scholarly journals Plasma pharmacokinetics of high dose oral versus intravenous rifampicin in patients with tuberculous meningitis: a randomized controlled trial

Author(s):  
Sean Wasserman ◽  
Angharad Davis ◽  
Cari Stek ◽  
Maxwell Chirehwa ◽  
Stephani Botha ◽  
...  

Background Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but is impractical in high burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral 35 mg/kg and intravenous 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis. Materials and methods We performed a randomized parallel group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (intravenous 20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using non-compartmental analysis and exposures compared by geometric mean ratio (GMR). Results Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; intravenous, n = 14). Median CD4 count was 130 cells/mm3 (IQR 66 - 253). Rifampicin geometric mean AUC0-24 was 42.9 μg·h/mL (95% CI, 24.5 – 75.0) for standard dose; 295.2 μg·h/mL (95% CI, 189.9 – 458.8) for high dose oral; and 206.5 μg·h/mL (95% CI, 154.6 – 275.8) for intravenous administration. Rifampicin AUC0-24 GMR was 1.44 (90% CI, 0.84 - 2.21) and Cmax GMR was 0.89 (90% CI, 0.63 – 1.23) for high dose oral with respect to intravenous dosing. Conclusions Plasma rifampicin AUC0-24 was higher after an oral 35 mg/kg dose compared with intravenous administration at 20 mg/kg dose over the first few days of TB treatment. Findings support oral rifampicin dosing in future tuberculous meningitis trials.

2021 ◽  
Author(s):  
Sean Wasserman ◽  
Angharad Davis ◽  
Cari Stek ◽  
Maxwell Chirehwa ◽  
Stephani Botha ◽  
...  

ABSTRACTBackgroundHigher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but is impractical in high burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral 35 mg/kg and intravenous 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis.Materials and methodsWe performed a randomized parallel group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (intravenous 20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using non-compartmental analysis and exposures compared by geometric mean ratio (GMR).ResultsForty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; IV, n = 14). Median CD4 count was 130 cells/mm3 (IQR 66 −253). Geometric mean AUC0-∞ was 47.7 µg·h/mL (90% CI, 33.2 – 68.5) for standard dose; 322.3 µg·h/mL (90% CI,234.6 – 442.7) for high dose; and 214.6 µg·h/mL (90% CI, 176.2 – 261.2) for intravenous. High dose oral dosing achieved higher rifampicin exposure than intravenous: AUC0-∞ GMR 0.67 (90% CI, 0.46 −1.0); however, Cmax GMR was 1.11 (90% CI, 0.81 – 1.59), suggesting equivalence.ConclusionsPlasma rifampicin exposure was similar with high dose oral and intravenous administration. Findings support oral rifampicin dosing in future tuberculous meningitis trials.


Author(s):  
Fiona V Cresswell ◽  
David B Meya ◽  
Enock Kagimu ◽  
Daniel Grint ◽  
Lindsey te Brake ◽  
...  

Abstract Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in HIV co-infection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomised to standard-of-care control (PO-10, rifampicin 10mg/kg/day), intravenous rifampicin (IV-20, 20mg/kg/day), or high-dose oral rifampicin (PO-35, 35mg/kg/day). We performed PK sampling on day 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration and grade 3-5 adverse events. Results We enrolled 61 adults, 92% were HIV-positive, median CD4 count was 50cells/µL (IQR 46–56). On day 2, geometric mean plasma AUC0-24hr was 42.9h.mg/L with standard-of-care 10mg/kg dosing, 249h.mg/L for IV-20 and 327h.mg/L for PO-35 (P<0.001). In CSF, standard-of-care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27mg/L, compared with 1.74mg/L (95%CI 1.2–2.5) for IV-20 and 2.17mg/L (1.6–2.9) for PO-35 regimens (p<0.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (p=0.34) Conclusion Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe, and respectively resulted in exposures ~6- and ~8-fold higher than standard-of-care, and CSF levels above the MIC


2018 ◽  
Vol 62 (12) ◽  
Author(s):  
S. Dian ◽  
V. Yunivita ◽  
A. R. Ganiem ◽  
T. Pramaesya ◽  
L. Chaidir ◽  
...  

ABSTRACT High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0–24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.)


