Effects of Dosage, Comorbidities, and Food on Isoniazid Pharmacokinetics in Peruvian Tuberculosis Patients

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Requena-Méndez, Ana ; Davies, Geraint ; Waterhouse, David ; Ardrey, Alison ; Jave, Oswaldo ; López-Romero, Sonia Llanet ; Ward, Stephen A. ; Moore, David A. J. (2014)
  • Publisher: American Society for Microbiology
  • Journal: Antimicrobial Agents and Chemotherapy, volume 58, issue 12, pages 7,164-7,170 (issn: 0066-4804, eissn: 1098-6596)
  • Related identifiers: doi: 10.1128/AAC.03258-14, pmc: PMC4249529
  • Subject: qv_38 | wf_360 | Pharmacology | wf_315

Poor response to tuberculosis (TB) therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic (PK) parameters can be affected by several factors, such as comorbidities or the interaction of TB drugs with food. This study aimed to determine the PK of isoniazid (INH) in a Peruvian TB population under observed daily and twice-weekly (i.e., biweekly) therapy. Isoniazid levels were analyzed at 2 and 6 h after drug intake using liquid chromatography mass spectrometric methods. A total of 107 recruited patients had available PK data; of these 107 patients, 42.1% received biweekly isoniazid. The mean biweekly dose (12.8 mg/kg of body weight/day) was significantly lower than the nominal dose of 15 mg/kg/day (P < 0.001), and this effect was particularly marked in patients with concurrent diabetes and in males. The median maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 6 h (AUC0–6) were 2.77 mg/liter and 9.71 mg·h/liter, respectively, for daily administration and 8.74 mg/liter and 37.8 mg·h/liter, respectively, for biweekly administration. There were no differences in the Cmax with respect to gender, diabetes mellitus (DM) status, or HIV status. Food was weakly associated with lower levels of isoniazid during the continuation phase. Overall, 34% of patients during the intensive phase and 33.3% during the continuation phase did not reach the Cmax reference value. However, low levels of INH were not associated with poorer clinical outcomes. In our population, INH exposure was affected by weight-adjusted dose and by food, but comorbidities did not indicate any effect on PK. We were unable to demonstrate a clear relationship between the Cmax and treatment outcome in this data set. Twice-weekly weight-adjusted dosing of INH appears to be quite robust with respect to important potentially influential patient factors under program conditions.
  • References (36)
    36 references, page 1 of 4

    1. Harries AD, Zachariah R, Corbett EL, Lawn SD, Santos-Filho ET, Chimzizi R, Harrington M, Maher D, Williams BG, De Cock KM. 2010. The HIV-associated tuberculosis epidemic-when will we act? Lancet 375:1906 -1919. http://dx.doi.org/10.1016/S0140-6736(10)60409-6.

    2. Ahmad Khan F, Minion J, Al-Motairi A, Benedetti A, Harries AD, Menzies D. 2012. An updated systematic review and meta-analysis on the treatment of active tuberculosis in patients with HIV infection. Clin. Infect. Dis. 55:1154 -1163. http://dx.doi.org/10.1093/cid/cis630.

    3. Baker MA, Harries AD, Jeon CY, Hart JE, Kapur A, Lonnroth K, Ottmani SE, Goonesekera SD, Murray MB. 2011. The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC Med. 9:81. http://dx.doi.org/10.1186/1741-7015-9-81.

    4. Harries AD, Lin Y, Satyanarayana S, Lonnroth K, Li L, Wilson N, Chauhan LS, Zachariah R, Baker MA, Jeon CY, Murray MB, Maher D, Bygbjerg IC, Enarson DA, Billo NE, Kapur A. 2011. The looming epidemic of diabetes-associated tuberculosis: learning lessons from HIVassociated tuberculosis. Int. J. Tuberc. Lung Dis. 15:1436 -1444, i. http: //dx.doi.org/10.5588/ijtld.11.0503.

    5. WHO. 2010. Guidelines for treatment of tuberculosis. WHO, Geneva, Switzerland.

    6. Menzies D, Benedetti A, Paydar A, Martin I, Royce S, Pai M, Vernon A, Lienhardt C, Burman W. 2009. Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: a systematic review and meta-analysis. PLoS Med. 6:e1000146. http://dx.doi.org/10.1371/journal .pmed.1000146.

    7. Jasmer RM, Seaman CB, Gonzalez LC, Kawamura LM, Osmond DH, Daley CL. 2004. Tuberculosis treatment outcomes: directly observed therapy compared with self-administered therapy. Am. J. Respir. Crit. Care Med. 170:561-566. http://dx.doi.org/10.1164/rccm.200401-095OC.

    8. Hesseling AC, Walzl G, Enarson DA, Carroll NM, Duncan K, Lukey PT, Lombard C, Donald PR, Lawrence KA, Gie RP, van Helden PD, Beyers N. 2010. Baseline sputum time to detection predicts month two culture conversion and relapse in non-HIV-infected patients. Int. J. Tuberc. Lung Dis. 14:560 -570.

    9. Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, GodfreyFaussett P. 2001. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 358:1687-1693. http://dx.doi.org/10.1016/S0140-6736(01)06712-5.

    10. Korenromp EL, Scano F, Williams BG, Dye C, Nunn P. 2003. Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin. Infect. Dis. 37: 101-112. http://dx.doi.org/10.1086/375220.

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