Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis

Hendrik Simon Schaaf, Marianne Willemse, Karien Cilliers, Demetre Labadarios, Johannes Stephanus Maritz, Gregory D Hussey, Helen McIlleron, Peter Smith, Peter Roderick Donald, Hendrik Simon Schaaf, Marianne Willemse, Karien Cilliers, Demetre Labadarios, Johannes Stephanus Maritz, Gregory D Hussey, Helen McIlleron, Peter Smith, Peter Roderick Donald

Abstract

Background: Rifampin is a key drug in antituberculosis chemotherapy because it rapidly kills the majority of bacilli in tuberculosis lesions, prevents relapse and thus enables 6-month short-course chemotherapy. Little is known about the pharmacokinetics of rifampin in children. The objective of this study was to evaluate the pharmacokinetics of rifampin in children with tuberculosis, both human immunodeficiency virus type-1-infected and human immunodeficiency virus-uninfected.

Methods: Fifty-four children, 21 human immunodeficiency virus-infected and 33 human immunodeficiency virus-uninfected, mean ages 3.73 and 4.05 years (P = 0.68), respectively, admitted to a tuberculosis hospital in Cape Town, South Africa with severe forms of tuberculosis were studied approximately 1 month and 4 months after commencing antituberculosis treatment. Blood specimens for analysis were drawn in the morning, 45 minutes, 1.5, 3.0, 4.0 and 6.0 hours after dosing. Rifampin concentrations were determined by liquid chromatography tandem mass spectrometry. For two sample comparisons of means, the Welch version of the t-test was used; associations between variables were examined by Pearson correlation and by multiple linear regression.

Results: The children received a mean rifampin dosage of 9.61 mg/kg (6.47 to 15.58) body weight at 1 month and 9.63 mg/kg (4.63 to 17.8) at 4 months after commencing treatment administered as part of a fixed-dose formulation designed for paediatric use. The mean rifampin area under the curve 0 to 6 hours after dosing was 14.9 and 18.1 microg/hour/ml (P = 0.25) 1 month after starting treatment in human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children, respectively, and 16.52 and 17.94 microg/hour/ml (P = 0.59) after 4 months of treatment. The mean calculated 2-hour rifampin concentrations in these human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children were 3.9 and 4.8 microg/ml (P = 0.20) at 1 month after the start of treatment and 4.0 and 4.6 microg/ml (P = 0.33) after 4 months of treatment. These values are considerably less than the suggested lower limit for 2-hour rifampin concentrations in adults of 8.0 microg/ml and even 4 microg/ml

Conclusion: Both human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children with tuberculosis have very low rifampin serum concentrations after receiving standard rifampin dosages similar to those used in adults. Pharmacokinetic studies of higher dosages of rifampin are urgently needed in children to assist in placing the dosage of rifampin used in childhood on a more scientific foundation.

Figures

Figure 1
Figure 1
Rifampin plasma concentrations (μg/ml) in human immunodeficiency virus (HIV)-infected and HIV-uninfected children being treated for tuberculosis determined on enrolment (A) and after 4 months of treatment (B).

