Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects.

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.

Insulin sensitivity in type 2 diabetes: univariate and multivariate techniques to derive estimates of insulin sensitivity from the insulin modified intravenous glucose tolerance test (FSIGT).

The use of univariate and multivariate techniques to derive estimates of insulin sensitivity from the insulin modified FSIGT were investigated in 12 Type 2 diabetic subjects aged (mean+/-S.D.) 59+/-9.5 years and BMI 28.1+/-2.2 kg m(-2), who underwent both a FSIGT and an isoglycemic hyperinsulinemic clamp. Reproducibility of the FSIGT was tested in four patients on three separate occasions. FSIGT data were assessed by both univariate and multivariate techniques. The sensitivity index for the FSIGT ranged from 0.162 to 3.292 (mean 1.378) x 10(-4) x l min(-1) mU(-1) for the univariate approach and from 0.163 to 2.727 (mean 1.378) x 10(-4) x l min(-1) mU(-1) for the multivariate method. Mean S(Iclamp) was 44.41 x 10(-4) x l(-2) min(-1) x mU(-1) (range 22.0-77.92). The correlation of the insulin sensitivity indices between the clamp and the FSIGT was 0.51 (P=0.056) for the univariate and 0.67 (P=0.017) for the multivariate analyses. Repeated FSIGTs showed a lower variability for the multivariate than for the standard approach.