title: Exposure to total and protein-unbound rifampin is not affected by malnutrition in Indonesian tuberculosis patients.
abstract: Nutritional status may have a profound impact on the pharmacokinetics of drugs, yet only few data are available for tuberculosis (TB) drugs. As malnutrition occurs frequently among TB patients, we assessed the effect of malnutrition on the steady-state pharmacokinetics of total and protein-unbound rifampin during the intensive phase of TB treatment. In a descriptive pharmacokinetic study in Bandung, Indonesia, patients received a fixed standard rifampin dose of 450 mg once daily during the intensive phase of TB treatment. A full pharmacokinetic curve for rifampin was recorded, and total and unbound concentrations of rifampin were analyzed in all samples. Rifampin pharmacokinetic parameters were compared between severely malnourished (BMI of <16.0 kg/m(2)), malnourished (BMI of <18.5 kg/m(2)), and well-nourished (BMI of ≥18.5 kg/m(2)) individuals. No difference in total and protein-unbound pharmacokinetic parameters between severely malnourished (n = 7), malnourished (n = 11), and well-nourished (n = 25) patients could be demonstrated. In addition, no significant correlation between BMI and exposure (area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration of drug in serum [Cmax]) was found. Females had significantly higher total AUC0-24 (geometric mean, 59.2 versus 48.2 h · mg/liter; P = 0.02) and higher unbound AUC0-24 (geometric mean, 6.2 versus 4.8 h · mg/liter; P = 0.02) than males. Overall, a marked 2-fold interindividual variation in the free fraction was observed (7.6 to 15.0%; n = 36). Nutritional status and BMI do not appear to have a major effect on total and protein-unbound pharmacokinetic parameters of rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships.
authors: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands Lindsey.teBrake@radboudumc.nl.
authors: L H M
authors: LH
authors: te Brake
authors: Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia.
authors: R
authors: R
authors: Ruslami
authors: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: H
authors: H
authors: Later-Nijland
authors: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: F
authors: F
authors: Mooren
authors: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: M
authors: M
authors: Teulen
authors: Health Research Unit, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia.
authors: L
authors: L
authors: Apriani
authors: Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: J B
authors: JB
authors: Koenderink
authors: Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: F G
authors: FG
authors: Russel
authors: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: D M
authors: DM
authors: Burger
authors: Health Research Unit, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia.
authors: B
authors: B
authors: Alisjahbana
authors: Institut de Recherche pour le Developpement, UMR Nutripass IRD-UM2-UM1, Montpellier, France.
authors: F
authors: F
authors: Wieringa
authors: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: R
authors: R
authors: van Crevel
authors: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: R E
authors: RE
authors: Aarnoutse
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015992:Body Mass Index; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007214:Indonesia; D008297:Male; D044342:Malnutrition / Q000378:metabolism* / Q000503:physiopathology*; D008875:Middle Aged; D012293:Rifampin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014376:Tuberculosis / Q000097:blood* / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D012293:Rifampin