Pharmacokinetics of Prothionamide in Patients with Multidrug-Resistant Tuberculosis

Pharmacokinetics of prothionamide in patients with multidrug-resistant tuberculosis

H. W. Lee,*† D. W. Kim,*† J. H. Park,‡ S-D. Kim,* M-S. Lim,*† P. B. Phapale,*† E-H. Kim,* S. K. Park,‡ Y-R. Yoon*† * Clinical Trial Centre, Kyungpook National University Hospital, Daegu, † Department of Molecular Medicine, Kyungpook National University School of Medicine, Daegu, ‡ International Tuberculosis Research Centre and National Masan Tuberculosis Hospital, Masan, Korea

SUMMARY

SETTING: National Masan Tuberculosis Hospital, Ma- tration was determined by a validated high-performance san, South Korea. liquid chromatography assay. OBJECTIVE: To evaluate the pharmacokinetics of pro- RESULTS: After steady-state administration of PTH, the thionamide (PTH) in South Korean patients with multi- mean area under the plasma concentration-time curve drug-resistant tuberculosis (MDR-TB) and to investigate from time 0 to 12 h (AUC0–12h) was 11.0 ± 3.7 μg h/ml. whether differences in body mass index (BMI) could ex- The mean Tmax and t1/2 were respectively 3.6 h and 2.7 h. plain observed differences in PTH disposition. No signifi cant difference in PTH disposition was ob-

DESIGN: Seventeen patients participated in the study; served between groups A and B, except for ke and t1/2. all had MDR-TB and had received combination anti- CONCLUSION: In the pharmacokinetic parameter esti- tuberculosis treatment, including PTH, cycloserine, ofl ox- mates for PTH in MDR-TB patients during routine treat- acin, para-aminosalicylic acid and streptomycin or ka- ment, the pharmacokinetics of PTH did not appear to cor- namycin, for at least 2 weeks. The patients were divided relate with extent of emaciation in MDR-TB patients. into two groups based on BMI: Group A (18.5 ⩽ KEY WORDS: prothionamide; MDR-TB; pharmaco- BMI < 23), and Group B (BMI < 18.5). Serum samples kinetics were collected over 24 h, and the plasma PTH concen-

RESISTANCE to anti-tuberculosis drugs is a global early in the course of treatment could therefore be a problem.1 Although the prevalence of multidrug- useful tool for providing objective information re- r esistant tuberculosis (MDR-TB, defi ned as resistance garding poor drug absorption and the need for dose to at least isoniazid and rifampicin) among old cases adjustment.5 in South Korea decreased from 27.5% in 1994 to PTH, a thioamide, has been used for more than 14.0% in 2004, a gradual and signifi cant increase 30 years in the treatment of patients with drug-resistant among new cases was noted from results of surveys TB.6 Although the pharmacokinetics of PTH have conducted in 1994, 1999 and 2003 (1.6%, 2.2% and been evaluated in healthy subjects,7,8 few reports have 2.4%, respectively).2 addressed the pharmacokinetics of PTH in patients Standardised MDR-TB regimens in Korea fol- with MDR-TB.6,9 These pharmacokinetics may differ lowing the failure of short-course chemotherapy from those in healthy subjects, as malabsorption of consist of second-line anti-tuberculosis drugs prothi- antimycobacterials has frequently been reported in onamide (PTH, 2-propylthioisonicotinamide), para- patients with Mycobacterium tuberculosis.10 Further- amino salicylic acid (PAS), ofl oxacin (OFX), cyclo- more, it was reported that the pharmacokinetics of serine (CYC) and streptomycin (SM) or kanamycin OFX in chronically debilitated MDR-TB patients (KM).3 Second-line treatment takes a minimum of were affected by the extent of malnutrition, as re- 18 months, compared with 6–9 months for fi rst-line fl ected in the body mass index (BMI).11 Accordingly, INH- and RMP-containing regimens.3,4 Poor out- the possibility that BMI affects the pharmacokinetics come of MDR-TB treatment in Korea is likely to be of PTH merits examination. associated with high levels of resistance to second- In this study, we sought to evaluate the pharmaco- line drugs.3 Therapeutic drug monitoring (TDM) kinetic disposition of PTH in patients with MDR-TB

