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Nov. 2011, Volume 8, No. 11 (Serial No. 84), pp. 661–666 Journal of US-China Medical Science, ISSN 1548-6648, USA Acute Pharmacokinetics of First Line Anti-tuberculosis
Drugs in Patients with Pulmonary Tuberculosis and in
Patients with Pulmonary Tuberculosis Co-infected with
Pierre Mugabo1, Mogamat Shafick Hassan2 and R. Slaughter3 1. Department of Pharmacology, University of the Western Cape, Cape Town, South Africa 2. Department of Health Sciences, Cape Peninsula University of Technology, Cape Town, South Africa 3. Department of Pharmacy Practice, College of Pharmacy and Health Sciences. Wayne State University, Detroit, Michigan 48202, Abstract: Background: The aim of this study was to compare the pharmacokinetics of antituberculosis drugs in patients with
pulmonary tuberculosis (PTB) and in patients with PTB and HIV during the first 24 h of treatment. Methods: Designed a case-control
study, it compares the pharmacokinetics of first line antituberculous drugs, in HIV-positive (cases) and HIV-negative (control) patients
both presenting with pulmonary tuberculosis. Blood samples were collected before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 8, 12 and 24 h
after administration of drugs. Drugs plasma levels were tested using HPLC assays. Results: Fourteen HIV positive (7 males and 7
females) and 17 HIV negative (9 males and 8 females) enrolled. Rifafour, a combination tablet including rifampicin, isoniazid,
pyrazinamide and ethambutol was used in HIV positive patients, CD4 counts were significantly lower, renal function mildly decreased
in 85% patients and moderately decreased in 7% patients. Liver function was normal in both groups. None of these patients was on
other drug therapy. In the HIV positive group isoniazid T1/2 and AUC were decreased and Cl increased whereas Tmax and Cmax were
unchanged. Pyrazinamide Tmax and Cmax were significantly decreased in HIV positive patients and no significant changes were
noticed in the T1/2, AUC and CL. Conclusion: The study suggest that ethambutol, pyrazinamide and rifampicin pharmacokinetics was
not affected by HIV infection and that isoniazid disposition is affected by HIV.
Key words: Pharmacokinetics, rifampicin, isoniazid, ethambutol, pyrazinamide, HIV infection.
new smear-positive patients with TB in South Africa 1. Introduction
was 64%. Therapeutic response is influenced by the Tuberculosis (TB), in sub-Saharan Africa, remains a method of administration with Directly Observed leading cause of mortality in HIV infected patients and Treatment (DOT) estimated to have averted 8 million is the leading cause of death in South Africa where the deaths related to TB [3]. Appropriate management of life expectancy is only 49 years of age. The country has TB in South Africa is particular important because of the highest incidence of HIV/AIDS world wide with an the high incidence of HIV, a known risk factor for estimated 5.7 million people infected in 2009 [1, 2]. development of TB, and the high rates of MDR-TB Co-infection of HIV/AIDS patients with TB is a with over 6,000 cases expected to be treated in South substantial health problem. The cure rate in 2008 of Drug treatment of tuberculosis consists of 2 months Corresponding author: Pierre Mugabo, professor, research
of isoniazid, refiampin, pyrazinamide and ethambutol fields: pharmacokinetics of antituberculous and antiretroviral drugs, cardiovascular pharmacology. E-mail: followed by 4 months of rifampin and isoniazid [4]. 662 Acute Pharmacokinetics of First Line Anti-tuberculosis Drugs in Patients with Pulmonary Tuberculosis
and in Patients with Pulmonary Tuberculosis Co-infected with HIV
Therapeutic response is related to serum concentrations consent to join the study, patients were admitted to the of drugs received with poor outcomes associated with Karl Bremer Hospital in Cape Town (South Africa), in low pyrazinamide and isoniazid concentrations [5, 6]. the evening before the start of TB treatment. They were Lower treatment outcomes are seen in patients excluded from the study on request by the patient, if co-infected with HIV [7], which may explain why the they were critically ill and in case of previous exposure to anti-TB drugs. Other exclusion criteria included the There have been a few studies that have investigated presence of chronic disease such as diabetes mellitus, the influence of AIDS on the absorption of drugs used hypertension and cardiac failure, as determined by to treat tuberculosis. Some authors concluded that drug malabsorption may contribute to the emergence of acquired drug resistance [7–10]; and they have