Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase.

The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.

Evaluation of pharmacokinetic and pharmacodynamic interaction between the dipeptidyl peptidase IV inhibitor vildagliptin, glyburide and pioglitazone in patients with Type 2 diabetes.

BACKGROUND: Vildagliptin is a selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control and pancreatic b-cell function in patients with Type 2 diabetes. Vildagliptin may be an appropriate agent to combine with other antihyperglycemic agents in patients requiring combination therapy to achieve optimal glycemic control. Two studies were performed to determine the potential for pharmacokinetic and pharmacodynamic interactions between vildagliptin and the sulfonylurea, glyburide, or pioglitazone in patients with Type 2 diabetes. METHODS: Two open-label, multiple-dose, 3-period, randomized, crossover studies in patients with Type 2 diabetes were carried out. Steady state drug pharmacokinetics and postprandial plasma glucose and insulin responses were assessed during treatment with vildagliptin 100 mg b.i.d. alone and in combination with glyburide 10 mg q.d. (n = 17) or with vildagliptin 100 mg q.d. alone or in combination with pioglitazone 45 mg q.d. (n = 15). RESULTS: Coadministration of vildagliptin with either glyburide or pioglitazone had no clinically significant effect on the pharmacokinetics of any of the 3 drugs. Changes in AUC and Cmax during combination treatment were small ( pound 15%), and 90% confidence intervals for the geometric mean ratios (drug coadministration/monotherapy) were generally contained within the acceptance range for bioequivalence (0.80 - 1.25). Vildagliptin/glyburide coadministration significantly reduced the area under the plasma glucose-time curve compared with glyburide alone (AUE0-5h reduced by 12% (p = 0.005) and AUE0-15h by 13% (p = 0.003)), and increased the area under the plasma insulin-time curve (AUE0-15h increased by 12% (p = 0.041)). Vildagliptin/pioglitazone coadministration also significantly reduced postprandial glucose exposure compared with pioglitazone alone (AUE0.5-5.5h reduced by 11% (p = 0.029) and AUE0-15.5h by 10% (p = 0.019)). Vildagliptin was generally well tolerated whether administered alone or in combination with glyburide or pioglitazone, and was not associated with hypoglycemia. CONCLUSIONS: Coadministration of vildagliptin with either glyburide or pioglitazone in patients with Type 2 diabetes improves postprandial glycemic control without notable effects on drug pharmacokinetics.

Bioequivalence of vildagliptin/metformin fixed-dose combination tablets and a free combination of vildagliptin and metformin in healthy subjects.

OBJECTIVE: To assess the bioequivalence of vildagliptin/metformin fixed-dose combination tablets (at doses of 50/500, 50/850 and 50/1,000 mg) with free combination of the individual drugs in healthy subjects. METHODS: The pharmacokinetics of vildagliptin and metformin following administration of a fixed-dose combination tablet of vildagliptin/metformin at doses of 50/500 mg (Study I), 50/850 mg (Study II) and 50/1,000 mg (Study III) compared with administration of the individual drugs as free combinations were investigated. All three studies were open-label, single-center, randomized, two-period, two-treatment crossover studies in healthy subjects. RESULTS: Pharmacokinetic parameters (AUC(0-infinity), C(max), t(max), t(1/2) and CL/F) for vildagliptin and metformin across the three studies were similar whether vildagliptin and metformin were administered as a single fixed-dose combination tablet (vildagliptin/metformin 50/500, 50/850 or 50/1,000 mg) or as the respective individual tablets. The point estimates and 90% CI of the geometric mean ratios for vildagliptin and metformin C(max), AUC(0-t), and AUC(0-infinity) were all within the predefined bioequivalence range of 0.80 - 1.25. Administration of the vildagliptin/metformin combination tablets was well tolerated; the incidence of adverse events was similar to that observed with the respective free combinations of vildagliptin and metformin, and the most common individual adverse events were mild gastrointestinal events, which are commonly observed with metformin treatment. CONCLUSIONS: The fixed-dose combination tablet of vildagliptin/metformin is bioequivalent to administration of the individual drugs as a free combination at dose levels of 50/500, 50/850 and 50/1,000 mg and is well tolerated. Consequently, the fixed-dose combination tablets are considered therapeutically equivalent and exchangeable to the free combination in clinical practice. Furthermore, the fixed-dose combination tablets are expected to enhance convenience and thereby improve compliance and improve glycemic control for patients with Type 2 diabetes on both medications.

Nonlinear pharmacokinetics of 5-fluorouracil in rats.

