Drug exposure (area under the concentration-time curve) is dose proportional for the dose range of 25 to 1,000 mg, and there is a 1.5- to three-fold drug accumulation at steady-state after once-daily dosing. Analysis of the relationship between PD (WBC reduction) and PK parameters at steady-state indicates that a dose of 400 mg or greater is required for maximal PD effect.

Purpose: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib. Experimental Design: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response. Results: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by f68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages. Conclusions: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.

ABSTRACT:Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of 14 C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (t max 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 ؎ 0.095 g/ml (mean ؎ S.D., n ‫؍‬ 4) for imatinib and 0.115 ؎ 0.026 g/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 ؎ 0.9 h for imatinib, 20.6 ؎ 1.7 h for CGP74588, and 57.3 ؎ 12.5 h for 14 C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC 0-24 h (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively.

The adequate distribution of STI-571 (Gleevec) to the central nervous system (CNS) is critical for its effective use in CNS tumors. P-glycoprotein-mediated efflux in the blood-brain barrier may play a role in the CNS delivery of this drug. Whether STI-571 is a substrate of P-glycoprotein was determined by examining the directional flux of [14 C]STI-571 in parental and MDR1-transfected Madin-Darby canine kidney (MDCK) II epithelial cell monolayers. The basolateral-to-apical flux of STI-571 was 39-fold greater than the apical-to-basolateral flux in the MDR1-transfected cells and 8-fold greater in the parental cell monolayers. This difference in directional flux was significantly reduced by a specific P-glycoprotein inhibitor (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (LY335979). The role of P-glycoprotein in the CNS distribution of STI-571 was examined in vivo, using wild-type and mdr1a/b (Ϫ/Ϫ) knockout mice that were orally administered 25 mg/kg [ 14 C]STI-571. In the wild-type mice, the brain-to-plasma STI-571 concentration ratio at all time points was low (1-3%); however, there was an 11-fold greater brain partitioning of STI-571 at 1 h postdose in the mdr1a/b (Ϫ/Ϫ) mice compared with the wild-type mice. When 12.5 mg/kg STI-571 was given intravenously, the brain-to-plasma ratio of STI-571 in the mdr1a/b (Ϫ/Ϫ) mice was approximately 7-fold greater than that of wild-type mice up to 120 min postdose. These data indicate that STI-571 is a substrate of P-glycoprotein, and that the inhibition of P-glycoprotein affects the transport of STI-571 across MDCKII monolayers. Moreover, P-glycoprotein plays an important role in limiting the distribution of STI-571 to the CNS.

We report on the electrical characterization of single-crystal ZnO and Au Schottky contacts formed thereon before and after bombarding them with 1.8 MeV protons. From capacitance–voltage measurements, we found that ZnO is remarkably resistant to high-energy proton bombardment and that each incident proton removes about two orders of magnitude less carriers than in GaN. Deep level transient spectroscopy indicates a similar effect: the two electron traps detected are introduced in extremely low rates. One possible interpretation of these results is that the primary radiation-induced defects in ZnO may be unstable at room temperature and anneal out without leaving harmful defects that are responsible for carrier compensation.

The "3 + 1" variant of the MacDonald condensation has been shown to be an excellent methodology for synthesizing carbaporphyrins. In particular, 1,3-indenedicarbaldehyde condenses with tripyrranes in the presence of TFA to give, following oxidation with DDQ, a series of benzocarbaporphyrins in excellent yields. Triformylcyclopentadienes also afford carbaporphyrin products, albeit in low yields ranging from 5 to 8%. These hybrid bridged annulene structures have porphyrin-like electronic absorption spectra with strong Soret bands near 420 nm and a series of Q-bands through the visible region. The proton NMR spectrum confirms the presence of a strong diamagnetic ring current, and the meso-protons show up at 10 ppm, while the internal CH is shielded to approximately -7 ppm. Carbaporphyrins undergo reversible protonation with TFA. Initial addition of acid affords a monocation, although mixtures of protonated species are observed in the presence of moderate concentrations of TFA. However, in the presence of 50% TFA a C-protonated dication is generated. The dications relocate the pi-delocalization pathway through the benzo moiety of benzocarbaporphyrins, and these therefore represent bridged benzo[18]annulenes, although they nevertheless retain powerful macrocyclic ring currents. Carbaporphyrins with fused acenaphthylene and phenanthrene rings have been prepared, and the former demonstrated significantly larger bathochromic shifts in UV-vis spectroscopy that parallel previous observations for acenaphthoporphyrins. A diphenyl-substituted benzocarbaporphyrin 19b was also characterized by X-ray crystallography, and these data show that the macrocycle is reasonably planar although the indene subunit is tilted out of the mean macrocyclic plane by 15.5 degrees. The structural data indicates that the preferred tautomer in the solid state has the two NH's flanking the pyrrolene unit in agreement with previous spectroscopic and theoretical studies. Cyclic voltammetry for carbaporphyrin 19a was more complex than for true porphyrins, showing five anodic waves and two quasi-reversible reductive couples.

Excellent yields of the carbaporphyrin 1 are obtained by application of the “3 + 1” methodology for the reaction of 1,3‐indenedicarboxaldehyde with a tripyrrane in the presence of 5% CF3CO2H in CH2Cl2. The related formylcarbaporphyrin 2 was prepared similarly. In contrast to earlier claims, no unusual tautomers or conformers are observed in solution.

BackgroundThis study evaluates the correlation between imatinib trough plasma concentrations (Cmin) and clinical response and safety in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in the Tyrosine Kinase Inhibitor OPtimization and Selectivity (TOPS) trial. Design and MethodsPatients were randomized 1:2 to 400 mg/day or 800 mg/day imatinib. Imatinib Cmin levels were collected at pre-dose before treatment, and at the end of months 1 (day 29), 6, 9, and 12. ResultsImatinib Cmin were stable over time in the 400 mg/day dose arm, but showed a slight decrease in the 800 mg/day arm due to dose adjustments between months 1-6. The overall median imatinib Cmin levels were 1040, 1200, 1935, and 2690 ng/mL for the actual 300, 400, 600, and 800 mg/day doses, respectively. The rates of major molecular response (MMR) at 3, 6, 9, and 12 months, and complete cytogenetic response (CCyR) at 6 and 12 months were significantly lower among patients with the lowest imatinib Cmin levels at Day 29 (<1165 ng/mL, 25 th percentile). There was an apparent association between high imatinib Cmin and the occurrence of grade 3/4 neutropenia and all-grade rash, diarrhea, arthralgia/myalgia, and all-cause edema. ConclusionsImatinib Cmin levels were relatively stable over time and proportional to the dose administered. Patients with an imatinib Cmin above 1165 ng/mL on Day 29 achieved MMR faster and had higher MMR and CCyR rates at 12 months. There appeared to be an association between imatinib Cmin and the frequency of some adverse events. This trial was registered at http://www.clinicaltrials.gov as NCT00124748.