advocated for routine therapeutic drug monitoring of For the initial phase of treatment (2 months) antituberculous drugs in HIV-infected patients, Rifafour® e-200 tablets were used. Each tablet particularly those with advanced HIV disease [7–10]. contains rifampicin (RIF) 120 mg, isoniazid (INH) 60 Other studies found that the call for screening of mg, pyrazinamide (PZA) 300 mg and ethambutol (ETH) antimycobacterial drug levels in HIV-infected patients 200 mg. Patients weighing 30–50 kg body weight (BW) with pulmonary tuberculosis is still premature since no received 4 tablets Rifafour® e-200 daily dose. Those impairment in the bioavailability of antituberculosis with a body weight (BW) > 50 kg received 5tablets Rifafour® e-200 daily dose. For the continuation phase The aim of this study was to describe the of treatment Rifinah ® – 150 and Rifinah ® – 300 were pharmacokinetics of the first line anti-tuberculosis (TB) used. Each Rifinah ® – 150 tablet contains RIF 150 mg drugs during the first 24 hours after drug administration and INH 100 mg. Each Rifinah ® – 300 tablet contains in patents infected with pulmonary tuberculosis (PTB) RIF 300 mg and INH 150 mg. Patients weighing less and compare the pharmacokinetic parameters obtained than 50 kg received 3 tablets of Rifinah ® – 150 and in patients co-infected with PTB and HIV. those with a BW ≥ 50 kg received 2 tablets of Rifinah ® – 300. Tablets were taken in front of a nurse every 2. Patients and Methods
day, five days a week (Monday to Friday). Each patient 2.1 Study Design, Subjects, Inclusion and Exclusion was also given pyridoxine 25 mg daily in order to prevent peripheral neuropathy due to INH. All tablets were supplied by Aventis Pharma (Pty) Ltd, 2 Bond Designed a case-control study, the study compares Street, Midrand 1685, South Africa. The acetylation the pharmacokinetics of first line antituberculous drugs, in HIV-positive (cases) and HIV-negative (control) patients both presenting with pulmonary tuberculosis. The study involved male and female patients without The following morning, after an 8-hour overnight previous history of TB, 18 to 60 years old, with sputum fast, blood samples were collected for base line tests microbiology test positive for Mycobacterium including liver function tests (LFTs), renal function tuberculosis (MTB) which was sensitive to rifampicin tests (RFTs), full blood count (FBC), CD4 counts and (RIF), isoniazid (INH), ethambutol (ETH) and plasma concentrations of the anti-TB drugs. Rifafour pyrazinamide (PZA). Patients were recruited from their was administered to patients for the first time using the home area TB clinics where they had just been tested dosages recommended by the Department of Health. for HIV after counseling. After informed and written Acute Pharmacokinetics of First Line Anti-tuberculosis Drugs in Patients with Pulmonary Tuberculosis 663
and in Patients with Pulmonary Tuberculosis Co-infected with HIV
Then blood samples were collected for TB drugs patient was plotted using Graph Pad Prism program. plasma levels determination at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, Drugs pharmacokinetic parameters were calculated 4, 4.5, 8, 12 and 24 hours after drug administration. based on the non-compartmental analysis (NCA) as Patients were served the same breakfast 1 hour after the beginning of the treatment. They were also offered the 2.5.1 Maximum Concentration and the Time to same meal at lunch and super time. The following morning, the 24 hours blood sample for TB drug The maximum concentration (Cmax) and the time to plasma levels determination was collected before reach the maximum concentration (Tmax) were obtained breakfast and administration of the following morning directly from the plasma concentration-time profile. anti-TB drugs. Blood samples for determination of TB drugs plasma levels were collected in a heparinized The half-life (T½) was calculated using the formula: vacutainer tube from an intravenous catheter fixed on a T½ = 0.639/Ke and Ke was determined from the forearm vein of the patient prior to dosing and terminal slope of the ln-concentration vs time curve. centrifuged immediately, with the plasma stored in a minus 20˚C freezer for no more than 12 hours. Thereafter, it was stored in a minus 80˚C deep freezer The area under the plasma concentration-time curve from zero to 24 hours (AUC0-24) was calculated by the trapezoidal method using Graph Pad Prism software. The following laboratory tests were conducted at the The apparent total body clearance (Cltot) was calculated using the following formula: Cltot = Dose/ (NHLS) Green Point Lab (Cape Town–South