What are the potential interactions between atovaquone and rifampin (Rifampicin)?

From the Guidelines

Atovaquone and rifampin should not be used together due to a significant drug interaction that reduces atovaquone's effectiveness. When co-administered, rifampin decreases atovaquone plasma concentrations by inducing the liver enzymes responsible for atovaquone metabolism, as indicated in the American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America guidelines for the treatment of tuberculosis 1. This reduction in atovaquone levels can lead to treatment failure, particularly when atovaquone is being used for conditions like Pneumocystis pneumonia or malaria prophylaxis.

The interaction between atovaquone and rifampin occurs because rifampin is a potent inducer of cytochrome P450 enzymes and P-glycoprotein, which accelerates the clearance of atovaquone from the body. Key points to consider in managing this interaction include:

• Monitoring for treatment failure if both medications must be used together
• Considering alternative medications to atovaquone for Pneumocystis prophylaxis, such as trimethoprim-sulfamethoxazole or dapsone
• Preferably using non-rifamycin antibiotics for patients on atovaquone who require antimicrobial therapy

Given the potential for reduced efficacy of atovaquone when co-administered with rifampin, alternative treatment strategies should be prioritized to ensure optimal patient outcomes, as suggested by the guidelines 1. This approach aligns with the goal of minimizing morbidity, mortality, and improving quality of life by avoiding drug interactions that could compromise the effectiveness of necessary medications.

From the FDA Drug Label

In a trial with 13 HIV-1-infected volunteers, the oral administration of rifampin 600 mg every 24 hours with atovaquone oral suspension 750 mg every 12 hours resulted in a 52% ± 13% decrease in the mean (±SD) steady-state plasma atovaquone concentration and a 37% ± 42% increase in the mean (±SD) steady-state plasma rifampin concentration The half-life of atovaquone decreased from 82 ± 36 hours when administered without rifampin to 50 ± 16 hours with rifampin Concomitant use of rifampin with atovaquone decrease concentrations of atovaquone and increase concentrations of rifampin which may increase the risk of rifampin toxicities. Coadministration of rifampin with atovaquone is not recommended

The concomitant administration of atovaquone and rifampin is known to reduce atovaquone concentrations.

• Rifampin decreases atovaquone concentrations by 52%
• Rifampin increases rifampin concentrations by 37%
• The half-life of atovaquone decreases from 82 hours to 50 hours when administered with rifampin
• Coadministration of rifampin with atovaquone is not recommended due to the potential risk of rifampin toxicities and reduced efficacy of atovaquone 2, 3, 2

From the Research

Potential Interactions between Atovaquone and Rifampin

The potential interactions between atovaquone and rifampin are primarily related to the effects of rifampin on the pharmacokinetics of other drugs. Rifampin is a potent inducer of hepatic drug metabolism, which can lead to decreased plasma concentrations of concomitantly administered drugs, including atovaquone 4, 5, 6, 7.

Mechanism of Interaction

• Rifampin induces the expression of cytochrome P450 (CYP) 3A4 in the liver and small intestine, which can increase the metabolism of atovaquone 6.
• Rifampin also induces the expression of P-glycoprotein, a drug transporter that can affect the absorption and distribution of atovaquone 6, 7.

Clinical Relevance

• The interaction between atovaquone and rifampin can lead to reduced plasma concentrations of atovaquone, potentially resulting in decreased efficacy 5, 6, 7.
• Clinicians should be aware of this potential interaction and monitor patients closely for signs of reduced efficacy or increased toxicity when atovaquone and rifampin are used concomitantly 5, 6, 7.

Recommendations

• Patients taking atovaquone and rifampin concomitantly should be closely monitored for signs of reduced efficacy or increased toxicity 5, 6, 7.
• The use of alternative antitubercular agents that do not induce CYP3A4, such as rifabutin, may be considered in patients taking atovaquone 7.

Note: There is limited direct evidence on the interaction between atovaquone and rifampin. The information provided is based on the known effects of rifampin on the pharmacokinetics of other drugs and the potential mechanisms of interaction.