Amit M. Patel, MD; Salimah Shariff, PhD; David G. Bailey, BScPhm, PhD; David N. Juurlink, MD, PhD; Sonja Gandhi, BSc; Muhammad Mamdani, PharmD, MPH; Tara Gomes, MHSc; Jamie Fleet, BSc; Y. Joseph Hwang, BMSc; Amit X. Garg, MD, PhD
Acknowledgment: The authors thank IMS Brogan (Ottawa, Ontario, Canada), for use of their Drug Product and Therapeutic Class Database; the late Dr. Milton Haines, Ms. Barbara Jones, Mr. Jeff Lamond, and others from Gamma Dynacare for use of their outpatient laboratory database; and Mr. Glen Kearns from the London Health Sciences Centre who facilitated the use of linked hospital laboratory databases.
Financial Support: The investigators received grant support from the Academic Medical Organization of Southwestern Ontario to conduct this research. This project was conducted at the Institute for Clinical Evaluative Sciences site at Western University. The Institute for Clinical Evaluative Sciences is funded by an annual grant from the Ontario Ministry of Health and Long-term Care. The Institute for Clinical Evaluative Sciences site at Western University is funded by an operating grant from the Academic Medical Organization of Southwestern Ontario. Dr. Garg was supported by a Canadian Institutes of Health Research Clinician Scientist Award.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1300.
Reproducible Research Statement: Study protocol, statistical code, and data set: Portions are available to approved individuals through written agreements with Dr. Garg (e-mail, firstname.lastname@example.org).
Requests for Single Reprints: Amit Garg, MD, PhD, London Kidney Clinical Research Unit, Room ELL-101, Westminster, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada; e-mail, email@example.com.
Current Author Addresses: Drs. Patel, Shariff, and Garg; Ms. Gandhi; Ms. Fleet; and Mr. Hwang: London Kidney Clinical Research Unit, Room ELL-101, Westminster, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada.
Dr. Bailey: University Hospital, Room B3-264, London Health Sciences Centre, 339 Windermere Road, London, Ontario N6G 2K3, Canada.
Dr. Juurlink and Ms. Gomes: Sunnybrook Health Sciences Centre, Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Dr. Mamdani: Keenan Research Centre, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.
Author Contributions: Conception and design: A.M. Patel, S. Shariff, D.G. Bailey, D.N. Juurlink, S. Gandhi, M. Mamdani, T. Gomes, J. Fleet, Y.J. Hwang, A.X. Garg.
Analysis and interpretation of the data: A.M. Patel, S. Shariff, D.G. Bailey, D.N. Juurlink, S. Gandhi, M. Mamdani, T. Gomes, J. Fleet, Y.J. Hwang, A.X. Garg.
Drafting of the article: A.M. Patel, D.G. Bailey, A.X. Garg.
Critical revision of the article for important intellectual content: A.M. Patel, S. Shariff, D.G. Bailey, D.N. Juurlink, S. Gandhi, M. Mamdani, T. Gomes, J. Fleet, Y.J. Hwang, A.X. Garg.
Final approval of the article: A.M. Patel, S. Shariff, D.G. Bailey, D.N. Juurlink, S. Gandhi, M. Mamdani, T. Gomes, J. Fleet, Y.J. Hwang, A.X. Garg.
Provision of study materials or patients: A.X. Garg.
Statistical expertise: S. Shariff, D.N. Juurlink, M. Mamdani, T. Gomes, A.X. Garg.
Obtaining of funding: A.X. Garg.
Administrative, technical, or logistic support: A.M. Patel, S. Shariff, T. Gomes, J. Fleet, A.X. Garg.
Collection and assembly of data: S. Shariff.
Patel A., Shariff S., Bailey D., Juurlink D., Gandhi S., Mamdani M., Gomes T., Fleet J., Hwang Y., Garg A.; Statin Toxicity From Macrolide Antibiotic Coprescription: A Population-Based Cohort Study. Ann Intern Med. 2013;158:869-876. doi: 10.7326/0003-4819-158-12-201306180-00004
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Published: Ann Intern Med. 2013;158(12):869-876.
Clarithromycin and erythromycin, but not azithromycin, inhibit cytochrome P450 isoenzyme 3A4 (CYP3A4), and inhibition increases blood concentrations of statins that are metabolized by CYP3A4.
To measure the frequency of statin toxicity after coprescription of a statin with clarithromycin or erythromycin.
Population-based cohort study.
Ontario, Canada, from 2003 to 2010.
Continuous statin users older than 65 years who were prescribed clarithromycin (n = 72 591) or erythromycin (n = 3267) compared with those prescribed azithromycin (n = 68 478).
The primary outcome was hospitalization with rhabdomyolysis within 30 days of the antibiotic prescription.