Africa) AUC0-24. Low Cmax values were defined using the for each patient: liver function tests (LFTs), renal following method reported by Jordan W. Tapero et al. function tests (RFTs), full blood counts (FBC), sputum [7]: isoniazid, < 3 µg/mL (300 mg dose); rifampicin, microscopy after Auromine or Ziehl-Neelsen stains. If <8 µg.mL (weight –adjusted dose, 450 or 600 mg); mycobacteria were observed, susceptibility tests were pyrazinamide, <35 µg/mL (median dose, 35 mk/kg); determined forall first — line anti TB agents mentioned and ethambutol, <2 µg/mL (median dose, 21 mk/kg). above HIV test (Elisa) was done at the University of Very low Cmax values were defined as follows: Cape Town (UCT) Virology Department for each isoniazid, <2 µg/mL (300 mg dose) or <3 µg/mL (400 patient. Plasma levels were performed using high mg dose); rifampicin, <4 µg/mL; pyrazinamide, <20 performance liquid chromatography (HPLC) assay methods. The lower limit of quantification for all four µg/mL; and ethambutol, <1 µg/mL. Delayed drugs was 0.05 µg/ml. The linear range for isoniazid absorption was defined as a Tmax >3 h. and rifampicin was 0.05–30 µg/ml and for 2.5.5 Ethical and Statistical Considerations pyrazinamide it was 0.05–100 µg/ml. All four drugs The study was conducted according to the declaration of Helsinki and ICH guidelines. The protocol was approved by the ethics committee of the 2.5 Determination of Pharmacokinetic Parameters University of the Western Cape. Permission to conduct After determination of rifampicin, isoniazid, the study was granted by the medical superintendent of pyrazinamide and ethambutol plasma concentrations, Karl Bremer Hospital. The information obtained the plasma concentration-time profile for each drug by during the study was treated as confidential. 664 Acute Pharmacokinetics of First Line Anti-tuberculosis Drugs in Patients with Pulmonary Tuberculosis
and in Patients with Pulmonary Tuberculosis Co-infected with HIV
For each of 4 drugs responses for those who are As indicated in Table 1, the age distribution is HIV Positive were compared to those who were similar in both groups. The mean age is 33.06±10.12 in negative on each of the 9 parameters. Some of the HIV negative group (control) and 35.14±12.05 in HIV parameters are related, so test results are not independent. Nevertheless there are many tests being Out of 14 HIV-positive patients, 9 were stage 3 done so a more stringent level of significance was used (WHO staging system) and 5 were stage 4 (WHO (a p value of < 0.01 rather than the customary 0.05 was staging system). The mean CD4 cells was 356.38 and required for significance). In many cases the the mean period of HIV infection was 5.9 yrs. distribution of the measurements was skewed and The CD4 counts were significantly lower in the HIV decidedly non-normal. Consequently groups were positive patients (cases) than in the HIV negative compared using the Wilcoxon Rank Sum test. patients (control). In the HIV control group, the renal function was normal. However, in cases group, the 3. Results
renal function was mildly decreased in 85.71% of Thirty one (31) patients were involved in the study patients, moderately decreased in 7.14% of patients with 14 (7 males and 7 females) patients determined to and normal in 7.14% of patients. The hepatic function be HIV positive (cases) and seventeen patients (9 males tests were normal in both groups. None of these and 8 females) HIV negative (control) (Table 1). All of them were infected with Mycobacterium tuberculosis Tables 2a, 2b, 2c and 2d provide the descriptive (MTB) sensitive to anti-TB drugs used. During the statistics for the pharmacokinetic parameters for the intensive phase (first 2 months) rifafour, a combination test drugs in HIV positive and HIV negative patients. tablet including rifampicin 120 mg, isoniazid 60 mg, In general the presence of HIV did not impact the pyrazinamide 300 mg and ethambutol 200 mg, was disposition of ethambutol, pyrazinamide and used at the dose of 4 tablets daily five days a week rifampicin. The one exception was isoniazid which (Monday to Friday) for patients under 50 kg body showed a modest effect of HIV on its disposition. A weight and 5 tablets daily for patients weighing 50 kg statistical reduction in Tmax in HIV positive patients was observed and borderline changes in half-life, AUC The median body weight was 54 (range 51–60) kg in 0-24 and Cl. It appears that the presence of HIV may modestly decrease AUC and half-life which is HIV-positive patients (cases) and 56 (range 51–65) kg consistent with either an observed increase in clearance Table 1 Demographics, renal and hepatic function data.
