Chapter 33 : Antifungal Drug Interactions

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The risk of an adverse effect with a drug interaction is further increased in patients with advanced age, malnutrition, malabsorption, chronic illness, hepatic or renal dysfunction, polypharmacy, or concomitant use of drugs with a narrow therapeutic index or in patients whose care is provided by multiple specialists or prescribers. As many or all of these risk factors are present in the patient populations predisposed to invasive fungal infections, drug interactions should be anticipated in any patient receiving systemic antifungal therapy for invasive aspergillosis. This chapter focuses on mechanisms and clinical implications of pharmacokinetic drug-drug interactions in the patient with aspergillosis. The density of P-gp expression in the gastrointestinal tract exhibits wide intra- and interpatient variability that is affected by diet, underlying disease, drug therapy, and genetics. Some chemotherapy agents and immunosuppressants used in solid organ or hematopoetic stem cell transplantation are extensively cleared through CYP3A4 biotransformation. Management of these interactions focuses on preventative measures to limit the severity of the reaction and careful monitoring and supplementation of electrolyte deficiencies. Patients with invasive aspergillosis have multiple risk factors for potentially harmful drug interactions. Although some drug interactions may be trivial or have minor effects, interactions that enhance the metabolism of antifungals used to treat infection, interactions that affect drugs with a narrow therapeutic index (i.e., immunosuppressants, chemotherapy, antiretrovirals), and interactions that increase cardiac QT prolongation should always be considered important and managed in a proactive fashion.

Citation: Lewis R. 2009. Antifungal Drug Interactions, p 445-456. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch33
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Image of Figure 1.
Figure 1.

Mechanisms of pharmacokinetic variability and drug-drug interactions in the gastrointestinal and hepatobiliary tracts. Most antifungal agents are absorbed by passive diffusion. Intestinal enterocytes can efflux drug out of the cell by action of the P-gp pump. Mixed function oxidases (primarily CYP3A4/3A5) oxidize the drug before it reaches the portal circulation. The overlapping substrate specificity of P-gp and CYP3A4/5 represents a complementary barrier against drug absorption that serves as a possible source for drug interactions with orally absorbed antifungal agents.

Citation: Lewis R. 2009. Antifungal Drug Interactions, p 445-456. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch33
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Image of Figure 2.
Figure 2.

TdP risk stratification schedules for antimicrobial agents. *, antimicrobial agent that is new to the market or still investigational and has minimal to no postmarketing data; based on additional data, the drug may be recategorized in a higher or lower schedule. I, rapid component of the delayed rectifier potassium current. Adapted from Owens (2004) with the permission of the publisher.

Citation: Lewis R. 2009. Antifungal Drug Interactions, p 445-456. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch33
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Table 1.

Antifungal characteristics that predispose to potential adverse drug interactions

Citation: Lewis R. 2009. Antifungal Drug Interactions, p 445-456. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch33
Generic image for table
Table 2.

Comparative CYP P450 interaction profiles of the triazole antifungals

Citation: Lewis R. 2009. Antifungal Drug Interactions, p 445-456. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch33
Generic image for table
Table 3.

Summary of common drug interactions affecting hepatic biotransformation and clearance in patients with aspergillosis

Citation: Lewis R. 2009. Antifungal Drug Interactions, p 445-456. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch33
Generic image for table
Table 4.

Recommendations for therapeutic drug monitoring of antifungal therapy in patients with aspergillosis

Citation: Lewis R. 2009. Antifungal Drug Interactions, p 445-456. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch33

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