blood samples were drawn: before intake, during 1-to 3-and 6-to 9-hour intervals after intake on day1, and before intake on days 2, 30, and 60. Plasma imatinib and CGP 74588 concentrations were quantified by reverse-phase high-performance liquid chromatography coupled with tandem mass spectrometry, and analyzed by the population pharmacokinetic method (NONMEM program). The influence of 17 covariates on imatinib clearance (CL) and CGP 74588 clearance (CLM/fm) was studied. These covariates included clinical and biological variables and occasion (OCC = 0 for pharmacokinetic data corresponding to the first administration, or OCC = 1for the day 30 or 60 administrations). Results: The best regression formulas were: CL (L/h) = 7.97 (AAG/1.15) À0.52 , and CLM/fm (L/h) = 58.6 (AAG/1.15) À0.60 Â 0.55 OCC , with the plasma a1-acid glycoprotein (AAG) levels indicating that both clearance values decreased at a higher AAG level. A significant timedependent decrease in CLM/fm was evidenced with a mean (+SD) CGP 74588/imatinib area under the curve (AUC) ratio of 0.25 (F0.07) at steady state, compared with 0.14 (F0.03) on day 1. Hematologic toxicity was correlated with pharmacokinetic variables: the correlation observed with the estimated unbound imatinib AUC at steady-state (r = 0.56, P < 0.001) was larger than that of the total imatinib AUC (r = 0.32, NS). Conclusions: The plasma AAG levels influenced imatinib pharmacokinetics. A protein-binding phenomenon needs to be considered when exploring the correlations between pharmacokinetics and pharmacodynamics.

ABSTRACT:Gemcitabine (2,2-difluorodeoxyribofuranosylcytosine; dFdC) is an anticancer nucleoside analog active against wide variety of solid tumors. However, this compound is rapidly inactivated by enzymatic deamination and can also induce drug resistance. To overcome the above drawbacks, we recently designed a new squalenoyl nanomedicine of dFdC [4-(N)-trisnorsqualenoyl-gemcitabine (SQdFdC)] by covalently coupling gemcitabine with the 1,1,2-trisnorsqualenic acid; the resultant nanomedicine displayed impressively greater anticancer activity compared with the parent drug in an experimental murine model. In the present study, we report that SQdFdC nanoassemblies triggered controlled and prolonged release of dFdC and displayed considerably greater t 1/2 (ϳ3.9-fold), mean residence time (ϳ7.5-fold) compared with the dFdC administered as a free drug in mice. It was also observed that the linkage of gemcitabine to the 1,1,2-trisnorsqualenic acid noticeably delayed the metabolism of dFdC into its inactive difluorodeoxyuridine (dFdU) metabolite, compared with dFdC. Additionally, the elimination of SQdFdC nanoassemblies was considerably lower compared with free dFdC, as indicated by lower radioactivity found in urine and kidneys, in accordance with the plasmatic concentrations of dFdU. SQdFdC nanoassemblies also underwent considerably higher distribution to the organs of the reticuloendothelial system, such as spleen and liver (p < 0.05), both after singleor multiple-dose administration schedule. Herein, this paper brings comprehensive pharmacokinetic and biodistribution insights that may explain the previously observed greater efficacy of SQdFdC nanoassemblies against experimental leukemia.

Hepatic veno-occlusive disease (HVOD) is a frequent life-threatening toxicity in patients undergoing bone marrow transplantation (BMT) after the administration of a high-dose busulfan-containing regimen. Recent studies have shown that the morbidity and mortality of HVOD may be reduced in adults by pharmacologically guided dose adjustment of busulfan. We analyzed the pharmacodynamic relationship between busulfan disposition and HVOD in 61 children (median age, 5.9 years) with malignant disease. Busulfan, given at a dose ranging from 16 mg/kg to 600 mg/m2, was combined with one or two other alkylating agents (cyclophosphamide, melphalan, thiotepa). Only 3 patients received the standard busulfan/cyclophosphamide (BUCY) regimen. A total of 24 patients (40%) developed HVOD, which resolved in all cases. A pharmacokinetics study confirmed the previously reported wide interpatient variability in busulfan disposition but did not reveal any significant alteration in children with HVOD. The mean area under the concentration-time curve (AUC) after the first dose of busulfan was higher in patients with HVOD (6,811 +/- 2,943 ng h ml-1) than in patients without HVOD (5,760 +/- 1,891 ng h ml-1., P = 0.10). This difference reflects the higher dose of busulfan given to patients with HVOD. No toxic level could be defined and, moreover, none of the toxic levels identified in adults were relevant. The high incidence of HVOD in children given 600 mg/m2 busulfan may be linked to the use of more intensive than usual high-dose chemotherapy regimens and/or drug interactions. Before the prospective evaluation of busulfan dose adjustment in children, further studies are required to demonstrate firmly the existence of a pharmacodynamic relationship in terms of toxicity and allogeneic engraftment, especially when busulfan is combined with cyclophosphamide. The maximal tolerated and minimal effective AUCs in children undergoing BMT are likely to depend mainly upon the disease, the nature of the combined high-dose regimen, and the type of bone marrow transplant.

