Pharmacokinetics of dexamethasone in tuberculosis meningitis

Pharmacokinetics of dexamethasone in tuberculosis meningitis | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Pharmacokinetics of dexamethasone in tuberculosis meningitis View ORCID Profile Jose M Calderin , View ORCID Profile Juan Eduardo Resendiz-Galvan , View ORCID Profile Noha Abdelgawad , View ORCID Profile Angharad Davis , View ORCID Profile Cari Stek , View ORCID Profile Lubbe Wiesner , View ORCID Profile Graeme Meintjes , View ORCID Profile Robert J. Wilkinson , View ORCID Profile Paolo Denti , View ORCID Profile Sean Wasserman doi: https://doi.org/10.1101/2025.07.14.25331510 Jose M Calderin 1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town, South Africa Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jose M Calderin Juan Eduardo Resendiz-Galvan 1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town, South Africa Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Juan Eduardo Resendiz-Galvan Noha Abdelgawad 1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town, South Africa Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Noha Abdelgawad Angharad Davis 2 Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Observatory, Cape Town, South Africa 3 The Francis Crick Institute , London, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Angharad Davis Cari Stek 2 Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Observatory, Cape Town, South Africa Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Cari Stek Lubbe Wiesner 1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town, South Africa Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Lubbe Wiesner Graeme Meintjes 4 Department of Medicine, University of Cape Town , Observatory, Cape Town, South Africa 5 Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London , London, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Graeme Meintjes Robert J. Wilkinson 2 Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Observatory, Cape Town, South Africa 3 The Francis Crick Institute , London, United Kingdom 4 Department of Medicine, University of Cape Town , Observatory, Cape Town, South Africa 6 Department of Infectious Diseases, Imperial College London , London, United Kingdom 8 Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town , Observatory, Cape Town, South Africa Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Robert J. Wilkinson Paolo Denti 1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town, South Africa Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Paolo Denti Sean Wasserman 2 Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Observatory, Cape Town, South Africa 7 Institute for Infection and Immunity, City St George’s, University of London , London, United Kingdom 8 Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town , Observatory, Cape Town, South Africa Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sean Wasserman For correspondence: swasserm{at}sgul.ac.uk Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF 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. 40-word summary of the article’s main point This pharmacokinetic analysis of dexamethasone in adults with HIV-associated tuberculosis meningitis found high oral clearance (131 L/h), likely due to a drug-drug interaction with rifampicin. High-dose rifampicin had no additional effect on dexamethasone exposure compared with standard dose. Introduction Tuberculous meningitis (TBM) is associated with high mortality, particularly among people with HIV, and survivors are often left with chronic neurological disability [ 1 ]. Disease severity in TBM is driven by intracerebral inflammation, caused by a dysregulated immune response to Mycobacterium tuberculosis . Host inflammation is modulated by dexamethasone, which confers modest survival benefit when provided with antituberculosis drugs in randomised controlled trials [ 2 – 4 ]. Adjunctive dexamethasone is therefore recommended by international treatment guidelines for all adults with TBM. Dexamethasone is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), making it susceptible to drug-drug interactions (DDI). Multiple doses of dexamethasone can also increase the transcription of both proteins [ 5 ]. Coadministration with rifampicin, the