References

    1. Kimmerling ME, Phillips P, Patterson P, Hall MH, Robinson CA, Dunlap NE. Low serum antimycobacterial drug levels in non-HIV-infected tuberculosis patients. Chest. 1998;113:1178–1183. doi: 10.1378/chest.113.5.1178.
    1. Um S-W, Lee SW, Kwon SY, Yoon HI, Park KU, Song J, Lee C-T, Lee J-H. Low serum concentrations of anti-tuberculosis drugs and determinants of their serum levels. Int J Tuberc Lung Dis. 2007;11:972–978.
    1. Peloquin CA, Nitta AT, Burman WJ, Brudney KF, Miranda-Massari JR, McGuinness ME, Berning SE, Gerena GT. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother. 1996;30:919–925.
    1. Gurumurthy P, Ramachandran G, Kumar AKH, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, Bhagavathy S, Venkatesan P, Sekar L, Mahilmaran N, Paramesh P. Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother. 2004;48:4473–4475. doi: 10.1128/AAC.48.11.4473-4475.2004.
    1. Perlman DC, Segal Y, Rosenkranz S, Rainey PM, Remmel RP, Salomon N, Hafner R, Peloquin CA. The clinical pharmacokinetics of rifampin and ethambutol in HIV-infected persons with tuberculosis. Clin Infect Dis. 2005;41:1638–1647. doi: 10.1086/498024.
    1. Choudhri SH, Hawken M, Gathua S, Minyiri GO, Watkins W, Sahai J, Sitar DS, Aoki FY, Long R. Pharmacokinetics of antimycobacterial drugs in patients with tuberculosis, AIDS and diarrhea. Clin Infect Dis. 1997;25:104–111. doi: 10.1086/514513.
    1. van Crevel R, Alisjahbana B, de Lange WCM, Borst F, Danusantoso H, Meer JWM, van der, Burger D, Nelwan RHH. Low plasma concentrations of rifampicin in tuberculosis patients in Indonesia. Int J Tuberc Lung Dis. 2002;6:497–502.
    1. Tappero JW, Bradford WZ, Agerton TB, Hopewell P, Reingold AL, Lockman S, Oyewo A, Talbot EA, Kenyon TA, Moeti TL, Moffat HJ, Peloquin CA. Serum concentrations of antimycobacterial drugs in patients with pulmonary tuberculosis in Botswana. Clin Infect Dis. 2005;41:461–469. doi: 10.1086/431984.
    1. McIlleron H, Wash P, Burger A, Norman J, Folb PI, Smith P. Determinants of rifampin, isoniazid, pyrazinamide and ethambutol pharmacokinetics in a cohort of tuberculosis patients. Antimicrob Agents Chemother. 2006;50:1170–1177. doi: 10.1128/AAC.50.4.1170-1177.2006.
    1. Taylor B, Smith PJ. Does AIDS impair the absorption of antituberculosis agents? Int J Tuberc Lung Dis. 1998;2:670–675.
    1. Jaruratanasirikul S. The pharmacokinetics of rifampicin in AIDS patients. J Med Assoc Thai. 1998;81:25–28.
    1. McIlleron H, Norman J, Kanyok TP, Fourie PB, Horton J, Smith PJ. Elevated gatifloxicin and reduced rifampicin concentration in a single-dose interaction study amongst healthy volunteers. J Antimicrob Chemother. 2007;60:1398–1401. doi: 10.1093/jac/dkm393.
    1. Mascarenas MR, Zemel B, Stallings VA. Nuritional assessment in pediatrics. Nutrition. 1998;14:105–115. doi: 10.1016/S0899-9007(97)00226-8.
    1. Zemel BS, Riley EM, Stallings VA. Evaluation of methodology for nutritional assessment in children: anthropometry, body composition, and energy expenditure. Annu Rev Nutr. 1997;17:211–235. doi: 10.1146/annurev.nutr.17.1.211.
    1. Pepys MB, Dash AC, Markham RE, Thomas HC, Williams BD, Petrie A. Comparative clinical study of protein SAP (amyloid A component) and C-reactive protein in serum. Clin Exp Immunol. 1978;32:119–124.
    1. Peloquin CA. Therapeutic drug monitoring: principles and applications in mycobacterial infections. Drug Ther. 1992;22:31–36.
    1. Krauer B. The Pharmacokinetics of Rimactane in Children Symposium on Rimactane. Vol. 5. Basel: Dettli L; 1968.
    1. Acocella G, Buniva G, Flauto U, Nicolis FB. Proceedings of the Sixth International Congress of Chemotherapy 1969; Tokyo. Vol. 2. Tokyo: University of Tokyo Press; 1970. Absorption and elimination of the antibiotic rifampicin in newborns and children; pp. 755–760.
    1. Bergamini N, Matnardi L, Rosaschino F. Tassi ematici eliminazione urinaria di Rifampicina nei lattanti. Aggiorn Pediatr. 1970;21:191–197.
    1. Hussels H, Kroening U, Magdorf K. Ethambutol and rifampicin serum levels in children: second report on the combined administration of ethambutol and rifampicin. Pneumonologie. 1973;149:31–38. doi: 10.1007/BF02179950.
