title: Pharmacokinetics of first-line tuberculosis drugs in Tanzanian patients.
abstract: East Africa has a high tuberculosis (TB) incidence and mortality, yet there are very limited data on exposure to TB drugs in patients from this region. We therefore determined the pharmacokinetic characteristics of first-line TB drugs in Tanzanian patients using intensive pharmacokinetic sampling. In 20 adult TB patients, plasma concentrations were determined just before and at 1, 2, 3, 4, 6, 8, 10, and 24 h after observed drug intake with food to estimate the areas under the curve from 0 to 24 h (AUC0-24) and peak plasma concentrations (Cmax) of isoniazid, rifampin, pyrazinamide, and ethambutol. Acetylator status for isoniazid was assessed phenotypically using the isoniazid elimination half-life and the acetylisoniazid/isoniazid metabolic ratio at 3 h postdose. The geometric mean AUC0-24s were as follows: isoniazid, 11.0 h · mg/liter; rifampin, 39.9 h · mg/liter; pyrazinamide, 344 h · mg/liter; and ethambutol, 20.2 h · mg/liter. The Cmax was below the reference range for isoniazid in 10/19 patients and for rifampin in 7/20 patients. In none of the patients were the Cmaxs for pyrazinamide and ethambutol below the reference range. Elimination half-life and metabolic ratio of isoniazid gave discordant phenotyping results in only 2/19 patients. A substantial proportion of patients had an isoniazid and/or rifampin Cmax below the reference range. Intake of TB drugs with food may partly explain these low drug levels, but such a drug intake reflects common practice. The finding of low TB drug concentrations is concerning because low concentrations have been associated with worse treatment outcome in several other studies.
authors: Department of Respiratory Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. A.Tostmann@elg.umcn.nl
authors: Alma
authors: A
authors: Tostmann
authors: Charles M
authors: CM
authors: Mtabho
authors: Hadija H
authors: HH
authors: Semvua
authors: Jossy
authors: J
authors: van den Boogaard
authors: Gibson S
authors: GS
authors: Kibiki
authors: Martin J
authors: MJ
authors: Boeree
authors: Rob E
authors: RE
authors: Aarnoutse
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004977:Ethambutol / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D011718:Pyrazinamide / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012293:Rifampin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013636:Tanzania; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin
references: Chest. 1998 May;113(5):1178-83
references: 9596291
references: Clin Infect Dis. 2005 May 15;40(10):1481-91
references: 15844071
references: Int J Tuberc Lung Dis. 2010 Jul;14(7):806-18
references: 20550762
references: Eur J Clin Microbiol Infect Dis. 2008 Jun;27(6):467-72
references: 18214560
references: Clin Infect Dis. 2004 Jan 15;38(2):280-3
references: 14699462
references: Antimicrob Agents Chemother. 2007 Jul;51(7):2546-51
references: 17452486
references: Tuber Lung Dis. 1995 Apr;76(2):109-13
references: 7780091
references: Clin Infect Dis. 2012 Jul;55(2):178-9
references: 22467672
references: J Infect Dis. 2011 Dec 15;204(12):1951-9
references: 22021624
references: Br J Clin Pharmacol. 1984 Apr;17(4):481-4
references: 6721995
references: Pharmacoepidemiol Drug Saf. 2001 Mar-Apr;10(2):127-34
references: 11499851
references: Tubercle. 1984 Sep;65(3):211-27
references: 6385429
references: Clin Infect Dis. 2005 Aug 15;41(4):461-9
references: 16028152
references: Clin Infect Dis. 2009 Jun 15;48(12):1685-94
references: 19432554
references: Chest. 1999 Jan;115(1):12-8
references: 9925057
references: J Assoc Physicians India. 1991 Jun;39(6):470-1
references: 1938852
references: Clin Infect Dis. 2001 Feb 1;32(3):515-7
references: 11170964
references: Chest. 2001 Nov;120(5):1520-4
references: 11713129
references: Am J Respir Crit Care Med. 1997 May;155(5):1717-22
references: 9154882
references: Am J Respir Crit Care Med. 2003 May 15;167(10):1341-7
references: 12531776
references: Antimicrob Agents Chemother. 2006 Apr;50(4):1170-7
references: 16569826
references: Br J Clin Pharmacol. 1986 Sep;22(3):343-5
references: 3768246
references: Clin Pharmacokinet. 1984 Nov-Dec;9(6):511-44
references: 6391781
references: Int J Tuberc Lung Dis. 1999 Aug;3(8):703-10
references: 10460103
references: Clin Infect Dis. 1997 Jul;25(1):104-11
references: 9243044
references: Pharmacotherapy. 2009 Dec;29(12):1468-81
references: 19947806
references: Drugs. 2002;62(15):2169-83
references: 12381217
references: Pharmacotherapy. 1998 Nov-Dec;18(6):1205-11
references: 9855317
references: Antimicrob Agents Chemother. 1999 Mar;43(3):568-72
references: 10049268
references: Clin Infect Dis. 2012 Jul;55(2):169-77
references: 22467670
references: Ann Intern Med. 1997 Aug 15;127(4):289-93
references: 9265429