Atorvastatin was the most commonly prescribed statin (73%) followed by simvastatin and lovastatin. Compared with azithromycin, coprescription of a statin with clarithromycin or erythromycin was associated with a higher risk for hospitalization with rhabdomyolysis (absolute risk increase, 0.02% [95% CI, 0.01% to 0.03%]; relative risk [RR], 2.17 [CI, 1.04 to 4.53]) or with acute kidney injury (absolute risk increase, 1.26% [CI, 0.58% to 1.95%]; RR, 1.78 [CI, 1.49 to 2.14]) and for all-cause mortality (absolute risk increase, 0.25% [CI, 0.17% to 0.33%]; RR, 1.56 [CI, 1.36 to 1.80]).
Only older adults were included in the study. The absolute risk increase for rhabdomyolysis may be underestimated because the codes used to identify it were insensitive.
In older adults, coprescription of clarithromycin or erythromycin with a statin that is metabolized by CYP3A4 increases the risk for statin toxicity.
Academic Medical Organization of Southwestern Ontario.
J. David Spence, MD, FRCPC, FAHA
Western University, London, Canada
June 21, 2013
Statin interactions, grapefruit, bioavailability and rhabdomyolysis
The report by Patel el al.(1) highlights the importance of interactions with statins that are metabolized in the intestinal wall by CYP3A4. This class of interactions is a particular problem with statins that have low bioavailability due to inactivation by intestinal CYP3A4, during absorption. Because simvastatin and lovastatin are only 5% bioavailable due to this mechanism, grapefruit and other inhibitors of CYP3A4 have the theoretical potential to increase blood levels 20-fold. Grapefruit, which inhibits intestinal CYP3a4 to the same extent as erythromycin, increases the area under the curve (AUC) of blood levels of both simvastatin(2) and lovastatin(3) 15-fold. Atorvastatin is ~ 50% bioavailable, so its AUC “only” doubles with grapefruit (4), and pravastatin and rosuvastatin are not affected.
One glass of grapefruit juice(2) or one grapefruit daily(5) is sufficient to markedly inhibit intestinal CYP3A4, and the effect persists for more than 24 hours. Although pharmacists will often detect potential drug interactions, grocers seldom inquire about medication history when dispensing grapefruit. This is a particular problem for simvastatin, which is more potent than lovastatin, and has been reported to cause severe rhabdomyolysis within 4 days after initiating consumption of one fruit daily(5). Simvastatin and lovastatin should be regarded as drugs with problem pharmacokinetics, and should probably by avoided because of the potential for huge interactions.
(1) Patel AM, Shariff S, Bailey DG, Juurlink DN, Gandhi S, Mamdani M et al. Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study. Ann Intern Med 2013; 158(12):869-876.
(2) Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol 2004; 58(1):56-60.
(3) Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998; 63(4):397-402.
(4) Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66(2):118-127.
(5) Dreier JP, Endres M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology2004; 62(4):670.
H. Farzin MD, M. Takematsu, MD, RS. Hoffman, MD
McGill University Montreal, Quebec, Canada, New York City Poison Control Center Bellevue Hospital Center New York University School of Medicine New York, NY
July 9, 2013
In response to statin toxicity form CPY3A4 interatction
We read with interest your recent study assessing statin toxicity and macrolide antibiotic concomitant prescription. While we commend the authors for performing this much-needed study, we have several concerns regarding their design and interpretation of the results.The investigators attempted to control for the CYP3A4 inhibiting macrolides with azithromycin, stating that it has indications and clinical use patterns similar to that of clarithromycin and erythromycin. Given the fact that the actual indications for antibiotic use is unknown in more than half the study participants, we believe that this comparison is fundamentally flawed, as the choice of antibiotic prescribed could have been affected by the type, location, or severity of the infection. Additionally, the choice of azithromycin as the comparison group implies that the investigators had assumed the increased risks were due to CYP3A4 metabolism. Inclusion of a non-drug comparison group would have addressed these concerns.
Finally, we believe that all-cause mortality is too broad of an outcome in such a study, and to attribute this increase to statin toxicity is too presumptive. We caution against drawing such conclusions from a retrospective cohort. Although the authors acknowledge that these associations do not imply causation, they suggest that the concomitant prescription increases the risk of statin toxicity in older adults.In conclusion, this study would have been strengthened by the inclusion of a non-drug control group as well as knowledge regarding the indications for antibiotic prescriptions in the remaining half of the study population. While the observed association in this study is strengthened by its large size, it is unclear if the observed differences are due to the effect of the antibiotic itself or as a result of the severity of the patient’s illness, and its impact on the prescriber’s choice of medication.
1. Patel AM, Shariff S, Bailey DG, Juurlink DN, Gandhi S, Mamdani M et al. Statin toxicity from macrolide antibiotic coprescription: a population-based Cohort Study. Ann Intern Med 2013; 158(12):869-876
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