Pharmacokinetics of dexamethasone in tuberculosis meningitis

Abstract

Introduction: Dexamethasone is recommended as adjunctive therapy for tuberculosis 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 randomised controlled trial comparing the safety of high-dose rifampicin (oral, 35 mg/kg; intravenous, 20 mg/kg) plus linezolid, with or without aspirin, vs 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 enrolment and analysed using nonlinear mixed-effects modelling.

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.

Keywords: Dexamethasone; Drug-Drug Interaction; HIV; Lopinavir/Ritonavir; NONMEM; Pharmacokinetics; Rifampicin; Tuberculous Meningitis.

Figure 1.

Visual predictive check of dexamethasone concentrations versus time after dose, stratified by co-administered rifampicin dose level and further stratified by lopinavir/ritonavir co-administration. Circles represent observed data. Solid and dashed lines indicate the 50th, 10th, and 90th percentiles of the observed data, while the shaded areas represent the 95% model-predicted confidence intervals for the same percentiles.

Figure 2.

Area under the concentration–time curve from 0 to 12 hours post-dose (AUC_0–12h) and maximum concentration (C_max), stratified by lopinavir/ritonavir co-administration. Dots represent individual values; lines indicate the median.

Figure 3.

Area under the concentration–time curve from 0 to 12 hours post-dose (AUC_0–12h) and maximum concentration (C_max), stratified by rifampicin dose level. Dots represent individual values; lines indicate the median.