Frequency and clinical relevance of drug interactions with lovastatin and simvastatin: an observational database study.
BACKGROUND
Concomitantly used cytochrome P450 (CYP) 3A4 inhibitors and inducers have been shown to alter the plasma concentrations of the HMG-CoA reductase inhibitors ('statins') lovastatin and simvastatin. Myopathy is a serious adverse effect of statins. Concurrent use of statins with fibrates in particular seems to increase the risk of this adverse effect.


OBJECTIVE
To evaluate the incidence and clinical consequences of the use of lovastatin or simvastatin with concomitant CYP3A4 inhibitors and inducers, and with fibrates.


METHODS
An observational database study of hospitalized patients treated in Turku University Hospital, Turku, Finland, covering the period 1 July 1996 to 30 June 2003, and of nationwide community data from the Finnish Prescription Register over the period 1 April to 30 June 2001 was conducted. In the hospital setting, the study population comprised 71 025 patients (93 467 treatment periods) over 7 years, with a total of 5320 treatment periods of lovastatin or simvastatin. The community-based, nationwide survey included all reimbursed prescriptions of lovastatin and simvastatin (n = 91 656) in Finland during a 3-month period. The frequency of drug-drug interactions involving lovastatin or simvastatin was studied. The efficacy and safety of the various statin/concomitant drug combinations was estimated by evaluating patients' laboratory data.


RESULTS
Concomitant use of lovastatin or simvastatin with interacting medication was detected in 13.3% (704) and 6.9% (6338) of patients in hospital and community settings, respectively. Co-administration of lovastatin or simvastatin with CYP3A4 inhibitors or inducers did not have a clinically significant effect on serum lipid values. Plasma creatine kinase (CK) activity was significantly higher in patients receiving a statin and a fibrate compared with a statin only (433 U/L vs 209 U/L, p = 0.053). Co-administration of a statin and a CYP3A4 inhibitor did not increase CK activity.


CONCLUSIONS
Although the pharmacokinetic interactions between lovastatin or simvastatin and CYP3A4 inhibitors and inducers are substantial, their clinical relevance seems to be limited, at least with lower statin doses. However, combining statins with fibrates, especially gemfibrozil, clearly increases the potential for muscular toxicity.
Tirkkonen
Tuire
T
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, FinlandMedbase Ltd, Turku, Finland. tuire.trikkonen@utu.fi
Ryynänen
Anna
A
Vahlberg
Tero
T
Irjala
Kerttu
K
Klaukka
Timo
T
Huupponen
Risto
R
Laine
Kari
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003402:Creatine Kinase / Q000187:drug effects / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005387:Finland; D006785:Hospitals, University; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D008148:Lovastatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003402:Creatine Kinase