    1. McCracken GH, Ginsburg CM, Zweighaft TC, Clahsen J. Pharmacokinetics of rifampin in infants and children: relevance to prophylaxis against Haemophilus influenzae type B disease. Pediatrics. 1980;66:17–21.
    1. Tan TQ, Mason EO, Ou C-N, Kaplan SL. Use of intravenous rifampin in neonates with persistent staphylococcal bacteraemia. Antimicrob Agents Chemother. 1993;37:2401–2406.
    1. Seth V, Beotra A, Bagga A, Seth S. Drug therapy in malnutrition. Indian Pediatr. 1992;29:1341–1346.
    1. Seth V, Beotra A, Seth SD, Semwal OP, Kabra S, Jain Y, Mukhopadhya S. Serum concentrations of rifampicin and isoniazid in tuberculosis. Indian Pediatr. 1993;30:1091–1098.
    1. Mahajan M, Rohatgi D, Talwar V, Patni SK, Mahajan P, Agarwal DS. Serum and cerebrospinal fluid concentrations of rifampicin at two dose levels in children with tuberculous meningitis. J Commun Dis. 1997;29:269–274.
    1. World Health Organization . Guidelines for National Programmes. WHO/CDS/TB/2003.313. Geneva; 2003. Treatment of tuberculosis.
    1. World Health Organization . Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. WHO/HTM/TB/2006.371. Geneva; 2006.
    1. Ansel HC, Stoklosa MJ. Pharmaceutical Calculations. Philadelphia, PA: Lippincott Williams & Wilkins; 2001. Calculation of doses; pp. 63–91.
    1. Weidle PJ, Abrams EJ, Gvetadze R, Rivadeneira E, Kline MW. A simplified weight-based method for pediatric drug dosing for zidovudine and didanosine in resource-limited settings. Pediatr Infect Dis J. 2006;25:59–64. doi: 10.1097/01.inf.0000195619.76277.3f.
    1. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603–662. doi: 10.1164/rccm.167.4.603.
    1. McIlleron H, Watkins ML, Folb PI, Ress SR, Wilkinson RJ. Rifampin levels, interferon-gamma release and outcome in complicated pulmonary tuberculosis. Tuberculosis (Edinb) 2007;87:557–564. doi: 10.1016/j.tube.2007.08.002.
    1. Chang KC, Leung CC, Yew WW, Kam KM, Yip CW, Ma CH, Tam CM, Leung EC, Law WS, Leung WM. Peak plasma rifampicin level in tuberculosis patients with slow culture conversion. Eur J Clin Microbiol Infect Dis. 2008;27:467–472. doi: 10.1007/s10096-007-0454-6.
    1. Chang KC, Leung CC, Yew WW, Ho SC, Tam CM. A nested case-control study on treatment-related risk factors for early relapse of tuberculosis. Am J Respir Crit Care Med. 2004;170:1124–1130. doi: 10.1164/rccm.200407-905OC.
    1. Chang KC, Leung CC, Yew WW, Chan SL, Tam CM. Dosing schedules of 6-month regimens and relapse for pulmonary tuberculosis. Am J Respir Crit Care Med. 2006;174:1153–1158. doi: 10.1164/rccm.200605-637OC.
    1. Nahid P, Gonzalez LC, Rudoy I, de Jong BC, Unger A, Masae Kawamura L, Osmond DH, Hopewell PC, Daley CL. Treatment outcomes of patients with HIV and tuberculosis. Am J Respir Crit Care Med. 2007;175:1199–1206. doi: 10.1164/rccm.200509-1529OC.
    1. Perriëns JH, St Louis ME, Mukadi YB. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months. N Eng J Med. 1995;332:779–784. doi: 10.1056/NEJM199503233321204.
    1. Long MW, Snider DE, Farer LS. U.S. Public Health Service trial of three rifampin-isoniazid regimens in treatment of pulmonary tuberculosis. Am Rev Respir Dis. 1979;119:879–894.
    1. Buniva G, Pagani V, Carozzi A. Bioavailability of rifampicin capsules. Int J Clin Pharmacol Ther Toxicol. 1983;21:404–409.
    1. Chan SL, Yew WW, Ma WK, Girling DJ, Aber VR, Felmingham D, Allen BW, Mitchison DA. The early bactericidal activity of rifabutin measured by sputum viable counts in Hong Kong patients with pulmonary tuberculosis. Tuberc Lung Dis. 1992;73:33–38. doi: 10.1016/0962-8479(92)90077-W.
    1. Sirgel FA, Fourie PB, Donald PR, Padayatchi N, Rustomjee R, Levin J, Roscigno G, Norman J, McIlleron H, Mitchison DA. The early bactericidal activities of rifampin and rifapentine in pulmonary tuberculosis. Am J Respir Crit Care Med. 2005;172:128–135. doi: 10.1164/rccm.200411-1557OC.
    1. American Academy of Pediatrics . Tuberculosis. In: Pickering LK, Baker CJ, Long SS, McMilan JA, editor. Red Book: 2006 Report of the Committee on Infectious Diseases. 27. Elk Grove Village, IL: American Academy of Pediatrics; 2006. pp. 678–704.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren