Coadministration of rifabutin (300 mg once daily) and efavirenz (600 mg once daily) decreased rifabutin AUC, Cmax and Cmin by 38%, 32% and 45% respectively. Rifabutin had no significant effect on the pharmacokinetics of efavirenz AUC or Cmax but decreased Cmin by 12%, via CYP3A4 induction. The daily dose of rifabutin should be increased by 50% when administered with efavirenz. Consider doubling the rifabutin dose in regimens where rifabutin is given two or three times a week in combination with efavirenz. The clinical effect of this dose adjustment has not been adequately evaluated. Individual tolerability and virological response should be considered when making the dose adjustment.

Coadministration of rifabutin (300 mg once daily for 14 days) with efavirenz (600 mg for 14 days) in 9 subjects led to decreases in rifabutin Cmax, AUC and Cmin of 32%, 38% and 45%, respectively. Data from 11 subjects showed no alteration in either efavirenz Cmax or AUC, but a 12% decrease in Cmin. Daily doses or rifabutin should be increased by 50% whilst consideration should be given to doubling the rifabutin doses in regimens where rifabutin is given twice or three times a week. 

The effect of an increase in rifabutin dose (from 300 to 600 mg twice weekly) after initiation of efavirenz (600 mg once daily) was investigated in 15 HIV/TB coinfected patients. The geometric mean rifabutin AUC following a 300 mg dose was 4.15 µg/ml.h and increased to 4.98 µg/ml.h when the dose was increased in the presence of efavirenz. Cmax was significantly higher following dose increase with efavirenz initiation (0.6 vs 0.4 µg/ml). Efavirenz AUC, Cmax and Cmin obtained with 600 mg rifabutin (203 µmol/L.h, 14.1 µmol/L, 6.0 µmol/L, respectively) were comparable to those obtained in HIV+ historical control subjects (184 µmol/L.h, 12.9 µmol/L, 5.6 µmol/L, respectively; n=35). Efavirenz trough concentrations were below target (3.5 µmol/L) in only 1/15 patients. The increase in rifabutin from 300 mg to 600 mg was adequate to compensate for the drug interaction with efavirenz in most patients. The standard efavirenz dosage of 600 mg once daily achieved adequate plasma concentrations during intermittent rifabutin therapy and was generally well tolerated. However, additional studies are needed to characterise optimal treatment regimens.

Coadministration of rifabutin (300 or 450 mg twice weekly) with efavirenz (600 mg daily) caused no alteration in efavirenz (4 and 24 hour) or rifabutin (2 hour) concentrations but there was a reduction in rifabutin levels at 6 hours. Patients on 300 mg dose of rifabutin did not appear to reach the expected PK range, supporting current recommendations for a 450 mg twice weekly dose when coadministering with efavirenz.

Efavirenz plasma concentrations in patients who were also receiving rifabutin (n=31; efavirenz dose of 800 mg/day in 26% and 1000 mg/day in 6% of patients) and who were not (n=334; efavirenz dose 600 mg/day) were compared. There was a significant decrease in efavirenz Ctrough in patients taking rifabutin.