2020 ◽  
Vol 4 ◽  
pp. 190
Author(s):  
Suzaan Marais ◽  
Fiona V Cresswell ◽  
Raph L. Hamers ◽  
Lindsey H.M. te Brake ◽  
Ahmad R. Ganiem ◽  
...  

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019)


2018 ◽  
Author(s):  
S Dian ◽  
V Yunivita ◽  
AR Ganiem ◽  
T Pramaesya ◽  
L Chaidir ◽  
...  

ABSTRACTBackgroundHigh doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response.MethodsIn a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival.ResultsA double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma in the critical early days (2±1) of treatment (AUC0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, p<0·001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 3/4 adverse events. Six-month mortality was 7/20 (35%, 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg groups, respectively (p=0·12).ConclusionsTripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. Survival benefit with this dose should now be evaluated in a larger phase III clinical trial.


2019 ◽  
Vol 4 ◽  
pp. 190
Author(s):  
Suzaan Marais ◽  
Fiona V Cresswell ◽  
Raph L. Hamers ◽  
Lindsey H.M. te Brake ◽  
Ahmad R. Ganiem ◽  
...  

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019)


PEDIATRICS ◽  
1982 ◽  
Vol 70 (6) ◽  
pp. 982-986 ◽  
Author(s):  
Peter A. Gross ◽  
Gerald V. Quinnan ◽  
Pureza F. Gaerlan ◽  
Carolyn R. Denning ◽  
Anne Davis ◽  
...  

High concentrations of split-product vaccine (SPV) are more immunogenic than lower concentrations. These studies were verified with another influenza strain, B/Singapore/22/79. Two ether-treated SPVs were compared in 80 children and young adults. The vaccine strains were influenza A/Bangkok/79, A/Brazil/78, and B/Singapore /79; 44 patients received a high-dose SPV containing 7, 7, and 60 µg each of the respective hemagglutinins (HA) and 36 received a standard dose SPV containing 7, 7, and 7 µg of HA, respectively. Among persons initially seronegative by hemagglutination inhibition (HAI) tests, the geometric mean titer (GMT) in 15 recipients of one high dose was 97 vs GMT of 37 in 18 recipients of one standard dose (P &lt; .05). Furthermore, 87% of high-dose recipients had HAI titer ≥ 40 vs 44% of standard dose recipients. In initially seropositive persons, GMT in 29 recipients of one high dose was 170 vs GMT of 84 in 18 recipients of one standard dose (P &lt; .05). Immune response to the other two virus strains was comparable for the two vaccines. The reaction index for the high dose vaccine was 0.70 vs 0.45 for the standard dose (P = NS). An A/Bangkok epidemic struck the New York metropolitan area. The attack rate in unvaccinated matched sibling control subjects was 35% (15/43). There were no vaccine failures. In conclusion, in the small number of patients studied, a 60-µg HA dose of B/Singapore/79 was significantly more immunogenic than a standard 7-µg HA dose without an increase in reactogenicity.


2020 ◽  
Vol 7 (5) ◽  
Author(s):  
Nathalie Loeb ◽  
Melissa K Andrew ◽  
Mark Loeb ◽  
George A Kuchel ◽  
Laura Haynes ◽  
...  

Abstract Background Although high-dose (HD) vaccines have been reported to stimulate higher antibody responses compared with standard-dose (SD) influenza vaccines, there have been limited studies on the impact of frailty on such responses. Methods We conducted a randomized, double-blind trial (2014/2015 to 2017/2018) of SD versus HD trivalent split-virus vaccine (Fluzone) in 612 study participants aged 65+ over 4 influenza seasons. Hemagglutination inhibition antibody titers for influenza H1N1, H3N2, and B vaccine subtypes were measured at baseline and at 4, 10, and 20 weeks postvaccination and frailty was measured using a validated frailty index. Results Geometric mean antibody titers were significantly higher in HD compared with SD vaccine recipients for all influenza subtypes at all time points postvaccination. However, frailty was positively correlated with 4-week titers and was associated with increased odds of being a vaccine responder. For influenza A subtypes, this was mostly limited to HD recipients. Conclusions Frailty was associated with higher titers and increased antibody responses at 4 weeks after influenza vaccination, which was partially dependent on vaccine dosage. Chronic inflammation or dysregulated immunity, both of which are commonly observed with frailty, may be responsible, but it requires further investigation.


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