The effects of dose on the pharmacokinetics of 5-fluorouracil (5-FU) were investigated following intravenous administration of 5-FU at 10, 50, and 100 mg/kg to adult male Sprague-Dawley rats. Six rats were studied at each dose level. The dose-normalized area under the curve (AUC) was significantly higher after administration of 100 mg/kg (1.14 +/- 0.55 mg.h/L/mg; mean +/- SD) than after 50 mg/kg (0.50 +/- 0.18 mg.h/L/mg) or 10 mg/kg (0.43 +/- 0.11 mg.h/L/mg), indicating nonlinear elimination of 5-FU in rats. Dose- and time-average pharmacokinetic parameters were calculated by area/moment analysis. The systemic clearance of 5-FU following administration of 100 mg/kg was significantly lower (1.1 +/- 0.49 L/h/kg) than after 50 mg/kg (2.2 +/- 0.72 L/h/kg) or 10 mg/kg (2.4 +/- 0.67 L/h/kg). There was no significant difference in renal clearance values between the three doses (0.47 +/- 0.26 L/h/kg). However, nonrenal clearance was significantly lower after the 100-mg/kg dose (0.77 +/- 0.2 L/h/kg) than after the 50-mg/kg (1.65 +/- 0.49 L/h/kg) and 10-mg/kg (1.87 +/- 0.75 L/h/kg) doses. There was no significant difference between the steady-state volume of distribution values (0.91 +/- 0.36 L/kg) at the three doses. The lower nonrenal clearance following the 100-mg/kg dose compared with that after the lower doses of 5-FU suggested nonlinear metabolism of 5-FU in rats. A two-compartment pharmacokinetic model with parallel first-order (renal excretion) and Michaelis-Menten elimination from the central compartment was simultaneously fit to mean plasma 5-FU concentration versus time data for the three doses. The maximum volume (Vmax) and Michaelis constant (Km) values averaged (mean +/- SE) 8.3 +/- 2.3 mg/h and 31.6 +/- 11.9 mg/L, respectively. The information obtained in this study will be valuable for the evaluation of prodrugs of 5-FU that are designed to reduce toxicities and to improve oral bioavailability of the anticancer agent.

High-performance liquid chromatographic determination of 5-fluorouracil and its prodrugs, tegafur and 4-deoxy-5-fluorouracil, in rat plasma.

A rapid, sensitive and reproducible ion-pair, reversed-phase high-performance liquid chromatographic (HPLC) method was developed to simultaneously quantitate 5-fluorouracil (5FU) and its prodrugs, tegafur (TF) and 4-deoxy-5-fluorouracil (DFU), in rat plasma. 5FU, TF, and internal standard 2', 3'-didehydro-2'-deoxythymidine (D4T, stavudine), were detected by UV absorption at 254 nm, and DFU was detected at 313 nm. Extraction recoveries for all compounds ranged between 80% and 92%. Retention times of 5FU, D4T, DFU and TF were 4.6, 5.5, 6.8 and 11.5 min, respectively. Calibration plots were linear over the range of 0.1 microgram/ml to 50 micrograms/ml for 5FU, and 0.25 microgram/ml to 50 micrograms/ml for TF and DFU. The limit of quantitation was 0.1 microgram/ml for 5FU and 0.25 microgram/ml for TF and DFU. The intra- and inter-day variations were less than 10% and accuracy was greater than 90%. This method was applied to plasma samples collected from rats that were administered 5FU, TF and DFU intravenously.

Pharmacokinetics of 5-carboranyl-2'-deoxyuridine in rats.

The pharmacokinetics of 5-carboranyl-2'-deoxyuridine (CDU) after intravenous administration of 25 mg/kg was investigated in rats. The uptake of CDU into brain was also examined. Concentrations of CDU in plasma, urine, and brain were measured by reverse phase HPLC. Plasma concentrations of CDU declined in a biexponential fashion with a terminal half-life of 1.26 +/- 0.28 h. The plasma protein binding of CDU was linear and the average fraction bound to plasma proteins was 0.95 +/- 0.02. The total clearance of CDU was 0.69 +/- 0.20 L/h/kg whereas clearance of unbound drug was much greater (15.33 +/- 4.44 L/h/kg). Thus, the total clearance of the drug is limited, in part, by the high degree of plasma protein binding, resulting in a moderate total clearance. No unchanged CDU was detected in urine. Furthermore, there was no trace of CDU glucuronide in urine samples. The steady-state volume of distribution of CDU was 0.70 +/- 0.23 L/kg. The brain:total plasma CDU concentration ratios determined in two rats were 0.47 and 0.36, while the brain:unbound plasma CDU concentration ratios were 10.26 and 7.87. The results of this study suggest that it is possible to achieve significant levels of CDU in brain. The high degree of plasma protein binding restricted extensive distribution of this lipophilic compound. The results of this study suggest further investigations of CDU as a neutron sensitizer for boron neutron capture therapy (BNCT) are warranted.