Correspondence to: Young-Ran Yoon, Department of Molecular Medicine and Clinical Trial Center, Kyungpook National University School of Medicine and Hospital, 200 Dongduk-Ro, Jung-gu, Daegu 700-721, Korea. Tel: (+82) 53 420 4950; Fax: (+82) 53 422 4950; e-mail: [email protected] Article submitted 28 July 2008. Final version accepted 20 May 2009. 1162 The International Journal of Tuberculosis and Lung Disease and to investigate whether the patient’s BMI infl u- Blood sampling and analysis of prothionamide enced this disposition. concentration To determine the steady-state pharmacokinetic pa- STUDY POPULATION AND METHODS rameters, 6 ml of blood was taken via an indwelling catheter inserted into an arm vein immediately before Patient selection and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 h Seventeen patients diagnosed with MDR-TB partici- after the ingestion of PTH. The blood samples were pated in the study. All were recruited from the Na- collected into heparinised vacuum tubes (Vacutainer, tional Masan Tuberculosis Hospital, a government- Becton Dickinson, Sparks, MD, USA) and centrifuged funded, 430-bed tertiary referral hospital specialising at 3000 rpm for 10 min. The plasma was harvested in TB in Masan, Korea. into labelled 2-ml microcentrifuge tubes and stored Before entry, the patients received written and oral at −70°C until analysis. information on the study and signed a consent docu- The PTH concentration in the plasma samples was ment approved by the institutional review board of assayed by high-performance liquid chromatography the National Masan Tuberculosis Hospital. using ultraviolet detection, with minor modifi cations Medical histories were obtained and physical ex- of a previously used method.14 Drug-free plasma was aminations were performed for each patient as part spiked with stock solutions of PTH to achieve fi nal of routine care. The serum chemistry (urea, creati- concentrations of 0.2, 0.5, 1, 3, 8 and 10 μg/ml. Plasma nine, total bilirubin, protein, albumin, alanine amino- standards (1000 μl) were mixed with 20 μl ETH transferase [ALT], aspartate aminotransferase [AST] (100 μg/ml) as the internal standard. After the addi- and alkaline phosphatase), complete blood cell count tion of 180 μl of 30% trichloroacetic acid, the mixture (haemoglobin, red cell count, white cell count, mean was immediately mixed by vortexing for 5 min and corpuscular volume and haematocrit), urinalysis and then centrifuged at 8000 rpm for 10 min. The super- electrocardiogram were obtained for all patients. Any natant was fi ltered through a 0.22-μm fi lter; 400 μl signifi cant cardiovascular, hepatic or renal disorders, of the supernatant and 90 μl of 1 M sodium bi- documented by history or physical or laboratory ex- carbonate were vortexed for 20 min and centrifuged aminations, were cause for exclusion (haemoglobin for 5 min at 8000 rpm at 4°C. Aliquots of 50 μl were < 11.5 g/dl; AST and ALT more than twice the upper separated on a Kromasil C4 column (5 μm, 150 × limit; serum bilirubin >1.5 mg/dl; serum creatinine 4.6 mm i.d.; Agilent, Chandler, AZ, USA) at 27°C. above the upper limit). Additional exclusion criteria The mobile phase consisted of water:acetonitrile at included pregnancy, a history of alcoholism in the 77:23 (vol/vol), and was delivered at a fl ow rate of last 6 months, or concomitant use of any drug known 1.0 ml/min. Absorbance was detected at 291 nm. to affect the pharmacokinetic responses of PTH, OFX There were no peaks interfering with PTH and ETH or CYC (for example, H2-receptor antagonists, anti- at their retention times (11.2 min and 6.4 min, re- histamines, antihypertensive regimens, diuretics, sed- spectively) in the human plasma blank. The lower atives or ethionamide [ETH]). limit of quantifi cation was 0.2 μg/ml, and the coeffi - The patients were divided into two groups based on cients of determination (r2) of the calibration curves their BMI: Group A (18.5 ⩽ BMI < 23) and Group B (range, 0.2–10 μg/ml) were all >0.99. (BMI < 18.5).12,13 As part of their treatment, all patients had received multiple oral doses of 375 mg or Pharmacokinetic analysis 250 mg PTH twice daily for at least 2 weeks, based Plasma PTH concentration was analysed by a non- on the clinical judgment of the attending physicians, compartmental model using WinNonlin® software according to body weight and nutritional status. The version 5.2 (Pharsight, Mountain View, CA, USA). patients had also received other concurrent anti- The maximum plasma concentration (Cmax) and time t uberculosis drugs (CYC, OFX, PAS, and SM or KM) to reach Cmax (Tmax) were estimated directly from the for at least 2 weeks, as determined by their physicians, observed plasma concentration vs. time data curve. based on in vitro susceptibility data. All the medica- The terminal elimination rate constant (ke) was de- tions were routinely administered at 08:00 and 20:00 termined by the log-linear regression slope of the fi - until the day prior to blood sampling for the pharmaco- nal data points (at least three). The apparent elimina- kinetic analysis. tion half-life (t1/2) of PTH was calculated as 0.693/ke. On the day of blood sampling, all anti-tuberculosis The area under the plasma concentration-time curve drugs were routinely administered at 08:00. At 20:00, from time 0 to 12 h (AUC0–12h) was calculated using however, all medications except PTH were adminis- the linear trapezoidal method. tered (i.e., the evening dose of PTH was omitted on the day of blood sampling). Although all patients Statistical analysis completed breakfast before 07:30, the timing of din- The data are reported as mean ± standard devia- ner was not controlled on the day of blood sampling. tion (SD), and the percentage coeffi cient of variation Alcohol and products containing nicotine were pro- (CV, %) was calculated as SD/mean × 100. Differ- hibited during the study period. ences in pharmacokinetic variables between Groups Pharmacokinetics of PTH in MDR-TB patients 1163

