Clinical pharmacokinetics of bezafibrate in patients with impaired renal function

Abstract

The pharmacokinetics of the new lipid-lowering drug bezafibrate has been investigated in patients with impaired renal function and hyperlipoproteinaemia. 12 patients received a single oral dose of bezafibrate 300 mg. Plasma and urine samples were collected and bezafibrate was analyzed by gas chromatography. Eight of the patients had moderately impaired renal function, with a creatinine clearance between 20 and 40 ml/min; the mean plasma half-life of bezafibrate in them was 7.8 +3.9 h (SD) and the plasma clearance was 0.03 +0.02 1/kg . h. Three of the patients had a creatinine clearance greater than 40 ml/min; in them the plasma half-life was shorter, 4.6 +1.2 h, and the plasma clearance was higher, 0.06 +0.01 1/kg . h. The slowest elimination of bezafibrate was found in a patient with a creatinine clearance of only 13 ml/min. This patient had a plasma half-life of 20.l h, which is ten times longer than has been reported in healthy volunteers. Thus, when treating hyperlipoproteinaemia in patients with impaired renal function, the dosage of bezafibrate must be individualized because of its reduced renal elimination.

The short term effects of bezafibrate on the hypertriglyceridaemia of moderate to severe uraemia.

“…i protein lipase (Kraemer et al, 1982) and hepatic triglyceride lipase (Mordasini et al, 1977) (Anderson & Norbeck, 1981) and even with the reduced dosage employed in this study drug levels far in excess of this recommended level were attained.…”

“…Serum levels of bezafibrate were determined by the manufacturer (Boehringer Mannheim Ltd, Germany) using a gas chromatography method (Endele, 1979) and the average steady state serum level calculated. The reduced dose of bezafibrate was chosen, as it has been shown that the drug half-life is prolonged in renal insufficiency (Anderson & Norbeck, 1981).…”

Steady-state kinetics of bezafibrate retard in hyperlipidemic geriatric patients

“…3. The straight regression line in this figure was calculated from data of Abshagen et al [2] and Anderson and Norbeck [5], demonstrating the influence of kidney function as judged by creatinine clearance on total clearance of bezafibrate. Nearly all of the values of the elderly are found unter the regression line.…”

“…The closer kinetics are in accordance with a one-compartment model, the less influence will be exerted by a change in total body clearance on apparent volume of distribution [18]. Elimination rate-corrected areas were also compared with literature data [1,3,5]. When comparisons between different bezafibrate preparations were made, i.e., normal-release and slow-release, data of the slowrelease preparations were corrected according to a bioavailability of 0.7 relative to the normal-release preparation (data not published).…”

“…Pharmacokinetics of bezafibrate have been investigated in healthy volunteers [1,3] and in patients with impaired renal function [2,5].These investigations demonstrated that 50% of unchanged bezafibrate is eliminated with the urine and therefore the kinetAbbreviations: AUCs~ = area under the curve within the dosing interval during steady-state; Cm~x=maximum concentration; CL = total clearance; CLcR = creatinine clearance; CL/f= clearance divided by bioavailability; CLR = renal clearance; f= bioavailability; lambdaz (2z) = elimination rate constant; tm.x = time to Cmax ; tl/2 = elimination half-life ics of this drug are dependent on renal function. Hyperlipidemia per se has no influence on bezafibrate kinetics [18].…”