4. Discussion and Conclusion
The current study evaluated the disposition of Table 2a Pharmacokinetic parameters in HIV negative
and HIV positive patients.
Acute Pharmacokinetics of First Line Anti-tuberculosis Drugs in Patients with Pulmonary Tuberculosis 665
and in Patients with Pulmonary Tuberculosis Co-infected with HIV
Table 2b Isoniazid pharmacokinetic parameters in HIV
mean age and mean CD4 lymphocytes count) of negative and HIV positive patients.
patients involved in this study are similar to those of patients who participated in the previous studies [12, 15–18]. Ethambutol Cmax, Tmax and half life found in this study are similar to those reported in previous studies and there is no significant difference between HIV-negative and HIV-positive patients [12, 15–18]. The presence of HIV does not influence the disposition of ethambutol. Isoniazid pharmacoki- netic parameters found in this study and those reported previously [12, 15–18] are quite variable. This could be explained by Table 2c Pyrazinamide pharmacokinetic parameters in
the differences between studies in the incidence of HIV negative and HIV positive patients.
rapid and slow acetylators in the population. However, (1500 mg HIV-negative HIV-positive significance for each study, there is no significant difference between pharmacokinetic values in HIV-negative and HIV-positive patients. Our study does show a modest Tmax (hrs) 2.5±0.26 2.4±0.43 0.084 37% reduction in AUC in HIV-positive patients. This result is in variance with other studies and does indicate the need for additional studies. The AUC that we report in HIV-negative patients is very comparable to that reported in normal health volunteers that are slow acetylators [19]. Whereas the AUC value we reported Table 2d Rifampicin pharmacokinetic parameters in HIV
negative and HIV positive patients.
in HIV-positive patients is between that reported for rapid and slow acetylators of INH. The differences that we report in INH AUC as a function of HIV status could very well reflect differences in the number of patients who are rapid acetylators between these In this study, pyrazinamide and rifampicin Tmax, 1/2 and AUC values are higher than in studies previously conducted [12, 15–18]. However, in each ethambutol, pyrazinamide, isoniazid and rifampcin in individual study, there is generally no significant patients with active TB who were either HIV-positive difference between HIV-negative and HIV-positive or HIV-negative. The data suggests that isoniazid patients. The most recent study from Botswana [6] disposition is affected by HIV with the Tmax and reported lower than expected concentrations of AUC0-∞ being lower in patients co-infected with HIV. pyrazinamide and showed that these were related to The presence of HIV had no effect in this study on the treatment outcomes. This study, however, showed only disposition of ethambutol, pyrazinamide or rifampicin. very modest influences (p < 0.04) of HIV infection on Several studies have evaluated the influence of HIV on the disposition pyrazinamide and rifampin. These the pharmacokinetics of first line anti-TB drugs. The results are not that much different that this study in demographic parameters (number, gender balance, 666 Acute Pharmacokinetics of First Line Anti-tuberculosis Drugs in Patients with Pulmonary Tuberculosis
and in Patients with Pulmonary Tuberculosis Co-infected with HIV
