Vildagliptin is rapidly and well absorbed with an estimated absolute bioavailability of 85%. Two possible sites of absorption were identified, and the absorption rates were slower than the elimination rate, indicating a flip-flop phenomenon after oral dosing.
Deferasirox (ICL670) is representative of a new class of tridentate iron chelators, formulated as tablets for dispersion. Deferasirox has exhibited high potency and a clinically manageable safety profile in preclinical models and in an extensive clinical program. The effect of food and time of food intake on the pharmacokinetics of deferasirox was investigated in healthy volunteers and patients with transfusional hemosiderosis. The bioequivalence of a single oral dose of deferasirox (20 mg/kg) was assessed following administration either before a high-fat or standard breakfast or concurrent with a standard breakfast in comparison with fasted conditions in healthy volunteers. The bioavailability of deferasirox was determined following a single oral dose (20 mg/kg) under fed and fasted conditions in patients. These data show that the type of food, caloric content, and fat content of the meal influence the bioavailability of deferasirox when consumed concomitantly. In contrast, this is not the case when deferasirox is administered at least 30 minutes before a meal. In conclusion, it is recommended that deferasirox be administered at least 30 minutes prior to meals. When this is not feasible, deferasirox should be administered consistently at the same time before meals to limit the sources of variability that affect absorption.
Enteric-coated mycophenolate sodium (EC-MPS) (myfortic) is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying the release of MPA until the small intestine. A randomized, calcineurin inhibitor crossover, steady-state pharmacokinetic study in stable renal transplant patients receiving EC-MPS demonstrated increased MPA exposure of 19% higher, MPA C(max,ss) 19% lower and MPA C(min,ss) approximately twofold higher with tacrolimus, than cyclosporine microemulsion. No study drug-related adverse events were recorded, but mean blood glucose concentration was higher in patients receiving tacrolimus (p = 0.031). The dose changes in relation to MPA exposure in patients is dependent on the clinical situation and may not always be warranted. These observations should be taken into consideration when switching from one calcineurin inhibitor to another, but the final dosage should be based on both this pharmacokinetic data and the clinical situation.
OBJECTIVES
Vildagliptin (V) is a potent and specific DPP‐4 inhibitor, which is developed for treatment of type 2 diabetes (T2D). The objective of this study was to investigate the absolute bioavailability (F) of V after oral and intravenous (iv) administration of V.
METHODS
This was an open label, single‐dose, randomized, cross‐over study in healthy volunteers. Thirteen subjects were enrolled and 12 completed the study. Each subject was randomly assigned to receive one of the two treatments in a sequential manner with 72‐hr interval between treatment periods: 50 mg po or 25 mg iv infusion over 30 minutes. Blood samples were collected after oral and iv administrations and the concentrations were measured by LC‐MS/MS.
RESULTS
The absolute oral F of V was estimated to be 85% with a 90% confidence interval over the range between 79 and 91%. After iv infusion, the total body clearance (CLtot) and the renal clearance (CLR) were 40.6±8.97 L/hr and 13.0±2.35 L/hr, respectively, demonstrating that CLRaccounted for 33% of the CLtot. The volume of distribution at steady‐state was 70.5±16.1 L, suggesting that V distributes into tissues and organs.
CONCLUSIONS
The oral absolute F of V was 85%. The total recovery of radioactivity in urine when[14C]‐V was given orally in a previous study was also ∼85%, suggesting that hepatic excretion has little contribution to the elimination of V. Single oral and iv administrations of V were well tolerated in this small number of healthy subjects.
Clinical Pharmacology & Therapeutics (2005) 79, P38–P38; doi:
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