Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failure.
Objectives - To study the effect of age and renal function on the pharmacokinetic profile of a modified release tablet of trimetazidine (TMZ MR 35 mg) administered twice daily.Methods- Study 1: Twelve healthy elderly subjects (CL(creat) 72+/-8 ml/min, 72+/-4 years mean+/-SD) and eight young volunteers (CL(creat) 134+/-18 ml/min, 25+/-8 years) received TMZ MR 35 mg b.i.d. (eight doses). Study 2: eight patients with severe renal failure (CL(creat.) 17+/-5 ml/min, 54+/-10 years), five patients with moderate renal failure (CL(creat.) 39+/-6 ml/min, 54+/-15 years) and eight volunteers (CL(creat.) 104+/-17 ml/min, 53+/-9 years) received TMZ MR 35 mg b.i.d. (patients: ten doses, volunteers: eight doses). Serial blood and urine samples were obtained following administration of the last dose in each study. TMZ plasma and urine concentrations were determined by gas chromatography (NPD-detector). The resulting data were analysed using standard non-compartmental pharmacokinetic methods.Results- Study 1: Elimination half-life of TMZ was significantly longer and renal clearance significantly lower in the elderly subjects. Study 2: In patients with either moderate or severe renal failure, exposure (AUC(0-24)) was significantly increased and renal clearance (CL(R)) was significantly decreased. Significant correlations were observed between CL(creat) and CL(R) (r=0.94) and between CL(creat) and AUC(0-24) (r=-0.94). Conclusion - With repeated administration of TMZ MR 35 mg b.i.d., a decrease in CL(creat) is directly related to a decrease in CL(R) and results in an increase in exposure to TMZ.
Barré
J
J
Pharmacology Department, Centre Hospitalier Intercommunal de Créteil, Créteil, France.
Ledudal
P
P
Oosterhuis
B
B
Brakenhoff
J P G
JP
Wilkens
G
G
Sollie
F A E
FA
Tran
D
D
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000378:metabolism*; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000503:physiopathology; D013607:Tablets; D014292:Trimetazidine / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D003692:Delayed-Action Preparations; D013607:Tablets; D014292:Trimetazidine