title: Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis.
abstract: Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculous meningitis (TBM). Considering that drug exposure is the intermediate link between dose and effect, we examined the concentration-response relationship for rifampicin and moxifloxacin in TBM patients. In an open-label, phase 2 clinical trial performed in Indonesia (ClinicalTrials.gov NCT01158755), 60 TBM patients were randomised to receive standard-dose (450mg oral) or high-dose rifampicin (600mg intravenous) plus either oral moxifloxacin (400mg or 800mg) or ethambutol (750mg). After 14 days, all patients continued with standard tuberculosis treatment. Pharmacokinetic sampling was performed once in every patient during the first three critical days. Differences in exposure between patients who died or survived were tested with independent samples t-tests. The relationship between drug exposure and mortality was examined using Cox regression. Compared with patients who died during the 2 weeks of intensified treatment, surviving patients had significantly higher rifampicin plasma AUC0-6h, plasma Cmax and CSF Chighest. Additionally, patients had a 32-43% lower relative likelihood of dying with an interquartile range increase in rifampicin exposure. Moxifloxacin exposure did not show a clear relationship with survival. From exposure-response curves, a rifampicin plasma AUC0-6h of ∼70mg·h/L (AUC0-24h of ∼116mgh/L) and a Cmax of ∼22mg/L were deduced as minimum target values for treatment. A strong concentration-effect relationship was found, with higher rifampicin exposure leading to better TBM survival. The current treatment dose of rifampicin is suboptimal; higher doses of rifampicin should be evaluated.
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands. Electronic address: Lindsey.teBrake@radboudumc.nl.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Te Brake
authors.affiliation: Department of Neurology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Sofiati
authors.initials: S
authors.lastname: Dian
authors.affiliation: Department of Neurology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Ahmad Rizal
authors.initials: AR
authors.lastname: Ganiem
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Carolien
authors.initials: C
authors.lastname: Ruesen
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Burger
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Donders
authors.affiliation: Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Rovina
authors.initials: R
authors.lastname: Ruslami
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Aarnoutse
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007214:Indonesia; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010949:Plasma / Q000737:chemistry; D012293:Rifampin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016019:Survival Analysis; D014390:Tuberculosis, Meningeal / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D000077266:Moxifloxacin; D012293:Rifampin
keywords: High-dose rifampicin; Moxifloxacin; PK/PD; Tuberculous meningitis