Table 1 Demographic characteristics and laboratory ﬁ ndings of 17 patients with multidrug-resistant tuberculosis*

All patients Group A† Group B‡ (N = 17) (n = 11) (n = 6) mean ± SD (range) mean ± SD (range) mean ± SD (range) Age, years 38.0 ± 8.8 (23–53) 37.4 ± 10.2 (23–53) 39.2 ± 6.2 (29–45) BMI 19.3 ± 2.2 (14.2–22.6) 20.5 ± 1.4 (18.7–22.6) 17.0 ± 1.5 (14.2–18.4)§ Sex, male/female 16/1 10/1 6/0 Weight, kg 57.5 ± 7.8 (40.0–67.0) 61.2 ± 5.9 (46.0–67.0) 50.7 ± 6.5 (40.0–57.1)§ Protein, mg/dl 6.8 ± 0.7 6.5 ± 0.8 7.2 ± 0.4 AST, U/ml 21.6 ± 7.6 22.9 ± 8.7 19.2 ± 4.5 ALT, U/ml 10.2 ± 6.3 10.7 ± 7.3 9.2 ± 4.6 BUN, mg/dl 13.2 ± 3.4 12.4 ± 3.5 14.8 ± 2.6 SCr, mg/dl 1.0 ± 0.1 1.0 ± 0.1 1.0 ± 0.1

* There were no statistical differences between groups, except for BMI and body weight. † Group A: 18.5 ⩽ BMI < 23. ‡ Group B: BMI < 18.5. § P < 0.05. SD = standard deviation; BMI = body mass index; AST = aspartate aminotransferase; ALT = alanine aminotransferase; BUN = blood urea nitrogen; SCr = serum creatinine.

A and B were determined using unpaired t-test and Pharmacokinetic parameters of prothionamide Mann-Whitney U-test. All statistical tests were per- The plasma PTH concentration-time profi les for the formed with the standard SPSS package (version 12.0 17 patients grouped by BMI are shown in the Figure. for Windows, SPSS, College Station, TX, USA). A The PTH pharmacokinetic parameters of patients P value <0.05 was deemed statistically signifi cant. grouped by BMI after steady-state administration are summarised in Table 2. The mean Cmax was ± μ ± RESULTS 2.2 1.1 g/ml; the mean Tmax was 3.6 1.3 h after steady-state administration; the t1/2 ranged from 1.5 to Patients 3.8 h, and the mean AUC0–12h was 11.0 ± 3.7 μg h/ml. Seventeen patients (16 males, 1 female) between the The mean plasma PTH concentration is highest at 4 h ages of 23 and 53 years (mean ± SD 38.0 ± 8.8) (1.9 ± 0.7 μg/ml). completed the study. Their average body weight was With regard to the effect of the differences in the 57.5 ± 7.8 kg. Their demographic characteristics and BMI on PTH disposition, Cmax, Tmax, AUC0–12h, appar- laboratory fi ndings are described in Table 1. When ent volume of distribution at steady state (Vdss/F) and divided into two groups based on BMI, Groups A apparent oral clearance (Cl/F) values showed no sig- and B comprised respectively 11 and 6 MDR-TB pa- nifi cant differences between the two groups. In Group tients. No serious adverse events associated with PTH A, ke values were found to be signifi cantly lower than were reported during the study period. those of Group B (P = 0.02). According to the secondary analyses of the effects of age and dose (mg/kg) on the pharmacokinetics, no age effects or dose-dependent differences were observed.

