Pharmacokinetics of Dexamethasone in Tuberculous Meningitis

Clinical Snapshot

Key Findings

• P Value: Not reported for main findings

• Effect Size: Typical CL/F 131 L/h, reduced to 11.5 L/h with lopinavir/ritonavir (91% reduction)

• Primary Outcome: Dexamethasone oral clearance (CL/F)

• Nnt Or Sensitivity: 11-fold reduction in clearance with lopinavir/ritonavir co-administration

• Confidence Interval: Not reported

Clinical Application

Findings suggest need for dexamethasone dose adjustment based on concomitant antiretroviral therapy, particularly with protease inhibitors Relevant to Australian infectious diseases and HIV specialists managing TBM. Findings support therapeutic drug monitoring considerations and may inform TGA-approved dexamethasone dosing protocols in complex drug interaction scenarios Adults with HIV-associated tuberculous meningitis receiving rifampicin-based anti-tuberculosis therapy

Abstract

BACKGROUND: Dexamethasone is recommended as adjunctive therapy for tuberculous meningitis (TBM). Co-administration with rifampicin is expected to reduce dexamethasone exposure in TBM, an effect that may be more pronounced with the higher rifampicin doses currently being evaluated in clinical trials. METHODS: This pharmacokinetic study was nested in a randomized controlled trial comparing the safety of high-dose rifampicin (oral, 35 mg/kg; intravenous, 20 mg/kg) plus linezolid, with or without aspirin, versus standard-dose rifampicin (10 mg/kg) for adults with HIV-associated TBM. All participants received adjunctive oral dexamethasone every 12 hours starting at a dose of 0.4 mg/kg/day. Dexamethasone concentrations were measured on intensively sampled plasma on day 3 after study enrollment and analysed using nonlinear mixed-effects modeling. RESULTS: In total, 261 dexamethasone concentrations from 43 participants were available for model development. Eight (18%) participants 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 pharmacokinetic sampling was 4 days (range: 0-7). Dexamethasone pharmacokinetics was best described by a one-compartment disposition model with first-order absorption and elimination. Typical oral clearance (CL/F) was 131 L/h, reduced to 11.5 L/h with concomitant lopinavir/ritonavir. High-dose rifampicin had no significant additional effect on dexamethasone pharmacokinetic parameters compared with the standard-dose. CONCLUSIONS: In adults with HIV-associated TBM, there was high dexamethasone clearance, likely related to a drug-drug interaction with rifampicin. High-dose rifampicin had no additional effect on dexamethasone exposure.

References

1. 1.Calderin, J. M., Resendiz-Galvan, J. E., Abdelgawad, N., Davis, A., Stek, C., Wiesner, L., Meintjes, G., Wilkinson, R. J., Denti, P., & Wasserman, S. (2026). Pharmacokinetics of dexamethasone in tuberculous meningitis. Clinical Infectious Diseases. https://doi.org/10.1093/cid/ciaf642