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Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients

par Lins, Robert;Matthys, Katelijne;Verpooten, Gert;Peeters, Patrick;Dratwa, Max ;Stolear, Jean Claude;Lameire, Norbert
Référence Nephrology, dialysis, transplantation, 18, 5, page (967-976)
Publication Publié, 2003-05

Article révisé par les pairs

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Résumé :

Background. Patients with chronic renal failure commonly suffer from a secondary form of complex dyslipidaemia, and may benefit from lipid-lowering treatment. Atorvastatin has been shown to reduce efficiently the levels of atherogenic lipoproteins also in patients with renal failure, but pharmacokinetic data in haemodialysis patients are lacking. Methods. In this study, hypercholesterolaemic haemodialysis patients received 40 mg (n = 12) or 80 mg (n = 11) atorvastatin once daily, first as a single dose and then continuously for 2 weeks. Plasma levels of atorvastatin and its active and inactive metabolites were measured by LC/MS/MS, and pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) compared between single and multiple dosing, and between the different doses. Results. The pharmacokinetic parameters of the parent drug atorvastatin acid were not significantly different after single and 2-week multiple dosing; they showed dose-proportionality between the 40 and 80 mg dose, and were comparable to findings in healthy volunteers. Dose-proportionality and absence of accumulation was also observed for the major active metabolite orthohydroxy-atorvastatin and the inactive metabolites atorvastatin lactone and ortho-hydroxy-atorvastatin lactone, but the levels of the active metabolite were relatively lower, and the inactive metabolites higher, compared with healthy volunteers. The para-hydroxymetabolites constituted only a minor pathway in atorvastatin's metabolic elimination. Haemodialysis did not cause enhanced clearance of atorvastatin or its metabolites, the drug was well tolerated and there were no serious adverse events. Conclusion. While subtle differences may exist in the metabolic processing of atorvastatin in haemodialysis patients, active drug did not accumulate nor did it show enhanced elimination, and levels were comparable to those measured in healthy volunteers. Therefore there is no need to adapt atorvastatin dosage in this particular patient population.