DISCUSSION The thioamide drugs PTH and ETH are clinically ef- fective in the treatment of some mycobacterial in- fections, including those caused by M. tuberculosis, M. leprae and M. avium.14 They are bacteriocidal and are frequently prescribed as second-line drugs, espe- cially in patients with MDR-TB.3,15,16 PTH and ETH have been reported to show similar pharmacokinetic properties, with the half-life and plasma concentration being lower for PTH than for ETH.7,17 Although the two thioamide drugs are used interchangeably, PTH appears to be better tolerated than ETH.8,15,18 Figure Mean steady-state plasma PTH concentration-time Furthermore, PTH has been reported to have supe- curves after multiple oral administration of PTH 250 mg or 375 mg twice daily, in two different groups. Group A: 18.5 ⩽ rior activity against M. leprae on the basis of total BMI < 23, Group B: BMI < 18.5. Vertical bars indicate standard percentage of biopsies harbouring viable M. leprae deviations. PTH = prothionamide; BMI = body mass index. and the loss of M. leprae viability.19 ETH and PTH 1164 The International Journal of Tuberculosis and Lung Disease

Table 2 Comparison of pharmacokinetic parameters of prothionamide after multiple oral administration of prothionamide among subjects, grouped by BMI

Group A* Group B† All patients Pharmacokinetic (n = 11) (n = 6) (N = 17) CV% parameters mean ± SD mean ± SD mean ± SD (n =17)

Cmax, μg/ml 2.5 ± 1.3 1.8 ± 0.6 2.2 ± 1.1 48.5 Tmax, h 3.4 ± 1.4 3.9 ± 1.2 3.6 ± 1.3 36.9 AUC0–12h, μg h/ml 11.3 ± 3.9 10.4 ± 3.4 11.0 ± 3.7 33.3 Dose of prothionamide administered, mg/kg (range) 5.9 ± 0.3 (5.4–6.6) 6.5 ± 0.7 (5.3–7.5) 6.2 ± 0.6 (5.3–7.5) AUC0–12h/(dose/kg), μg h/ml/(6 mg/kg) 11.4 ± 3.7 9.7 ± 4.1 10.8 ± 3.8 35.1 ke, /h 0.2 ± 0.1 0.3 ± 0.1‡ 0.3 ± 0.1 33.4 ‡ t1/2, h 3.0 ± 0.7 2.2 ± 0.5 2.7 ± 0.7 26.4 Vdss/F, l/kg 2.6 ± 1.4 2.3 ± 1.1 2.5 ± 1.3 50.7 Cl/F, l/h/kg 0.6 ± 0.2 0.7 ± 0.2 0.6 ± 0.2 36.7