cornerstone of TBM treatment and a potent inducer of CYP3A4 and P-gp transporter activity, may reduce dexamethasone exposure [ 6 , 7 ], potentially affecting anti-inflammatory efficacy. This DDI may be more pronounced with higher rifampicin doses (≥20 mg/kg) currently being evaluated in TBM trials [ 8 ]. Additionally, antiretroviral drugs may be CYP3A4 inhibitors or inducers, further increasing the risk for dexamethasone DDI in HIV-associated TBM. We aimed to characterise the pharmacokinetics of dexamethasone co-administered with standard (10 mg/kg) or high-dose rifampicin (35 mg/kg) among adults with HIV-associated TBM, specifically to evaluate whether use of high-dose rifampicin reduced dexamethasone exposure in this population. Methods Study design This pharmacokinetic study was nested in the LASER-TBM trial ( NCT03927313 ), which evaluated safety of intensified antituberculosis therapy among South African adults with HIV-associated TBM [ 9 ]. Participants were randomized within five days of starting TBM treatment to receive either the standard antituberculosis regimen containing rifampicin 10 mg/kg together with isoniazid, pyrazinamide, and ethambutol (R 10 HZE) or an experimental regimen containing high dose oral rifampicin 35 mg/kg (or intravenous 20 mg/kg) (R 35 HZE) and adding linezolid, with or without daily aspirin 1000 mg. Oral dexamethasone was administered to all participants every 12 hours for 4 weeks, starting at a dose of 0.4 mg/kg/day and tapering by 0.1 mg/kg per week, as recommended by national treatment guidelines. Experimental therapy was provided for 56 days, after which participants continued standard treatment. Pharmacokinetic sampling Plasma samples were collected on day 3 (±2 days) after study enrolment pre-dose, at 0.5, 1, 2, 3, 6, and 8-10 hours following the morning dose, and at 12 hours post-evening dose. Immediately following collection, samples were processed on-site and stored at −80 °C. Dexamethasone concentrations were quantified using a validated liquid chromatography-tandem mass spectrometry assay (lower limit of quantification [LLOQ]: 0.938 ng/mL) performed at the Division of Clinical Pharmacology, University of Cape Town (supplementary material S1) . Pharmacokinetic modelling Dexamethasone concentrations were described using nonlinear mixed-effects modelling in NONMEM v7.5.1 [ 10 ]. One- and two-compartment disposition models were tested with first-order absorption (with or without lag time or chain of transit compartments) and first-order elimination. Allometric scaling was applied for disposition parameters, testing body weight or fat-free mass (FFM)[ 11 ] as body size descriptors, with the exponents for clearance and volume fixed to 0.75 and 1, respectively [ 12 ]. Other covariates, including creatinine clearance (calculated using the Cockcroft-Gault formula [ 13 ]), age, treatment arm, time on rifampicin, and concomitant antiretroviral therapy (ART), were also assessed on pharmacokinetic parameters. Model development was guided by improvements in the objective function value (ΔOFV), goodness-of-fit plots, physiological plausibility and clinical relevance. Random effects were included on the pharmacokinetic parameters if statistically significant, using a log-normal distribution [ 10 ]. Between-subject variability (BSV) was explored for disposition parameters, and between-occasion variability (BOV) was explored for absorption parameters and bioavailability, with an occasion defined as a dosing event and its subsequent observations. Residual unexplained variability was described using an error model with both additive and proportional components, with the additive component constrained to be at least 20% of the assay’s LLOQ. Concentrations below the limit of quantification (BLQ) were handled using an adaptation of the M6 method proposed by Wijk et al [ 14 ]. Details of population pharmacokinetic modelling and handling of missing covariate data are presented in supplementary material S2 . The final population pharmacokinetics model was used to estimate dexamethasone 12-hour area under the curve (AUC 0-12h ) and maximum concentration (C max ). Geometric mean ratios (GMR) for secondary pharmacokinetic parameters were computed for high-dose versus standard-dose rifampicin. A post hoc power calculation showed that our study had >80% power at an alpha of 0.05 to detect a 40% reduction in dexamethasone exposure due to high-dose rifampicin. Results Study data Dexamethasone concentrations from 43 individuals were available, consisting of 261 observations after excluding samples taken 12 hours post-evening dose which could not be used because the exact dose timing was unknown. 