Effect of Rifampin and Rifabutin on Serum Itraconazole Levels in Patients with Chronic Pulmonary Aspergillosis and Coexisting Nontuberculous Mycobacterial Infection

Abstract

We investigated the effects of rifampin and rifabutin on serum itraconazole levels in patients with chronic pulmonary aspergillosis. Serum itraconazole concentrations were significantly lower in patients who received itraconazole with rifampin (median, 0.1 μg/ml; P < 0.001) or rifabutin (median, 0.34 μg/ml; P < 0.001) than those receiving itraconazole alone (median, 5.92 μg/ml). Concomitant use of rifampin or rifabutin and itraconazole should be avoided in patients with chronic pulmonary aspergillosis and coexisting mycobacterial infections.

TEXT

Chronic pulmonary aspergillosis (CPA) is a slowly progressive pulmonary infectious disease secondary to local invasion by a species of Aspergillus, usually Aspergillus fumigatus (1, 2). Although the optimal therapeutic regimen and duration of treatment have not been established, long-term oral itraconazole is currently recommended as the primary treatment for CPA (3–5). CPA usually occurs in middle-aged and elderly patients, for whom the most common underlying disease is pulmonary tuberculosis (6, 7). In addition, there is increasing evidence that nontuberculous mycobacterial (NTM) lung disease is an important underlying condition associated with CPA (7–12), with some patients having CPA and coexisting NTM lung disease (12, 13).

Mycobacterium avium complex (MAC) is the most common etiology of NTM lung disease (14–16). Rifampin is recommended as part of a multidrug antibiotic regimen for the treatment of MAC lung disease (14–16). Rifampin is a potent inducer of hepatic cytochrome P450 enzymes, which in turn can accelerate the hepatic metabolism of antifungal agents. In this way, rifampin presents a practical challenge for choosing the appropriate antibiotics for treating CPA with coexisting NTM lung disease (17, 18). Indeed, previous case reports have demonstrated that concurrent administration of rifampin with itraconazole can greatly reduce serum itraconazole concentrations (19–22).

Rifabutin has less severe drug-drug interactions than does rifampin and is used as a substitute for rifampin in the treatment of tuberculosis and NTM lung disease, especially for patients who are receiving medications that have unacceptable interactions with rifampin, such as antiretroviral agents (14, 23). Nevertheless, there are no published studies that evaluated the interaction between rifabutin and itraconazole. Thus, the objective of the present study was to investigate the effects of rifampin and rifabutin on serum itraconazole levels in patients with CPA and coexisting mycobacterial lung disease.

This study was a single-institution retrospective review of 66 patients with CPA who were treated with oral itraconazole (Sporanox, Janssen Pharmaceutica) (200 mg twice daily) and for whom serum itraconazole concentrations were measured between January 2013 and June 2014. Peripheral venous sampling was performed prior to morning itraconazole administration to determine trough concentrations after at least 7 days of treatment. The serum concentrations of itraconazole and hydroxyl-itraconazole were determined using a 6460 triple-quadrupole mass spectrometer with a 1260 Infinity liquid chromatography system (Agilent Technologies, Palo Alto, CA). The lower limit of quantification was 0.1 μg/ml, and values that were below this level were recorded as 0.1 μg/ml. Trough itraconazole (combined itraconazole and hydroxyl-itraconazole) concentrations of >1.0 μg/ml were considered to be in the therapeutic range (24). The institutional review board of Samsung Medical Center approved this retrospective study, and informed consent was waived for the use of patient medical data.

Among the 66 patients with CPA, 47 (71%) were male. The median age was 61 years (interquartile range [IQR], 50 to 69 years), and the median body mass index was 19.1 kg/m² (IQR, 16.9 to 22.2 kg/m²). Forty-five (68%) patients received itraconazole without rifampin or rifabutin, and 21 (32%) received itraconazole together with rifampin (450 to 600 mg/day, n = 11) or rifabutin (300 mg/day, n = 10). Of the 21 patients who received rifampin or rifabutin, 17 had concurrently active NTM lung disease, and 4 had active pulmonary tuberculosis. Three of these 21 patients also received isoniazid. The most common etiology of NTM lung disease was M. intracellulare (n = 13), followed by M. avium (n = 2), Mycobacterium kansasii (n = 1), and Mycobacterium xenopi (n = 1).