* Group A: 18.5 ⩽ BMI < 23. † Group B: BMI < 18.5. BMI = body mass index; CV = coefﬁ cient of variation; Cmax = maximum plasma concentration; Tmax = time to reach Cmax; AUC0–12h = area under the plasma concentration-time curve from time 0 to 12h; AUC0–12h /(dose/kg) = AUC0–12h normalised to dose/kg (6 mg/kg); ke = terminal elimination rate constant; t1/2 = elimination half-life; Vdss /F = apparent volume of distribution at steady state; Cl/F = apparent oral clearance. ‡ P < 0.05, compared between the two groups by unpaired t-test and Mann-Whitney U-test. are usually given as 500–750 mg per day as a single hibitory concentration (MIC) (0.6 μg/ml) for 5–12 h 3,20,21 22 dose or in two separate doses. each day. The target range of Cmax is 1–5 μg/ml after According to studies by Zhu et al., the pharmaco- the administration of 250–500 mg of ETH.5,24 In the kinetic parameters of ETH are different in TB pa- present study, the PTH plasma concentrations were tients and healthy volunteers.22,23 A plausible expla- kept above the MIC of 0.5 μg/ml for approximately nation for the lower AUC and the higher Cl/F and 16 h by a regimen of 250–375 mg twice daily.15,18 Vdss/F observed in TB patients is decreased bioavail- The impact of the extent of emaciation on the ability.22,23 According to studies by Jenner et al., peak pharmacokinetic properties of PTH in MDR-TB pa- plasma concentration occurred at 0.5–2 h, and t1/2 tients was also investigated. In the present study, no values ranged from 1.2 to 2.0 h after a single-dose statistically signifi cant differences were observed in administration of 125–500 mg PTH in healthy vol- the pharmacokinetic parameters between Group A 6–8 unteers, while the AUC0–6 was reported to be and Group B, except in ke and t1/2. The estimated ke 870 μg min/ml after a single oral dose of 500 mg of PTH was signifi cantly greater (0.3 ± 0.1 /h) in PTH in a healthy volunteer.6 To date, the pharmaco- Group B than in Group A (0.2 ± 0.1 /h). Plausible kinetic characteristics of PTH in TB patients have explanations for this result may be the combined ef- not been evaluated extensively.6,9 In the present study, fects of decreased Vdss/F and increased Cl/F in Group the mean Tmax and t1/2 were respectively 3.6 ± 1.3 h B, although the values are not signifi cantly different and 2.7 ± 0.7 h after multiple-dose administration between the two groups. of PTH, and steady-state values for AUC0–12h ranged One patient in the BMI <18.5 group showed in- from 5.9 to 18.1 μg h/ml (11.0 ± 3.7 μg h/ml). The creased Tmax (6.0 h) after receiving 6.3 mg/kg of PTH, mean trough concentration at 12 h in all patients was compared with 3.6 h in all patients. The mean peak 0.2 ± 0.2 μg/ml (0.2 ± 0.2 and 0.2 ± 0.1 μg/ml in plasma concentration and AUC0–12h, normalised to Groups A and B, respectively). dose/kg (6 mg/kg), were decreased to respectively Insuffi cient data are available to make a reason- 0.9 μg/ml and 5.7 μg h/ml in the patient. One possi- able historical comparison of PTH pharmacokinetics ble explanation for the increased Tmax and decreased between MDR-TB patients and healthy controls. The AUC0–12h and peak plasma concentration identifi ed limitations of the data include the small number of in the extremely emaciated patient in Group B may control patients, regimen differences (single dose of be malabsorption. However, no clinical history, co- 125–500 mg vs. multiple doses of 250–375 mg), and morbid conditions, other medications or risk factors the different ethnic backgrounds. From the present for malabsorption were found. study, new steady-state pharmacokinetic data were There are several differences in the treatment of obtained with a twice-daily, usual-dose PTH regimen, patients with MDR-TB compared with those with adding to the knowledge of normal ranges in MDR- drug-susceptible TB: more frequent use of second-line TB patients receiving PTH-containing regimens. anti-tuberculosis drugs, with less effectiveness and In the case of ETH, the administration of a 500 mg greater toxicity, a more narrow therapeutic range and dose appears to be the minimum required to achieve a longer duration of treatment.22,23 Although TDM a serum concentration above the typical minimal in- has not been used routinely in the management of Pharmacokinetics of PTH in MDR-TB patients 1165 drug-susceptible TB, which shows a dose-response 9 Yew W W, Cheung S W, Chau C H, et al. Serum pharmaco- relationship, it is recommended as a useful tool in the kinetics of antimycobacterial drugs in patients with multidrug- resistant tuberculosis during therapy [abstract]. Int J Clin management of MDR-TB with second-line drugs.25,26 Pharmacol Res 1999; 19: 65–71. In the present study, the CVs for Vdss/F/kg, and Cmax 10 Peloquin