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 purpose of this study was to investigate the absolute bioavailability of a single oral dose of imatinib (Glivec), 400 mg (capsules vs. oral solution), compared with imatinib, 100 mg (intravenous [i.v.] infusion), in healthy subjects. Twelve subjects received a single treatment in each treatment period: a 400-mg oral dose of imatinib in capsule form or as a solution or a 100-mg i.v. infusion of imatinib. Plasma imatinib concentrations were measured following each treatment; pharmacokinetic parameters and absolute bioavailability were determined. Absolute bioavailability values (compared with i.v. infusion) for the imatinib capsule and oral solution were 98.3% and 97.2%, respectively. Both the rate and extent of imatinib absorption, as measured by C(max), partial AUC, and total AUC, were similar for the oral solution and the imatinib capsule intended for the market. The 400-mg oral dose of imatinib, as a capsule or a solution, was completely absorbed and was almost completely bioavailable (> 97%).

Aliskiren (2(S),4(S),5(S),7(S)-

The study under discussion was a drug-drug interaction study in which the effect of ketoconazole, a potent CYP450 3A4 inhibitor, on the pharmacokinetics of Glivec (imatinib) was investigated. A total of 14 healthy subjects (13 male, 1 female) were enrolled in this study. Each subject received a single oral dose of imatinib 200 mg alone, and a single oral dose of imatinib 200 mg coadministered with a single oral dose of ketoconazole 400 mg according to a two-period crossover design. The treatment sequence was randomly allocated. Subtherapeutic imatinib doses and a short exposure were tested in order not to overexpose the healthy volunteers. There was a minimum 7-day washout period between the two sequences. Blood samples for determination of plasma concentrations were taken up to 96 h after dosing. Imatinib and CGP74588 (main metabolite of imatinib) concentrations were measured using LC/MS/MS method and pharmacokinetic parameters were estimated by a non-compartmental analysis. Following ketoconazole coadministration, the mean imatinib C(max), AUC((0-24)) and AUC((0- infinity )) increased significantly by 26% ( P<0.005), 40% ( P<0.0005) and 40% ( P <0.0005), respectively. There was a statistically significant decrease in apparent clearance (CL/f) of imatinib with a mean reduction of 28.6% ( P<0.0005). The mean C(max) and AUC((0-24)) of the metabolite CGP74588 decreased significantly by 22.6% ( P<0.005) and 13% ( P<0.05) after ketoconazole treatment, although the AUC((0- infinity )) of CGP74588 only decreased by 5% ( P=0.28). Coadministration of ketoconazole and imatinib caused a 40% increase in exposure to imatinib in healthy volunteers. Given its previously demonstrated safety profile, this increased exposure to imatinib is likely to be clinically significant only at high doses. This interaction should be considered when administering inhibitors of the CYP3A family in combination with imatinib.

Concomitant use of imatinib and rifampicin or other potent inducers of CYP4503A may result in subtherapeutic plasma concentrations of imatinib. In patients in whom rifampicin or other CYP3A inducers are prescribed, alternative therapeutic agents with less potential for enzyme induction should be selected.