1. The Potential for Treatment Shortening With Higher Rifampicin Doses : Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis
- Author
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Lilian T. Minja, Rob E. Aarnoutse, Ulrika S. H. Simonsson, Rodney Dawson, Lindsey H.M. te Brake, Andreas H. Diacon, Sarah Konsten, Ian Sanne, Martin J. Boeree, Gibson S. Kibiki, Norbert Heinrich, Nyanda E Ntingiya, Patrick P. J. Phillips, Michael Hoelscher, Elin M. Svensson, Gavin J. Churchyard, Stephen H. Gillespie, Robin J. Svensson, University of St Andrews. Infection and Global Health Division, University of St Andrews. Global Health Implementation Group, University of St Andrews. Gillespie Group, University of St Andrews. School of Medicine, University of St Andrews. Biomedical Sciences Research Complex, and University of St Andrews. Infection Group
- Subjects
0301 basic medicine ,Male ,Time Factors ,Antibiotics ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Infektionsmedicin ,Tanzania ,Medical and Health Sciences ,South Africa ,0302 clinical medicine ,Moxifloxacin ,RA0421 ,RA0421 Public health. Hygiene. Preventive Medicine ,80 and over ,Medicine ,sputum culture conversion ,030212 general & internal medicine ,Lung ,pharmacometrics ,media_common ,Aged, 80 and over ,Pulmonary ,Middle Aged ,Biological Sciences ,Farmakologi och toxikologi ,Infectious Diseases ,6.1 Pharmaceuticals ,Female ,medicine.symptom ,Rifampin ,Drug ,Infection ,medicine.drug ,Microbiology (medical) ,Adult ,medicine.medical_specialty ,RM ,Infectious Medicine ,Tuberculosis ,Adolescent ,medicine.drug_class ,media_common.quotation_subject ,030106 microbiology ,Clinical Trials and Supportive Activities ,high-dose rifampicin ,NDAS ,exposure-response ,Pharmacology and Toxicology ,Microbiology ,Dose-Response Relationship ,03 medical and health sciences ,Young Adult ,Rare Diseases ,Pharmacokinetics ,SDG 3 - Good Health and Well-being ,Clinical Research ,Internal medicine ,Humans ,Tuberculosis, Pulmonary ,Ethambutol ,Aged ,Dose-Response Relationship, Drug ,business.industry ,PK-PD ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,RM Therapeutics. Pharmacology ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Sputum ,business ,Rifampicin - Abstract
This work was supported by the European and Developing Countries Clinical Trials partnership (grants IP.2007.32011.011, IP.2007.32011.012, and IP.2007.32011.013) and the German Ministry for Education and Research (grant 01KA0901). The original study conducted within the PanACEA consortium. Background: Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods: Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed. Results: Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%-41%) to 55% (49%-61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L·h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109. Conclusions: Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority. Publisher PDF
- Published
- 2018