C A, MacPhee A A, Berning S E. Malabsorption of were respectively 50.7% and 48.5%. The wide range antimycobacterial medications. N Eng J Med 1993; 329: 1122– of these important pharmacokinetic parameters sug- 1123. gests the importance of TDM for optimising thera- 11 Park S K, Yoon Y R, Lee W C, et al. Pharmacokinetics of peutic benefi ts. ofl oxacin in patients with multidrug-resistant tuberculosis. Tuberc Respir Dis (Korea) 2002; 52: 128–136. In conclusion, we have shown the pharmaco- 12 World Health Organization. Obesity: preventing and manag- kinetic parameter estimates for PTH in MDR-TB pa- ing the global epidemic. Report of a WHO consultation. WHO tients during routine treatment. The pharmacokinetic Technical Report Series No. 894. Geneva, Switzerland: WHO, parameters derived from this study may be useful for 2000. TDM. Although the extent of emaciation did not seem 13 James W P T, Chunming C, Inuoe S. Appropriate Asian body mass indices? Obes Rev 2002; 3: 139. to infl uence the pharmacokinetics of PTH in chroni- 14 Bartels H, Bartels R. Simple, rapid and sensitive determination cally debilitated MDR-TB patients, further study is of prothionamide in human serum by high-performance liquid needed to confi rm this observation. chromatography. Chromatogr B Biomed Sci Appl 1998; 707: 338–341. Acknowledgements 15 Wang F, Langley R, Gulcin G, et al. Mechanism of thioamide This study was supported by the International Tuberculosis Re- drug action against tuberculosis and leprosy. J Exp Med 2007; search Centre (ITRC, core-2006-002), a grant from the Korea 204: 73–78. Health 21 R&D Project, Ministry of Health & Welfare, Republic 16 Goble M, Iseman M D, Madsen L A, Waite D, Ackerson L, of Korea (A050584) and by the Brain Korea 21 Project. Horsburgh C R. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med References 1993; 328: 527–532. 17 Venkatesan K. Clinical pharmacokinetic considerations in the 1 World Health Organization. Anti-tuberculosis drug resistance treatment of patients with leprosy. Clin Pharmacokinet 1989; in the world: the WHO/International Union Against Tubercu- 16: 365–386. losis and Lung Disease Global Project on Anti-tuberculosis 18 Handbook of anti-tuberculosis agents. Prothionamide. Tuber- Drug Resistance Surveillance 2002–2007: fourth global re- culosis (Edinb) 2008; 88: 139–140. port. WHO/HTM/TB/2008.394. Geneva, Switzerland: WHO, 19 Fajardo T T, Guinto R S, Cellona R V, Abalos R M, Dela Cruz 2008. E C, Gelber R H. A clinical trial of ethionamide and prothiona- 2 Bai G H, Park Y K, Choo Y W, et al. Trend of anti-tuberculosis mide for treatment of lepromatous leprosy. Am J Trop Med drug resistance in Korea, 1994–2004. Int J Tuberc Lung Dis Hyg 2006; 74: 457–461. 2007; 11: 571–576. 20 Blumberg H M, Burman W J, Chaisson R E, et al. American 3 Park S K, Lee W C, Lee D H, Mitnick C D, Han L, Seung K J. Thoracic Society/Centers for Disease Control and Prevention/ Self-administered, standardized regimens for multidrug-resistant Infectious Society of America: treatment of tuberculosis. Am J tuberculosis in South Korea. Int J Tuberc Lung Dis 2004; 8: Respir Crit Care Med 2003; 167: 603–662. 361–368. 21 Rieder H L. Interventions for tuberculosis control and elimina- 4 Ollé-Goig J E, Sandy R. Outcomes of individualized treatment tion. Paris, France: International Union Against Tuberculosis for multidrug-resistant tuberculosis before DOTS-Plus. Int J and Lung Disease, 2002: p 161. Tuberc Lung Dis 2005; 9: 765–770. 22 Zhu M, Namdar R, Stambaugh J J, et al. Population pharma- 5 Peloquin C A. Therapeutic drug monitoring in the treatment of cokinetics of ethionamide in patients with tuberculosis. Tuber- tuberculosis. Drugs 2002; 62: 2169–2183. culosis 2002; 82: 91–96. 6 Jenner P J, Smith S E. Plasma levels of ethionamide and pro- 23 Handbook of anti-tuberculosis agents. Ethionamide. Tubercu- thionamide in a volunteer following intravenous and oral dos- losis (Edinb) 2008; 88: 106–108. ages. Lepr Rev 1987; 58: 31–37. 24 Iseman M D. Treatment of multidrug-resistant tuberculosis. N 7 Jenner P J, Ellard G A. High performance liquid chromato- Engl J Med 1993; 329: 784–791. graphic determination of ethionamide and prothionamide in 25 Li J, Burzynski J N, Lee Y A, et al. Use of therapeutic drug body fl uids. J Chromatogr 1981; 225: 245–251. monitoring for multidrug-resistant tuberculosis patients. Chest 8 Jenner P J, Ellard G A, Gruer P J K, Aber V R. A comparison of 2004; 126: 1770–1776. the blood levels and urinary excretion of ethionamide and pro- 26 Centers for Disease Control and Prevention. Treatment of tu- thionamide in man. J Antimicrob Chemother 1984; 13: 267– berculosis: American Thoracic Society, CDC, and Infectious 277. Diseases Society of America. MMWR 2003; 52: 44.