In HIV positive patients, renal function was mildly HIV-infected cohort of adults with tuberculosis from Botswana, Clin Inf Dis 48 (2009) 1685–1694. decreased in 85.71% of patients and moderately [7] S. E. Berning, G. A. Huit, M. Iseman et al., Malabsorption decreased in 7.14% of patients. This however did not of antituberculous medications by a patient with AIDS, influence the pharmacokinetics of isoniazid, ethambutol, pyrazinamide and rifampicin. [8] C. A. Peloquin, A. A. MacPhee, S. E. Burning, Malabsorption of antimycobacterial medications, N Engl J pharmacokinetics were not affected by HIV infection. [9] Patel KB, Belmonte R, Crowe HM. Drug malabsorption and resistant tuberculosis in HIV-infected patients, N Engl [10] C. A. Peloquin, A. T. Nitta and W. J. Burman et al., Low were unchanged. Pyrazinamide, Tmax and Cmax were antituberculosis drug concentrations in patients with AIDS, significantly decreased in HIV positive patients and no significant changes were notices in the T [11] S. H. Choudhri, M. Hawken, S. Gathua, G. O. Minyiri, W. Watkins, Jan Sahai, D. S. Sitar, F. Y. Aoki and R. Long, Pharmacokinetics of antimycobacterial drugs in patients with tuberculosis, AIDS, and diarrhea, CID 25 (1997) Acknowledgement
University of the Western Cape and Cape Peninsula [12] B. Taylor and P. J. Smith, Does AIDS impair the absorption of antituberculosis agents? Int J Tuberc Lung University of Technology for financial support of the study. We thank patients who participated in this study. [13] J. W. Tappero, W. Z. Bradford, T. B. Agerton, P. We also thank the management of Karl Bremer Hopewell, A. L. Reingold, S. Lockman, A. Oyewo, E. A. Talbot, T. A. Kenyon, T. L. Moeti, H. J. Moffat and C. A. Hospital and staff members from the Department of Peloquin, Serum Concentrations of antimycobacterial Internal Medicine, Ward 1 A, Karl Bremer Hospital drugs in patients with pulmonary tuberculosis in Botswana, and from the Department of Pharmacology, University [14] D. L. Horn, Dial Hewlett, Celia Alfalla and Stephen Peterson, Fatal hospital-acquired multidrug-resistant References
tuberculous pericarditis in two patients with AIDS, The New England Journal of Medicne 327 (25) (1992) 1817. [1] Available online at: [15] S. H. Choudhri et al., Pharmacokinetics of factsheets /fs104/en/, accessed May 24, 2010. antimycobacterial drugs in patients with tuberculosis, [2] Available online at: AIDS, and diarrhoea, Clinical Infectiuous Diseases 25 Report/2010/southafrica_2010_country_progress_report_ [16] J. W. Tappero et al., Serum concentrations of [3] Available online at: antimycobacterial drugs in patients with pulmonary [4] M. D. Iseman, Tuberculosis therapy: Past, present and tuberculosis in Botswana, Clinical Infectious Diseases 41 future, Eur Respir J Suppl 20 (2001) 87s-94s. [5] Marc Weiner, William Burman, Andrew Vernon, Debra [17] P. Gurumurthy et al., Decreased bioavailability of Benator, Charles A. Peloquin, Awal Khan, Stephen Weis, rifampin and other antituberculosis drugs in patients with Barbara King, Nina Shah, Thomas Hodge, and the advanced human immunodeficiency virus disease, Tuberculosis Trials Consortium, Low isoniazid Antimicrobial Agents and Chemotherapy 48 (11) (2004) concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine, Am J Respir Crit [18] D. C. Perlman et al., The clinical pharmacokinetics of Rifampin and ethambutol in HIV infected persons with [6] S. Chideya, C. A. Winston, C. A. Peloquin, W. Z. tuberculosis, Clinical Infectious Diseases 41 (2005) Bradford, P. C. Hopewell, C. D. Wells, A. L. Reingold, T. A. Kenyon, T. L. Moeti and J. W. Tappero, Isoniazid, [19] C. A. Peloquin, G. S. Jaresko, C. L. Yong, A. C. Keung, A. rifampin, ethambutal, and pyrazinamide pharmacokinetics E. Bulpitt and R. W. Jelliffe, Population pharmacokinetic and treatment outcomes among a predominantly modeling of isoniazid, rifampin and pyrazinamide, Antimicrob Ag Chemother 41 (1997) 2670–2679.



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