Rifampicin Interaction Raises Dexamethasone Clearance in Tuberculosis Meningitis
Sean Wasserman reports that in HIV-associated TBM dexamethasone clearance was high—likely from rifampicin co-administration—and that high-dose rifampicin did not further reduce exposure.
Tuberculosis meningitis (TBM) is a severe form of tuberculosis that affects the brain, and dexamethasone is recommended as an adjunctive therapy to reduce inflammation. The team led by corresponding author Sean Wasserman set out to measure how much dexamethasone patients actually have in their blood when it is given alongside powerful tuberculosis drugs. In particular, rifampicin—an essential anti-TB antibiotic—is known to speed the breakdown of many medicines, and the researchers were concerned that co-administration could lower dexamethasone exposure. This may be especially important now that higher rifampicin doses are being tested in clinical trials. The pharmacokinetic study was nested within a randomized controlled trial that compared the safety of high-dose rifampicin (oral, 35 mg/kg; intravenous, 20 mg/kg) plus linezolid, with or without aspirin, against standard-dose rifampicin (10 mg/kg). All trial participants were adults with HIV-associated TBM and received adjunctive oral dexamethasone every 12 hours, starting at a dose of 0.4 mg/kg/day, allowing the investigators to study drug levels in a real-world, trial setting.
This study measured dexamethasone concentrations in intensively sampled plasma on day 3 after study enrolment and analysed the data using nonlinear mixed-effects modelling. The analysis used 261 dexamethasone concentrations from 43 participants to develop a pharmacokinetic model. Among these participants, eight (18%) were on efavirenz-based ART and five (11%) were on a lopinavir/ritonavir-based regimen. The median duration of rifampicin therapy at the time of sampling was 4 days (range: 0-7). Dexamethasone pharmacokinetics were best described by a one-compartment disposition model with first-order absorption and elimination. The typical oral clearance (CL/F) estimate for dexamethasone was 131 L/h, but this was markedly reduced to 11.5 L/h in participants taking concomitant lopinavir/ritonavir. Crucially, high-dose rifampicin produced no significant additional effect on dexamethasone pharmacokinetic parameters compared with the standard-dose rifampicin used in the trial.
Taken together, the findings show that adults with HIV-associated TBM had high dexamethasone clearance, an effect the authors describe as likely related to a drug-drug interaction with rifampicin. The large dataset and the modelling approach allowed the team to identify a clear pharmacokinetic pattern: while rifampicin co-administration was associated with increased dexamethasone clearance, increasing rifampicin to the high doses tested (oral 35 mg/kg; intravenous 20 mg/kg) did not further change dexamethasone exposure compared with standard-dose rifampicin (10 mg/kg). The data also highlight a distinct influence of lopinavir/ritonavir, which markedly reduced dexamethasone clearance in the participants on that regimen. These results clarify how commonly used TB and HIV drug combinations interact with dexamethasone in the specific context of HIV-associated TBM, information that is directly relevant to the ongoing evaluation of intensified rifampicin regimens in clinical trials.
The study documents that rifampicin co-administration is associated with high dexamethasone clearance in adults with HIV-associated TBM, which affects drug exposure. Increasing rifampicin dose did not further reduce dexamethasone exposure in this trial population.
Author: José Miguel Calderín Miranda