DNRS 6521 Week 6 Interaction Analysis Example

Interaction Analysis: Clarithromycin Added to Daily Colchicine in a 72-Year-Old Man With Reduced Kidney Function

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College of Nursing, Walden University

DNRS 6521: Advanced Pharmacology (DNP level)

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Month Day, Year

Interaction Analysis: Clarithromycin Added to Daily Colchicine in a 72-Year-Old Man With Reduced Kidney Function

The Shared Pathway and Who Occupies It

A composite 72-year-old man with gout takes colchicine 0.6 mg daily as prophylaxis while his allopurinol dose is being titrated, a use supported by the gout guideline (FitzGerald et al., 2020). His estimated glomerular filtration rate is 42 mL/min/1.73 m2. At an urgent care visit for community-acquired pneumonia, he leaves with a week of twice-daily clarithromycin.

Colchicine is cleared by two routes that clarithromycin blocks. It is metabolized by cytochrome P450 3A4 and pumped out of intestinal and liver cells, and into bile, by P-glycoprotein; a smaller share is excreted unchanged by the kidney. It has a narrow therapeutic range, so modest increases in exposure can move it from effective to toxic (Niel & Scherrmann, 2006). Clarithromycin is a strong inhibitor of CYP3A4 and also inhibits P-glycoprotein (Rodvold, 1999). The interaction is directional, not mutual: clarithromycin occupies the pathway far more strongly than colchicine does, so it changes colchicine's exposure while colchicine does little to clarithromycin's.

From Competition at the Pathway to a Change in Exposure

With both of its main clearance routes inhibited, colchicine is absorbed more completely, because less is pumped back into the gut lumen, and eliminated more slowly, because less is metabolized and less is excreted into bile. The direction is clear: exposure rises, and it rises both in peak and in total. The magnitude is substantial. In open-label drug interaction studies in healthy volunteers, most CYP3A4 and P-glycoprotein inhibitors tested raised colchicine's peak and total exposure well above the 125% threshold used to define an interaction, and the authors calculated that colchicine doses would need to be cut by roughly one third to two thirds for acute gout and by one half to three quarters for prophylaxis during coadministration with such inhibitors (Terkeltaub et al., 2011). Those reductions imply that exposure can roughly double or more.

In this man, the kidney adds to the problem. His reduced kidney function removes some of the renal route that would otherwise partly compensate, so the rise in exposure is likely to be greater than in the healthy volunteers who were studied.

What Is Established and What Is Extrapolated

Two things are established. The pharmacokinetic interaction is established by controlled studies in healthy adults given single colchicine doses (Terkeltaub et al., 2011). The clinical harm is established by a retrospective study of 116 hospitalized patients who received both drugs during the same admission: 9 of 88 (10.2%) who received them together died, compared with 1 of 28 (3.6%) who received them one after the other, and baseline kidney impairment was independently associated with death among those given both (Hung et al., 2005).

Two things are extrapolated. The size of the rise in exposure during chronic daily dosing, rather than single doses, is inferred from single-dose studies. The size of the rise in a patient with an eGFR of 42 is inferred from the combination of the interaction studies and the observational data on kidney impairment; no controlled study measured it. The analysis therefore rests on established direction and harm, with an extrapolated magnitude for this particular patient.

Timing

The change appears quickly. Clarithromycin's inhibition of CYP3A4 begins with the first doses, and colchicine levels rise over the following days as the patient continues his daily dose. It also persists after clarithromycin is stopped. Clarithromycin is a mechanism-based inhibitor: it forms a complex that inactivates CYP3A4, so activity returns only as the liver and gut make new enzyme (Zhou et al., 2005). Enzyme recovery takes days, so colchicine exposure may stay elevated for several days after the last clarithromycin dose. Separating the two drugs in time on the same day does nothing; separation has to be measured in days.

Timing also explains how toxicity presents. Colchicine toxicity usually begins with gastrointestinal symptoms, nausea, vomiting, and diarrhea, before the dangerous effects on bone marrow and muscle. In the retrospective series, the development of pancytopenia was strongly associated with death among patients who received both drugs (Hung et al., 2005). A patient told to expect some stomach upset from an antibiotic may ignore exactly the early warning that matters, which is why the counseling at the urgent care visit would have needed to be specific.

The Documented Consequence

The clarithromycin prescription is replaced. For an outpatient with a comorbidity such as chronic kidney disease, the pneumonia guideline supports pairing amoxicillin-clavulanate or another beta-lactam with either a macrolide or doxycycline (Metlay et al., 2019). The choice of partner matters here. Among the inhibitors tested in the interaction studies, azithromycin was the exception that did not require any colchicine dose adjustment (Terkeltaub et al., 2011), unlike clarithromycin, and doxycycline is not a meaningful inhibitor of this pathway. His new regimen is amoxicillin-clavulanate with doxycycline, and his colchicine continues unchanged. If no suitable alternative existed, colchicine would be held for the whole course and for several days afterward, accepting a higher short-term risk of a gout flare, because the interaction's documented harm is fatal toxicity (Hung et al., 2005). His medication record now carries an alert naming strong CYP3A4 and P-glycoprotein inhibitors as agents to avoid with his colchicine, and he has been told to show his medication list at any urgent care visit.

References

FitzGerald, J. D., Dalbeth, N., Mikuls, T., Brignardello-Petersen, R., Guyatt, G., Abeles, A. M., Gelber, A. C., Harrold, L. R., Khanna, D., King, C., Levy, G., Libbey, C., Mount, D., Pillinger, M. H., Rosenthal, A., Singh, J. A., Sims, J. E., Smith, B. J., Wenger, N. S., . . . Neogi, T. (2020). 2020 American College of Rheumatology guideline for the management of gout. Arthritis Care & Research, 72(6), 744-760. https://doi.org/10.1002/acr.24180

Hung, I. F. N., Wu, A. K. L., Cheng, V. C. C., Tang, B. S. F., To, K. W., Yeung, C. K., Woo, P. C. Y., Lau, S. K. P., Cheung, B. M. Y., & Yuen, K. Y. (2005). Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: A retrospective study. Clinical Infectious Diseases, 41(3), 291-300. https://doi.org/10.1086/431592

Metlay, J. P., Waterer, G. W., Long, A. C., Anzueto, A., Brozek, J., Crothers, K., Cooley, L. A., Dean, N. C., Fine, M. J., Flanders, S. A., Griffin, M. R., Metersky, M. L., Musher, D. M., Restrepo, M. I., & Whitney, C. G. (2019). Diagnosis and treatment of adults with community-acquired pneumonia: An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. American Journal of Respiratory and Critical Care Medicine, 200(7), e45-e67. https://doi.org/10.1164/rccm.201908-1581ST

Niel, E., & Scherrmann, J.-M. (2006). Colchicine today. Joint Bone Spine, 73(6), 672-678. https://doi.org/10.1016/j.jbspin.2006.03.006

Rodvold, K. A. (1999). Clinical pharmacokinetics of clarithromycin. Clinical Pharmacokinetics, 37(5), 385-398. https://doi.org/10.2165/00003088-199937050-00003

Terkeltaub, R. A., Furst, D. E., DiGiacinto, J. L., Kook, K. A., & Davis, M. W. (2011). Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis & Rheumatism, 63(8), 2226-2237. https://doi.org/10.1002/art.30389

Zhou, S., Chan, S. Y., Goh, B. C., Chan, E., Duan, W., Huang, M., & McLeod, H. L. (2005). Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clinical Pharmacokinetics, 44(3), 279-304. https://doi.org/10.2165/00003088-200544030-00005