35/261 (13%) of the samples were below the assay’s lower limit of quantification, most of which were pre-dose observations. The median duration of rifampicin therapy at the time of pharmacokinetic sampling was 4 days (range: 0–7). All participants were HIV-positive, 8 (18%) of whom were on efavirenz-based ART and 5 (11%) on lopinavir/ritonavir-based ART, provided at double the standard-dose ( Table 1 ) . Participants receiving high-dose rifampicin had lower body weight (57 kg; range 30–96) and thus received a lower total dexamethasone dose (9 mg; range 6–16) compared with those on standard-dose rifampicin (64 kg; range 42–107 and 12 mg; range 8–20, respectively) (supplementary material Figure S3) . Other baseline characteristics were similar between the groups (supplementary material S4) . View this table: View inline View popup Table 1. Demographic and clinical characteristics Pharmacokinetic modelling Dexamethasone pharmacokinetics was best described by a one-compartment disposition model with first-order absorption and elimination. The effect of body size was best characterized using allometric scaling based on FFM (ΔOFV = -17.7), compared with total body weight (ΔOFV = -12.3). The typical subject (FFM: 45 kg) was estimated to have a volume of distribution (V/F) of 26.6 L and an oral clearance (CL/F) of 131 L/h, which was reduced to 11.5 L/h with concomitant lopinavir/ritonavir (ΔOFV = -34.6, 1 degree of freedom, p 0.05; bioavailability: ΔOFV = -0.09, p > 0.05) ( Figure 1 ) . No other covariates, including efavirenz and aspirin, significantly influenced dexamethasone pharmacokinetics. Download figure Open in new tab 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. View this table: View inline View popup Download powerpoint Table 2. Final pharmacokinetic parameter estimates for dexamethasone The median dexamethasone AUC 0-12h among participants not receiving lopinavir/ritonavir-based ART was 0.0864 mg·h/L (range: 0.0333–0.201 mg·h/L), following a median dose of 10.5 mg (range: 6–20 mg). Among those co-treated with lopinavir/ritonavir-based ART, the median AUC 0-12h was approximately 12 times higher, at 1.06 mg·h/L (range: 0.591–2.51 mg·h/L), after a median dose of 10 mg (range: 8–16 mg) ( Figure 2 ) . Dexamethasone median AUC 0-12h was 0.0841 mg·h/L (range: 0.0333–1.05) in the high-dose rifampicin group and 0.111 mg·h/L (range: 0.0364–2.51) in the standard-dose group, corresponding to a GMR of 0.80 (95% CI: 0.43–1.50). Median C max was 0.0275 mg/L (range: 0.0113–0.128) and 0.0347 mg/L (range: 0.00998–0.314) in the high-dose and standard-dose groups, respectively (GMR: 0.77; 95% CI: 0.47 – 1.25) ( Figure 3 ) . These differences are in line with the lower median total dexamethasone dose in the high-dose rifampicin group compared to the standard-dose group (GMR: 0.83; 95% CI: 0.72– 1.00). Download figure Open in new tab 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. Download figure Open in new tab 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. Discussion We characterised the pharmacokinetics of oral dexamethasone among adults with HIV-associated TBM receiving rifampicin-based treatment. In this clinical trial population, receipt of higher rifampicin doses had no additional effect on dexamethasone pharmacokinetics, and dexamethasone exposure was similar among participants receiving high-dose rifampicin (35 mg/kg) compared with standard dose rifampicin (10 mg/kg). By contrast, there was a strong inhibitory effect from lopinavir/ritonavir-based ART on dexamethasone clearance. Limited data exist regarding dexamethasone pharmacokinetics in TBM patients, as well as its interactions with antituberculosis and antiretroviral drugs. Pharmacokinetic studies in healthy individuals receiving dexamethasone as monotherapy have reported CL/F values of 15.6 L/h following oral administration of 1.5 mg [ 5 ], and 18.1 L/h following an average intravenous dose of 5.7 mg [ 15 ]. We