In all 45 patients who received itraconazole without rifampin or rifabutin, the serum concentrations of itraconazole reached the therapeutic range of >1 μg/ml. As shown in Fig. 1, the serum itraconazole concentrations were significantly lower in patients who received itraconazole with rifampin (median, 0.1 μg/ml; IQR, 0.1 to 0.1 μg/ml; P < 0.001) or rifabutin (median, 0.34 μg/ml; IQR, 0.16 to 0.77 μg/ml; P < 0.001) than those who received itraconazole alone (median, 5.92 μg/ml; IQR, 4.59 to 7.52 μg/ml). However, there were no significant differences in serum itraconazole concentrations between the patients treated with itraconazole and rifampin and those treated with itraconazole and rifabutin (P = 0.220; Fig. 1).

FIG 1.

Box-and-whisker plot of trough serum levels of itraconazole. The boxes indicate the IQR, and the line within each box indicates the median. Whiskers indicate the 10th and 90th percentiles. Open circles indicate atypical outliers (values of 1.5× to 3× the IQR), and the asterisk represents an extreme outlier (value of >3× the IQR). Serum itraconazole concentrations were significantly lower in patients receiving itraconazole and rifampin (median, 0.1 μg/ml; P < 0.001) or rifabutin (median, 0.34 μg/ml; P < 0.001) than in patients receiving itraconazole without rifampin or rifabutin (median, 5.92 μg/ml), while serum itraconazole concentrations were similar between patients treated with itraconazole and rifampin and those treated with itraconazole and rifabutin (P = 0.220).

The administration of rifampin or rifabutin was discontinued and serum itraconazole concentrations were repeatedly measured in eight patients, including one patient who continuously received isoniazid. The serum concentrations of itraconazole increased significantly from a median of 0.14 μg/ml (IQR, 0.10 to 0.40 μg/ml) to a median of 5.96 μg/ml (IQR, 3.92 to 8.37 μg/ml; P = 0.012) after the discontinuation of rifampin (n = 3) or rifabutin (n = 5), and the serum itraconazole concentrations in all eight patients reached the therapeutic range.

Rifampin is one of the most valuable drugs for the standard treatment of tuberculosis or NTM infections such as MAC lung disease; however, it is also well documented to cause clinically significant drug interactions (18). Rifabutin is also associated with drug interactions, but it is generally not as potent an enzyme inducer as rifampin (18). Furthermore, rifabutin has been used in patients coinfected with Mycobacterium tuberculosis or NTM and human immunodeficiency virus (14, 23). Therefore, the use of rifabutin instead of rifampin may be an option for the itraconazole treatment of patients with CPA and coexisting NTM lung disease.

Several existing case reports have evaluated the effect of rifampin on the pharmacokinetics of antifungal agents, such as fluconazole (25), itraconazole (19–22), voriconazole (26), and posaconazole (27). However, data concerning the drug interactions between rifabutin and antifungal azoles are very limited. In a pharmacokinetic study in 24 healthy men, coadministration with rifabutin decreased the maximum plasma concentration of posaconazole by 43% and the area under the plasma concentration-time curve over the dosing interval by 31% (28).

Our study demonstrated that rifabutin and rifampin significantly reduced serum itraconazole concentrations. Specifically, serum itraconazole concentrations did not reach the therapeutic range of 1 μg/ml in 80% (8/10) of the patients treated with itraconazole and rifabutin and 100% (11/11) of the patients treated with itraconazole and rifampin. However, after the discontinuation of rifabutin or rifampin, serum itraconazole concentrations increased to the therapeutic range of >1.0 μg/ml in all the patients for whom serum itraconazole concentrations were repeatedly measured.

In conclusion, we found that rifampin or rifabutin significantly reduces serum itraconazole concentrations, which may result in a loss of the therapeutic efficacy of itraconazole. Concomitant use of rifampin or rifabutin and itraconazole should be avoided in patients with CPA and coexisting NTM lung disease.