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Increased bacterici...
Increased bactericidal activity but dose-limiting intolerability at 50 mg.kg(-1) rifampicin
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- te Brake, Lindsey H. M. (författare)
- Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
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- de Jager, Veronique (författare)
- TASK Appl Sci, Cape Town, South Africa.
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- Narunsky, Kim (författare)
- Univ Cape Town, Lung Inst, Fac Hlth Sci, Cape Town, South Africa.
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- Vanker, Naadira (författare)
- TASK Appl Sci, Cape Town, South Africa.
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- Svensson, Elin, 1985- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
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- Phillips, Patrick P. J. (författare)
- Univ Calif San Francisco, UCSF Ctr TB, San Francisco, CA 94143 USA.
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- Gillespie, Stephen H. (författare)
- Univ St Andrews, Sch Med, St Andrews, Fife, Scotland.
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- Heinrich, Norbert (författare)
- Univ Munich, Div Infect Dis & Trop Med, Med Ctr, Munich, Germany.;German Ctr Infect Res DZIF, Munich, Germany.
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- Hoelscher, Michael (författare)
- Univ Munich, Div Infect Dis & Trop Med, Med Ctr, Munich, Germany.;German Ctr Infect Res DZIF, Munich, Germany.
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- Dawson, Rodney (författare)
- Univ Cape Town, Lung Inst, Fac Hlth Sci, Cape Town, South Africa.
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- Diacon, Andreas H. (författare)
- TASK Appl Sci, Cape Town, South Africa.
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- Aamoutse, Rob E. (författare)
- Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
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- Boeree, Martin J. (författare)
- Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Lung Dis, Med Ctr, Nijmegen, Netherlands.
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Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands TASK Appl Sci, Cape Town, South Africa. (creator_code:org_t)
- 2021-02-04
- 2021
- Engelska.
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 58:1
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Accumulating data have indicated that higher rifampicin doses are more effective and shorten tuberculosis treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 7 and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Here we report the results of the final cohorts of PanACEA HIGHRIF1, a dose-escalation study in treatment-naive adult smear-positive patients with tuberculosis. Patients received, in consecutive cohorts, 40 or 50mg/kg rifampicin once daily in monotherapy (day 1-7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between day 8-14. In the 40mg/kg cohort (n=15), 13 patients experienced a total of 36 adverse events (AEs) during monotherapy, resulting in one treatment discontinuation. In the 50mg/kg group (n=17), all patients experienced AEs during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. AEs were mostly mild/moderate and tolerability-rather than safety-related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean AUC(0-24h) for 50mg/kg compared to 40mg/kg; 571 mg/L*h (range 320-995) versus 387 mg/L*h (201-847), while peak exposures saw proportional increases. Protein-unbound exposure after 50mg/kg (11%, 8-17%) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (day-3 Spearman's rho 0.670, p<0.001). EBA increased considerably with dose, with the highest seen after 50mg/kg; 14-day EBA -0.427 logCFU/mL/day (95%CI -0.500, -0.355). In conclusion, although associated with an increased bactericidal effect, the 50mg/kg dose was not well tolerated. Rifampicin at 40mg/kg was well tolerated and therefore selected for evaluation in a phase IIC treatment shortening trial.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Lungmedicin och allergi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Respiratory Medicine and Allergy (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
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te Brake, Lindse ...
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Narunsky, Kim
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Gillespie, Steph ...
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Aamoutse, Rob E.
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Boeree, Martin J ...
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