observed substantially higher dexamethasone CL/F of 131 L/h in our cohort of South African patients with HIV-associated TBM. This value exceeds hepatic blood flow (∼90 L/h) [ 16 ], indicating low bioavailability from significant first-pass metabolism [ 17 ]. A plausible explanation for the large dexamethasone CL/F observed in our study is a DDI with rifampicin via induction of CYP3A4 and increased expression of P-gp, enhancing dexamethasone clearance and reducing its bioavailability [ 18 ]. Previous reports support this hypothesis. A Japanese cohort (n=27) involving TB patients and healthy volunteers receiving intravenous dexamethasone reported a five-fold increase in clearance among individuals co-administered rifampicin compared with those receiving dexamethasone alone [ 7 ]. Similarly, another study involving healthy volunteers (n=16) found that, following oral administration, dexamethasone concentrations measured at 8-hours post-dose were 5- to 10-fold lower in participants co-treated with rifampicin compared with those not receiving rifampicin [ 6 ]. Indirect confirmation of the DDI with rifampicin is the much higher dexamethasone exposure observed among participants co-treated with lopinavir/ritonavir-based ART, likely due to a DDI with ritonavir, a potent CYP3A4 inhibitor [ 19 ]. Dexamethasone CL/F in this subgroup (11.5 L/h) is consistent with previous reports of dexamethasone administered alone [ 5 ], suggesting that the potent inhibitory effect of ritonavir counteracts rifampicin induction. There is an established relationship between rifampicin concentration and CYP3A4 induction. This has been demonstrated in vitro , where a concentration-dependent effect from rifampicin on CYP3A4 induction was shown in liver cell lines [ 20 ], and among pulmonary TB patients (n = 24), where higher doses of rifampicin (40 mg/kg) reduced exposure of the CYP3A4 probe drug midazolam by 38% compared with standard rifampicin doses (10mg/kg) [ 8 ]. Our study had >80% power to detect such a drop in dexamethasone exposure due to high-dose rifampicin, but no trend towards faster CL/F in this group was visible in our data. An explanation for lack of observed effect in our study is that differences in probe substrate exposure between high-dose and standard-dose rifampicin are minor compared to the large overall effect of rifampicin itself (versus no rifampicin) [ 21 ]. Illustrating this, the mean oral midazolam exposure after a single 15 mg dose without rifampicin is 170 µg·h/L [ 21 ] and, in the study of pulmonary TB patients, was reduced by 95.8% (to 7.10 µg·h/L) with 10 mg/kg rifampicin and by 97.4% (to 4.4 µg·h/L) with 40 mg/kg rifampicin [ 8 ]. This may indicate that the small additional effect of higher rifampicin doses on CYP3A4 induction does not necessarily translate into clinically significant lower dexamethasone exposures, as demonstrated in our study. The slightly lower exposures we observed in the high-dose group was attributable to receipt of lower total dexamethasone doses rather than a DDI effect from high-dose rifampicin. Our analysis, and the probe substrate data, suggest that CYP3A4 induction from rifampicin significantly reduces dexamethasone exposure, which could potentially influence its efficacy. The recommended dexamethasone dose was established from a randomized controlled trial (n = 545) conducted in Vietnam, which demonstrated a modest survival benefit among predominantly HIV-negative patients receiving rifampicin-based TBM treatment [ 2 ]. Dexamethasone was administered intravenously in that trial, at the same dose used for oral administration in our study. Oral dexamethasone has a bioavailability of approximately 70–80% [ 22 ] resulting in lower systemic concentrations compared with intravenous dosing; this reduced bioavailability could be exacerbated because rifampicin induction is likely to have a more pronounced effect on oral dexamethasone due to extensive CYP3A4-mediated first-pass metabolism [ 23 ]. Therefore, providing oral dexamethasone alongside rifampicin to TBM patients may achieve substantially lower dexamethasone exposures than those in the Vietnam trial, with potentially reduced clinical benefit. A more recent trial found a smaller, non-significant effect from adjunctive intravenous dexamethasone on survival among patients