Drug-drug interactions impacting antituberculous therapy

September 2004

In the July 2004 Pharmacology Consult, clinically significant drug-drug interactions associated with antiretroviral medications were reviewed. Another therapeutic area with significant potential for therapeutic misadventures as a result of drug interactions is antituberculous therapy.

Based on 2003 statistics from the CDC, there were nearly 15,000 new cases of tuberculosis (TB) reported for every 100,000 members of the population. While this represented a 2% decrease in the incidence of disease compared to 2002, a more alarming fact is the prevalence of resistant TB.

A total of 8% of cases were reported resistant to isoniazid in vitro, while 1% were resistant to both isoniazid and rifampin. Patients with resistant disease require more complicated therapeutic regimens containing an increasing number of drugs. Also of concern is the immunosuppressed patient population at highest risk for this disease. Greater than 10% of patients are coinfected with HIV, further increasing the potential for drug-drug interactions in this patient population.

The basic principles of drug-drug interactions are the same as those associated with antiretroviral medications. Pharmacokinetic interactions involve alterations of drug absorption, distribution, metabolism and excretion. Pharmacodynamic effects (such as antagonism, synergy, additive efficacy or toxicity) may be independent of pharmacokinetic changes or result as a consequence of such interactions. Finally, pharmaceutical interactions (such as chemical or physical incompatibility) may also be clinically relevant.

The most common drug-drug interactions that impact absorption involve changes to the gastric pH. Such changes can occur as a result of the presence or absence of food or administration of medications to inhibit acid production, such as H2 antagonists or proton pump inhibitors. These mechanisms appear less important for antituberculous therapy. However, decreased isoniazid concentrations have been reported when coadministered with calcium- or magnesium-containing antacids. While not a drug-drug interaction, rifampin absorption may be delayed in the presence of food.

Underlying diseases may influence the extent of antituberculous drug absorption. Coinfection with HIV, as well as diarrheal illness, have been implicated as causes of failed therapy due to malabsorption of antituberculous medications, namely isoniazid and rifampin. Other cases of therapeutic failures have been associated with low serum drug concentrations in individuals who do not have HIV. Common patient characteristics among these patients included advanced age and the absence of regular alcohol consumption. For these patients, who were all receiving directly observed therapy, the cause of these low concentrations remains unclear.

With increasing interest surrounding use of fluoroquinolones to treat mycobacterial diseases, it is important to consider the impact of divalent and trivalent cations such as iron, calcium or aluminum-containing products on the absorption of these regimens. Although such interactions with fluoroquinolones have been well described, a recent survey of physicians and pharmacists revealed that only 20% could correctly identify a potential interaction between levofloxacin and calcium supplements. If these agents need to be coadministered, the quinolone should be separated by at least two hours before or after the divalent cation.

Most clinically significant drug-drug interactions associated with antituberculosis therapy occur through changes to drug metabolism, due primarily to their dependence or interaction with the cytochrome P450 enzyme system.

Rifamycins

All rifamycins are potent inducers of cyctochrome P450 3A4. Rifampin is the most potent inducer, followed by rifapentene. Rifabutin (Mycobutin, Pharmacia) exhibits the least degree of induction among members of the class. Based on this, published guidelines for antiretroviral medication have listed rifabutin as the preferred agent for patients requiring treatment of tuberculosis concomitantly with selected antiretrovirals that act as substrates for this enzyme.

In contrast to most antituberculous agents, rifabutin is also a substrate for the cytochrome P450 enzyme system. Therefore, caution should be used when administering this agent with potent inhibitors of this isoenzyme, such as protease inhibitors.

Isoniazid

Isoniazid metabolism occurs via N-acetylation in the liver. Genetic variances in N-acetyltranferase that occur in greater than 80% of Egyptians, 15% of Asians and nearly 60% of whites lead to slower metabolism of isoniazid and, therefore, higher concentrations.

Isoniazid can also increase serum concentrations and potentiate toxicities associated with the anticonvulsant agents phenytoin and carbamazepine. This can be especially true in those individuals who are slow acetylators of isoniazid. Therefore, it is recommended that concentrations of carbamazepine and phenytoin be carefully monitored prior to initiating or discontinuing therapy with isoniazid in these patients.

Isoniazid is also an inhibitor of CYP-2C9. This may impact the metabolism of multiple agents, including the non-steroidal anti-inflammatory agents (diclofenac, ibuprofen and piroxicam among others) and oral sulfonylurea hypoglycemic agents. Toxicities of these agents should also be considered when initiating isoniazid therapy.

Other interactions

Pharmacodynamic drug-drug interactions can occur among the antituberculosis medications themselves. The most recent example of this was the combination of rifampin and pyrazinamide resulting in severe hepatic injury. After a survey of more than 7,000 patients who had reportedly received this combination, a total of 48 cases of severe liver injury were reported including 11 (23%) deaths. The CDC revised its recommendations in August 2003 for treatment of latent tuberculosis to no longer routinely recommend this regimen. If this regimen is used, it should never be used in:

• People taking concomitant hepatotoxins
• People who drink excessive amounts of alcohol
• People with underlying liver disease
• People with a history of isoniazid-associated liver injury

Dealing with drug interactions

Awareness of clinically significant drug interactions is the first step in avoiding detrimental consequences. Recommendations regarding dose adjustments and monitoring, particularly in combination with antiretroviral therapy, have been published. Specialized therapeutic drug monitoring for antituberculosis medications can be performed. However, it is not widely available outside of specialized referral laboratories, like the Infectious Disease Pharmacokinetics Laboratory at National Jewish Medical and Research Center in Denver.

For more information:

• Visit www.drug-interactions.com, www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm, www.aidsinfo.nih.gov/guidelines and www.cdc.gov/nchstp/tb/pubs/mmwrhtml/maj_guide.htm.

• Elizabeth Dodds Ashley, PharmD, BCPS, is from the Division of Infectious Diseases, Duke University Medical Center, and Richard H. Drew, PharmD, MS, MS, is from Duke University Medical Center.