title: Pharmacokinetics and safety/tolerability of higher oral and intravenous doses of rifampicin in adult tuberculous meningitis patients.
abstract: High-dose intravenous (i.v.) rifampicin improved the outcome of tuberculous meningitis (TBM) in a previous study. Unfortunately, i.v. rifampicin is not available in many high-endemic settings. This study examined exposures to and safety of higher oral rifampicin doses compared with i.v. rifampicin. Thirty adult Indonesian TBM patients were randomised to rifampicin 750 mg (ca. 17 mg/kg) orally, 900 mg (ca. 20 mg/kg) orally or 600 mg (ca. 13 mg/kg, as used previously) i.v. over 1.5 h for 14 days, combined with other TB drugs. The pharmacokinetics of rifampicin was assessed in the critical phase of TBM treatment (≤3 days after treatment initiation) and at ≥9 days. In the first days of treatment, the geometric mean (range) plasma AUC0-24 values following rifampicin 750 mg orally, 900 mg orally and 600 mg i.v. were 131.4 (38.1-275.1), 164.8 (66.9-291.2) and 145.7 (77.7-430.2) mg⋅h/L, respectively; Cmax values were 14.3 (6.1-22.2), 16.2 (5.7-28.3) and 24.7 (13.9-37.8) mg/L. CSF concentrations correlated with plasma exposures. After ≥9 days, AUC0-24 values had decreased to 100.1, 101.2 and 94.9 mg⋅h/L. Transient grade 3 ALT increases (8/30 patients) and one grade 4 ALT increase occurred, not related to rifampicin exposure. Higher oral rifampicin doses resulted in approximately similar plasma AUC0-24 but lower plasma Cmax values compared with 600 mg i.v. over 1.5 h. Exposures to rifampicin varied substantially and decreased due to autoinduction. Liver function disturbances occurred in this severely ill population. Future studies should examine even higher rifampicin doses in TBM treatment.
authors.affiliation: Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Vycke
authors.initials: V
authors.lastname: Yunivita
authors.affiliation: Department of Neurology, Faculty of Medicine, Hasan Sadikin Hospital, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Sofiati
authors.initials: S
authors.lastname: Dian
authors.affiliation: Department of Neurology, Faculty of Medicine, Hasan Sadikin Hospital, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Ahmad Rizal
authors.initials: AR
authors.lastname: Ganiem
authors.affiliation: Department of Neurology, Faculty of Medicine, Hasan Sadikin Hospital, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Ela
authors.initials: E
authors.lastname: Hayati
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Tri
authors.initials: T
authors.lastname: Hanggono Achmad
authors.affiliation: Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Atu
authors.initials: A
authors.lastname: Purnama Dewi
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Geert Grooteplein Zuid 10, Nijmegen 65625 GA, The Netherlands.
authors.forename: Marga
authors.initials: M
authors.lastname: Teulen
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Geert Grooteplein Zuid 10, Nijmegen 65625 GA, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Meijerhof-Jager
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, Nijmegen 65625 GA, The Netherlands. Electronic address: Rob.Aarnoutse@radboudumc.nl.
authors.forename: Rob
authors.initials: R
authors.lastname: Aarnoutse
authors.affiliation: Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
authors.forename: Rovina
authors.initials: R
authors.lastname: Ruslami
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D007214:Indonesia; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D011897:Random Allocation; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D013997:Time Factors; D014390:Tuberculosis, Meningeal / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000904:Antibiotics, Antitubercular; D012293:Rifampin
keywords: Indonesia; Pharmacokinetics; Rifampicin; Tolerability; Tuberculous meningitis