with HIV-associated TBM in Vietnam and Indonesia (n=520) [ 3 ]. The reason for the reduced efficacy in this population is uncertain. It may be related to secular trends in standard of care which had better outcomes compared with the original trial, reducing the relative effect from dexamethasone on survival. Another potential explanation is a DDI with efavirenz, a CYP3A4 inducer [ 24 ], resulting in increased dexamethasone clearance, as around half of participants in the dexamethasone arm (104/263) were on efavirenz-based ART [ 3 ]. In our study no differences in dexamethasone pharmacokinetics were observed among the eight participants on efavirenz-based ART, although this small sample size may have limited power to detect an effect. Additionally, since the enzyme induction pathway of efavirenz largely overlaps with that of rifampicin via activation of the pregnane X receptor [ 24 ], it is possible that no discernible effect of efavirenz was observed because participants had already been exposed to rifampicin for a median of 4 days by the time of the pharmacokinetic visit. Our study has some limitations. First, we were unable to directly evaluate the DDI between rifampicin and dexamethasone in this population because there was no comparator group without rifampicin. However, the inhibitory effect of lopinavir/ritonavir—resulting in dexamethasone clearance values comparable to those reported historically for dexamethasone administered alone—provides indirect evidence of a DDI with rifampicin. Second, measurement of dexamethasone concentrations occurred after a median of 4 days of rifampicin exposure, prior to the full induction effect on CYP3A4. This may lead to underestimation of a DDI effect from high-dose rifampicin, which may be more pronounced after more prolonged coadministration [ 25 ]. Finally, since all patients in our study received dexamethasone orally, we were unable to estimate dexamethasone bioavailability and separate the potentially different effects of rifampicin induction on first-pass metabolism and systemic clearance. In summary, our analysis suggests that CYP3A4 induction from rifampicin significantly reduces oral dexamethasone exposure, which could potentially influence its efficacy. Although the clinical implications are unclear—given that the target exposure for dexamethasone in TBM is unknown—prior knowledge of CYP3A4 substrate metabolism suggests that the reduction in dexamethasone exposure with oral dosing is much more pronounced than with intravenous dosing. The similar dexamethasone exposures observed between standard- and high-dose rifampicin in our study reduce the likelihood of potential harm from high-dose rifampicin in TBM due to reduced dexamethasone exposure and, consequently, a reduced anti-inflammatory effect. FUNDING SW was supported by the Bill & Melinda Gates Foundation (INV 052110). This work was supported by Wellcome through core funding of the Wellcome Discovery research Platform in Infection (226817/Z/22/Z). AGD was supported by a UCL Wellcome Trust PhD Programme for Clinicians Fellowship (award number 175479). GM was supported by the Wellcome Trust (214321/Z/18/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (64787). RJW receives support from the Francis Crick Institute which is funded by Wellcome (CC2112), Cancer Research UK (CC2112) and UK Research and Innovation (CC2112). He also receives support from NIH (R01145436) and in part from the NIHR Biomedical Research Center of the Imperial College Healthcare NHS Trust. The University of Cape Town Clinical PK Laboratory is supported in part via the Adult Clinical Trial Group (ACTG), by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701; as well as the Infant Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), funding provided by National Institute of Allergy and Infectious Diseases (U01 AI068632), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute of Mental Health grant AI068632. The content is solely the responsibility of the authors and does not necessarily represent the official views of the sponsors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. For the purpose of Open Access, the authors have applied for a CC-BY public copyright license to any Author Accepted Manuscript version arising from this submission. CONFLICT OF