Objectives:Vandetanib was approved by the U.S. Food and Drug Association for the treatment of advanced medullary thyroid cancer (MTC). Because body weight (BW) loss is observed in MTC and because low skeletal muscle mass (SM) is associated with drug toxicity, this study assessed effects of vandetanib on SM and adipose tissue (AT) and explored the association between SM, toxicity, and serum concentration of vandetanib. Methods:Thirty-three patients with MTC received vandetanib (n ϭ 23) or placebo (n ϭ 10) in the ZETA study. Visceral AT (VAT), sc AT (SAT), and SM were assessed with computed tomography imaging by measuring tissue cross-sectional areas (square centimers per square meter). Doselimiting toxicities (DLTs) were prospectively recorded.Results: Early at 3 months, compared with placebo group who lost BW, muscle, and SAT, patients treated with vandetanib gained 1.5 kg BW (P ϭ 0.02), 1.3 cm 2 /m 2 (ϳ0.7 kg) of SM (P ϭ 0.009), and 4.5 cm 2 /m 2 (ϳ0.5 kg) of SAT (P ϭ 0.004) and gained more VAT, 5.1 cm 2 /m 2 (ϳ0.7 kg) (P ϭ 0.02).Patients with DLT had lower SM index (37.2 vs 44.3 cm 2 /m 2 , P ϭ 0.003) and a higher vandetanib serum concentration (1091 vs 739 ng/mL, P ϭ 0.03). Patients with SM index Ͻ43.1 cm 2 /m 2 had a higher probability of DLT (73% vs 14%, P ϭ 0.004) and a higher vandetanib serum concentration (1037 vs 745 ng/mL, P ϭ 0.04). Patients with the highest compared with the intermediate and lower levels of vandetanib serum concentration experienced more DLT, respectively, 78% vs 40% vs 20% (P ϭ 0.04). M edullary thyroid carcinoma (MTC) accounts for 4% to 8% of thyroid carcinomas, and 10-year overall survival ranges, according to TNM (tumor, node, metastasis) classification, from almost 100% for stage I to 21% for stage IV disease (1, 2). Vandetanib, a tyrosine kinase inhibitor (TKI) targeting the rearranged during Conclusions

EAA26 (VESMNEELKKIIAQVRAQAEHLKTAY) is a better inhibitor of human immunodeficiency virus, type1, integrase than its parent Lys-159, reproducing the enzyme segment 147-175 with a nonpolar-polar/charged residue periodicity defined by four helical heptads (abcdefg) prone to collapse into a coiled-coil. Circular dichroism, nuclear magnetic resonance, sedimentation equilibrium, and chemical cross-linking were used to analyze EAA26 in various trifluoroethanol/H 2 O mixtures. In pure water the helix content is weak but increases regularly up to 50 -60% trifluoroethanol. In contrast the multimerization follows a bell-shaped curve with monomers in pure water, tetramers at 10% trifluoroethanol, and dimers at 40% trifluoroethanol. All suggest that interhelical interactions between apolar side chains are required for the coiled-coil formation of EAA26 and subsist at medium trifluoroethanol concentration. The N H temperature coefficients measured by nuclear magnetic resonance show that at low trifluoroethanol concentration the amide groups buried in the hydrophobic interior of four ␣-helix bundles are weakly accessible to trifluoroethanol and are only weakly subject to its hydrogen bond strengthening effect. The increased accessibility of trifluoroethanol to buried amide groups at higher trifluoroethanol concentration entails the reduction of the hydrophobic interactions and the conversion of helix tetramers into helix dimers, the latter displaying a smaller hydrophobic interface. The better inhibitory activity of EAA26 compared with Lys-159 could arise from its better propensity to form a helix bundle structure with the biologically important helical part of the 147-175 segment in integrase.The well defined conformational properties exhibited by many peptides in solution have led to their use as models for protein folding and stability but also for the design of peptide inhibitors of enzymes (1-3). The model peptides are either artificial (4 -6) or may reproduce protein segments (7-13). When they have defined conformations, the peptides can provide useful information on the relationships between local interactions, secondary structures, and tertiary structures (14 -17).We have previously tested the hypothesis that synthetic peptides reproducing amphipathic helical segments of enzymes may interact with these segments and interfere with the catalytic properties. Examples concern topoisomerase II (10, 11), an enzyme involved in the maintenance of DNA topology, and also retroviral integrase (IN) 1 (12, 13) that catalyzes the integration of viral DNA into host cellular DNA (two recent reviews, Refs. 18 and 19). IN has no cellular counterpart and can be therefore considered as a specific target for development of anti-HIV therapy (20). In an earlier study, we have reported (13) that Lys-159, a peptide corresponding to the 147-175 segment of HIV-1 IN, inhibited the integration catalyzed by IN, most likely through specific binding to its counterpart in the protein. Such a specific binding was plausible since in the crystal struct...

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An increased knowledge of oxazaphosphorines' metabolism and toxicity may allow the development of new anticancer drugs combined with drug delivery systems to circumvent drug toxicity, providing increased tumoral specificity and greater anticancer activity.

We report the synthesis and metabolic and biological evaluation of a series of 17 novel heterocyclic derivatives of isocombretastatin-A4 (iso-CA-4) and their structure−activity relationships. Among these derivatives, the most active compound, 4f, inhibited the growth of a panel of seven cancer cell lines with an IC 50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. It also induced G 2 /M cell-cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-tostraight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood-vessel-like assembly formed by human umbilical-vein endothelial cells in vitro, suggesting its function as a vascular-disrupting agent. An in vitro metabolism study of 4f showed its high human-microsomal stability in comparison with that of iso-CA-4. The physicochemical properties of 4f may be conducive to CNS permeability, suggesting that this compound may be a possible candidate for the treatment of glioblastoma.