Calcium-Channel Blocker�Clarithromycin Drug Interactions and Acute Kidney Injury

• Autores: Sonja Gandhi, Jamie L. Fleet, David G. Bailey, Eric McArthur, Ron Wald, Amit X. Garg
• Localización: JAMA: the journal of the American Medical Association, ISSN 0098-7484, Vol. 310, Nº. 23, 2013, págs. 2544-2553
• Idioma: inglés
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• Resumen

  • Importance Calcium-channel blockers are metabolized by the cytochrome P450 3A4 (CYP3A4; EC 1.14.13.97) enzyme. Blood concentrations of these drugs may rise to harmful levels when CYP3A4 activity is inhibited. Clarithromycin is an inhibitor of CYP3A4 and azithromycin is not, which makes comparisons between these 2 macrolide antibiotics useful in assessing clinically important drug interactions.

    Objective To characterize the risk of acute adverse events following coprescription of clarithromycin compared with azithromycin in older adults taking a calcium-channel blocker.

    Design, Setting, and Participants Population-based retrospective cohort study in Ontario, Canada, from 2003 through 2012 of older adults (mean age, 76 years) who were newly coprescribed clarithromycin (n?=?96?226) or azithromycin (n?=?94?083) while taking a calcium-channel blocker (amlodipine, felodipine, nifedipine, diltiazem, or verapamil).

    Main Outcomes and Measures Hospitalization with acute kidney injury (primary outcome) and hospitalization with hypotension and all-cause mortality (secondary outcomes examined separately). Outcomes were assessed within 30 days of a new coprescription.

    Results There were no differences in measured baseline characteristics between the clarithromycin and azithromycin groups. Amlodipine was the most commonly prescribed calcium-channel blocker (more than 50% of patients). Coprescribing clarithromycin vs azithromycin with a calcium-channel blocker was associated with a higher risk of hospitalization with acute kidney injury (420 patients of 96?226 taking clarithromycin [0.44%] vs 208 patients of 94?083 taking azithromycin [0.22%]; absolute risk increase, 0.22% [95% CI, 0.16%-0.27%]; odds ratio [OR], 1.98 [95% CI, 1.68-2.34]). In a subgroup analysis, the risk was highest with dihydropyridines, particularly nifedipine (OR, 5.33 [95% CI, 3.39-8.38]; absolute risk increase, 0.63% [95% CI, 0.49%-0.78%]). Coprescription with clarithromycin was also associated with a higher risk of hospitalization with hypotension (111 patients of 96?226 taking clarithromycin [0.12%] vs 68 patients of 94?083 taking azithromycin [0.07%]; absolute risk increase, 0.04% [95% CI, 0.02%-0.07%]; OR, 1.60 [95% CI, 1.18-2.16]) and all-cause mortality (984 patients of 96?226 taking clarithromycin [1.02%] vs 555 patients of 94?083 taking azithromycin [0.59%]; absolute risk increase, 0.43% [95% CI, 0.35%-0.51%]; OR, 1.74 [95% CI, 1.57-1.93]).

    Conclusions and Relevance Among older adults taking a calcium-channel blocker, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically significant greater 30-day risk of hospitalization with acute kidney injury. These findings support current safety warnings regarding concurrent use of CYP3A4 inhibitors and calcium-channel blockers.

    The commonly used macrolide antibiotics clarithromycin and erythromycin are clinically important inhibitors of the cytochrome P450 3A4 (CYP3A4; EC 1.14.13.97) enzyme, while azithromycin is much less so.1,2 In older adults, coprescription of clarithromycin or erythromycin with a CYP3A4 metabolized statin (atorvastatin, simvastatin, and lovastatin) has been shown to be associated with a greater risk of hospitalization with rhabdomyolysis, hospitalization with acute kidney injury, and all-cause mortality compared with azithromycin coprescription.3 Calcium-channel blockers are a popular class of antihypertensive drugs that are metabolized by the CYP3A4 enzyme. In pharmacokinetic studies, coadministration of various inhibitors of this enzyme (eg, erythromycin, antifungals, protease inhibitors, and grapefruit juice) raised plasma calcium-channel blocker concentrations by up to 500%.4- 6 As a result, there is the possibility of excessive systemic calcium-channel blocker concentration and associated toxicity with concurrent use of a CYP3A4 inhibitor.

    Enhanced blood pressure lowering was observed in several studies (up to 12 healthy volunteers) after a CYP3A4 inhibitor was administrated with a calcium-channel blocker.4,7,8 Several case reports described hospitalization with hypotension soon after a CYP3A4 inhibitor was taken with a calcium-channel blocker.9- 12 Moreover, a population-based case-crossover study of older adults found a greater risk of hospitalization with hypotension when a calcium-channel blocker was coprescribed with erythromycin or clarithromycin compared with azithromycin.13 Currently, the US Food and Drug Administration warns that �serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates, which includes hypotension with calcium-channel blockers metabolized by CYP3A4 (eg, verapamil, amlodipine, diltiazem).�14 Yet calcium-channel blockers and clarithromycin continue to be frequently coprescribed in routine care.

    When hypotension occurs, the kidney is particularly prone to acute ischemic injury from poor perfusion. Acute kidney injury is a clinically important event that impacts morbidity, mortality, and resource use.15 Despite this knowledge, the risk of acute kidney injury following coprescription of clarithromycin with a calcium-channel blocker is unknown. Therefore, we conducted a population-based cohort study of older adults to investigate the interaction between calcium-channel blockers and the antibiotic clarithromycin with a focus on acute kidney injury.