INTEREST All authors declare no conflict of interest. AUTHOR CONTRIBUTIONS SW conceptualised the study with methodology input from PD. AD and CS collected the data, provided by SW, GM and RJW. LW did the drug concentration assays. JMC, JR, and NA did the analysis and visualisation, supervised by PD. JMC and SW wrote the original draft; all coauthors reviewed and edited the manuscript. All authors approved the final draft of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. DATA AVAILABILITY The data and model codes supporting the findings of this study are available from the corresponding author, SW, upon reasonable request. ACKNOWLEDGMENTS Computations were performed using the facilities provided by the University of Cape Town’s ICTS High Performance Computing team ( https://ucthpc.uct.ac.za/ ). We would like to thank Dr. Roeland Wasmann for his valuable assistance during the modelling process. REFERENCES 1. ↵ Dodd PJ , Osman M , Cresswell F V. , et al. The global burden of tuberculous meningitis in adults: A modelling study . PLOS Global Public Health 2021 ; 1 : e0000069 . Available at: https://dx.plos.org/10.1371/journal.pgph.0000069 . OpenUrl 2. ↵ Thwaites GE , Bang ND , Dung NH , et al. Dexamethasone for the Treatment of Tuberculous Meningitis in Adolescents and Adults . New England Journal of Medicine 2004 ; 351 : 1741 – 1751 . Available at: http://www.nejm.org/doi/abs/10.1056/NEJMoa040573 . OpenUrl CrossRef PubMed Web of Science 3. ↵ Donovan J , Bang ND , Imran D , et al. Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults . New England Journal of Medicine 2023 ; 389 : 1357 – 1367 . Available at: http://www.nejm.org/doi/10.1056/NEJMoa2216218 . OpenUrl PubMed 4. ↵ Prasad K , Singh MB , Ryan H . Corticosteroids for managing tuberculous meningitis . Cochrane Database of Systematic Reviews 2016 ; 2016 . Available at: http://doi.wiley.com/10.1002/14651858.CD002244.pub4 . 5. ↵ Loew D , Schuster O , Graul EH . Dose-dependent pharmacokinetics of dexamethasone . Eur J Clin Pharmacol 1986 ; 30 : 225 – 230 . Available at : doi: 10.1007/BF00614309 . OpenUrl CrossRef PubMed Web of Science 6. ↵ Kyriazopoulou V , Vagenakis AG . Abnormal overnight dexamethasone suppression test in subjects receiving rifampicin therapy . J Clin Endocrinol Metab 1992 ; 75 : 315 – 317 . Available at: https://academic.oup.com/jcem/article-lookup/doi/10.1210/jcem.75.1.1619024 . OpenUrl CrossRef PubMed Web of Science 7. ↵ Kawai S. A Comparative Study of the Accelerated Metabolism of Cortisol, Prednisolone and Dexamethasone in Patients under Rifampicin Therapy . Folia Endocrinologica Japonica 1985 ; 61 : 145 – 161 . Available at: https://www.jstage.jst.go.jp/article/endocrine1927/61/3/61_145/_article/-char/ja/ . OpenUrl PubMed 8. ↵ Stemkens R , Jager V de , Dawson R , et al. Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis . Antimicrob Agents Chemother 2023 ; 67 . Available at: https://journals.asm.org/doi/10.1128/aac.00683-23 . 9. ↵ Davis AG , Wasserman S , Stek C , et al. A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus–Associated Tuberculous Meningitis: The LASER-TBM Trial . Clinical Infectious Diseases 2023 ; 76 : 1412 – 1422 . Available at : doi: 10.1093/cid/ciac932 . OpenUrl CrossRef PubMed 10. ↵ Mould DR , Upton RN . Basic Concepts in Population Modeling, Simulation, and Model-Based Drug Development—Part 2: Introduction to Pharmacokinetic Modeling Methods . CPT Pharmacometrics Syst Pharmacol 2013 ; 2 : 38 . Available at : doi: 10.1038/psp.2013.14 . OpenUrl CrossRef 11. ↵ Janmahasatian S , Duffull SB , Ash S , Ward LC , Byrne NM , Green B . Quantification of lean bodyweight . Clin Pharmacokinet 2005 ; 44 : 1051 – 65 . OpenUrl CrossRef PubMed Web of Science 12. ↵ Anderson BJ , Holford NHG . Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics . Annu Rev Pharmacol Toxicol 2008 ; 48 : 303 – 332 . Available at: https://www.annualreviews.org/doi/10.1146/annurev.pharmtox.48.113006.094708 . OpenUrl CrossRef PubMed Web of Science 13. ↵ Cockcroft DW , Gault H . Prediction of Creatinine Clearance from Serum Creatinine . Nephron 1976 ; 16 : 31 – 41 . Available at: https://karger.com/article/doi/10.1159/000180580 . OpenUrl CrossRef PubMed Web of Science 14. ↵ Wijk M , Wasmann RE , Jacobson KR , Svensson EM , Denti P . A Pragmatic Approach to Handling Censored Data Below the Lower Limit of Quantification in Pharmacokinetic Modeling . CPT Pharmacometrics Syst Pharmacol 2025 ; 14 : 1042 – 1049 . Available at : doi: 10.1002/psp4.70015 . OpenUrl CrossRef PubMed 15. ↵ Hong Y , Mager DE , Blum RA , Jusko WJ . Population Pharmacokinetic/Pharmacodynamic Modeling of Systemic Corticosteroid Inhibition of Whole Blood Lymphocytes: Modeling Interoccasion Pharmacodynamic Variability . Pharm Res 2007 ; 24 : 1088 – 1097 . Available at: https://link.springer.com/10.1007/s11095-006-9232-x . OpenUrl PubMed 16. ↵ Pang KS , Rowland M . Hepatic clearance of drugs. I . Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance . J Pharmacokinet Biopharm 1977 ; 5 : 625 – 653 . Available at: http://link.springer.com/10.1007/BF01059688 . OpenUrl CrossRef PubMed Web of Science 17. ↵ Thummel KE , O’Shea D , Paine MF , et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism* . Clin Pharmacol Ther 1996 ; 59 : 491 – 502 . Available at: http://doi.wiley.com/10.1016/S0009-9236(96)90177-0 . OpenUrl CrossRef PubMed Web of Science 18. ↵ Jacobs TG , Marzolini C , Back DJ , Burger DM . Dexamethasone is a dose-dependent perpetrator of drug–drug interactions: implications for use in people living with HIV . Journal of Antimicrobial Chemotherapy 2022 ; 77 : 568 – 573 . Available at: https://academic.oup.com/jac/article/77/3/568/6430404 . OpenUrl PubMed 19. ↵ Katzenmaier S , Markert C , Riedel K-D , Burhenne J , Haefeli WE , Mikus G . Determining the Time Course of CYP3A Inhibition by Potent Reversible and Irreversible CYP3A Inhibitors Using A Limited Sampling Strategy . Clin Pharmacol Ther 2011 ; 90 : 666 – 673 . Available at: http://doi.wiley.com/10.1038/clpt.2011.164 . OpenUrl CrossRef PubMed 20. ↵ Williamson B , Dooley KE , Zhang Y , Back DJ , Owen A . Induction of Influx and Efflux Transporters and Cytochrome P450 3A4 in Primary Human Hepatocytes by Rifampin, Rifabutin, and Rifapentine . Antimicrob Agents Chemother 2013 ; 57 : 6366 – 6369 . Available at: https://journals.asm.org/doi/10.1128/AAC.01124-13 . OpenUrl Abstract / FREE Full Text 21. ↵ Backman JT , Olkkola KT , Neuvonen PJ . Rifampin drastically reduces plasma concentrations and effects of oral midazolam . Clin Pharmacol Ther 1996 ; 59 : 7 – 13 . Available at: http://doi.wiley.com/10.1016/S0009-9236(96)90018-1 . OpenUrl CrossRef PubMed Web of Science 22. ↵ Duggan DE , Yeh KC , Matalia N , Ditzler CA , McMahon FG . Bioavailability of oral dexamethasone . Clin Pharmacol Ther 1975 ; 18 : 205 – 209 . Available at: https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt1975182205 . OpenUrl PubMed Web of Science 23. ↵ Thummel KE . Gut instincts: CYP3A4 and intestinal drug metabolism . Journal of Clinical Investigation 2007 ; 117 : 3173 – 3176 . Available at: http://www.jci.org/cgi/doi/10.1172/JCI34007 . OpenUrl CrossRef PubMed Web of Science 24. ↵ Hariparsad N , Nallani SC , Sane RS , Buckley DJ , Buckley AR , Desai PB . Induction of CYP3A4 by Efavirenz in Primary Human Hepatocytes: Comparison With Rifampin and Phenobarbital . The Journal of Clinical Pharmacology 2004 ; 44 : 1273 – 1281 . Available at: https://accp1.onlinelibrary.wiley.com/doi/10.1177/0091270004269142 . OpenUrl PubMed 25. ↵ Niemi M , Backman JT , Fromm MF , Neuvonen PJ , Kivist KT . Pharmacokinetic Interactions with Rifampicin . Clin Pharmacokinet 2003 ; 42 : 819 – 850 . Available at: http://link.springer.com/10.2165/00003088-200342090-00003 . OpenUrl CrossRef PubMed Web of Science View the discussion thread. Back to top Previous Next Posted July 15, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Pharmacokinetics of dexamethasone in tuberculosis meningitis Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Pharmacokinetics of dexamethasone in tuberculosis meningitis Jose M Calderin , Juan Eduardo Resendiz-Galvan , Noha Abdelgawad , Angharad Davis , Cari Stek , Lubbe Wiesner , Graeme Meintjes , Robert J. Wilkinson , Paolo Denti , Sean Wasserman medRxiv 2025.07.14.25331510; doi: https://doi.org/10.1101/2025.07.14.25331510 Share This Article: Copy Citation Tools Pharmacokinetics of dexamethasone in tuberculosis meningitis Jose M Calderin , Juan Eduardo Resendiz-Galvan , Noha Abdelgawad , Angharad Davis , Cari Stek , Lubbe Wiesner , Graeme Meintjes , Robert J. 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