RÉSUMÉ

CONTEXTE : Hôpital National de Tuberculose de Masan, SCHÉMA : Au total, 17 patients ont participé à l’étude. Masan, Corée du Sud. Tous souffraient de MDR-TB et avaient reçu un traite- OBJECTIF : Evaluer chez les patients sud-coréens atteints ment antimycobactérien combiné comportant le PTH, de tuberculose à germes multirésistants (TB-MDR) la la cyclosérine, l’ofl oxaxine, l’acide para-aminosalicylique pharmacocinétique du prothionamide (PTH) et investi- et la streptomycine ou la kanamycine depuis au moins guer dans quelle mesure des différences de masse corpo- 2 semaines. Les patients ont été divisés en deux groupes relle (BMI) pourraient expliquer les différences obser- en fonction de leur BMI : le groupe A (18,5 ⩽ BMI < 23) vées dans le métabolisme du PTH. et le groupe B (BMI < 18,5). Les échantillons sériques 1166 The International Journal of Tuberculosis and Lung Disease

ont été prélevés sur 24 heures et la concentration plas- CONCLUSION : Cette étude a évalué les estimations des matique de PTH a été déterminée par une technique paramètres pharmacocinétiques du PTH chez les pa- validée de HPLC. tients souffrant de TB-MDR au cours d’un traitement RÉSULTATS : Après une administration de PTH jusqu’au de routine. La pharmacocinétique du PTH ne semble steady-state, l’aire sous la courbe moyenne (AUC0–12h) a pas en corrélation avec la gravité de l’amaigrissement été de 11,0 ± 3,7 μg h/ml. La Tmax moyenne et la t½ ont chez les patients atteints de TB-MDR. été respectivement à 3,6 h et à 2,7 h. On n’a observé aucune différence dans le métabolisme du PTH dans les groupes A et B sauf pour le ke et le t½.

RESUMEN

MARCO DE REFERENCIA : El National Masan Tubercu- concentración de PTH mediante una técnica homolo- losis Hospital, en Masan, Corea del Sur. gada de cromatografía líquida de alta efi ciencia. OBJETIVO : Evaluar las características farmacocinéticas RESULTADOS : Una vez alcanzado el estado de equili- de la protionamida (PTH) en pacientes de Corea del Sur brio tras la administración de PTH, el área bajo la curva con tuberculosis multidrogorresistente (TB-MDR) e in- (AUC0–12h) fue 11,0 ± 3,7 μg h/ml. La media del tiempo vestigar si las diferencias en el índice de masa corporal hasta alcanzar la concentración máxima fue 3,6 y la (BMI) pueden explicar la variación de la disponibilidad vida media fue de 2,7 horas. No se observó una diferen- de PTH. cia signifi cativa en la disponibilidad de la PTH entre los MÉTODOS : Participaron en el estudio 17 pacientes con grupos A y B, con excepción de la constante de la tasa TB-MDR que habían recibido un tratamiento anti- de eliminación y la vida media. tuberculoso combinado con PTH, cicloserina, ofl oxacino, CONCLUSIÓN : En el presente estudio se evaluaron los ácido paraminosalicílico y estreptomicina o kanamicina, parámetros farmacocinéticos de la PTH en pacientes como mínimo durante 2 semanas. Los pacientes se divi- con TB-MDR, durante un tratamiento sistemático. Estas dieron en dos grupos en función del BMI : en el grupo A características no exhibieron ninguna correlación con el 18,5 ⩽ BMI < 23 y el grupo B BMI < 18,5. Se recogie- grado de caquexia de los pacientes con TB-MDR. ron muestras séricas durante 24 horas y se determinó la