INT J TUBERC LUNG DIS 19(11):1383–1387 Q 2015 The Union http://dx.doi.org/10.5588/ijtld.14.0935

Rifampicin-moxifloxacin interaction in treatment: a real-life study

K. Manika,* K. Chatzika,* M. Papaioannou,† P. Kontou,† A. Boutou,* K. Zarogoulidis,* I. Kioumis* *Respiratory Infections Unit, Pulmonary Department, Aristotle University of Thessaloniki, Thessaloniki, †A’ Intensive Care Unit, G Papanikolaou Hospital, Thessaloniki, Greece

SUMMARY

SETTING: (RMP) has been reported to reduce body mass index, days of MFX treatment or MFX dose/ moxifloxacin (MFX) levels, which may interfere with the kg. Neither the peak concentration (Cmax) nor the 24 h effectiveness of MFX in treating tuberculosis (TB). area under the curve (AUC24) differed significantly OBJECTIVE: To study the MFX-RMP interaction in between the two groups (Group 1, Cmax median 3.9 patients receiving MFX with or without RMP as part of [range 1.9–4.5] mg/l; AUC24 29.1 [10–47.4] mgh/l and their anti-tuberculosis treatment regimen. Group 2, Cmax 4.1 [2–6.4] mg/l; AUC24 36.5 [14.6– DESIGN: Patients with pulmonary TB followed up by 54.2] mgh/l). the Tuberculosis Out-patient Clinic of the Pulmonary CONCLUSION: Although a decrease in MFX exposure Department, Aristotle University of Thessaloniki, was observed in the RMP-treated group, the effect was Greece, who underwent treatment with MFX during lower than previously reported in a real-life setting. The the periods 1 May 2012–30 April 2014 and 1 January– large variability observed in MFX in 31 March 2015, were included in the study. MFX levels both groups may suggest the need for dose readjustment were compared between 12 patients who were receiving in some patients, regardless of RMP co-administration. RMP (Group 1) and 10 who were not (Group 2). KEY WORDS: MFX pharmacokinetics; MFX dose; RESULTS: The participants did not significantly differ in resistant TB

MOXIFLOXACIN (MFX) HAS EMERGED as an concentration is generally accepted as the best important drug in the treatment of tuberculosis (TB) parameter for predicting not only the in vivo efficacy due to its bactericidal and sterilising capacity and of MFX, but also the probability of emergence of favourable safety profile.1,2 Official guidelines recom- resistance.1,9,10 However, as by definition treatment mend the use of MFX for the treatment of drug- of TB requires a combination of drugs, the interaction resistant TB and in case of intolerance to first-line of MFX with other first- and second-line anti- agents.3–5 However, the role of MFX as part of the tuberculosis drugs is of exceptional significance. first-line regimen is currently under debate.6 Arecent The clinically most relevant interaction is that of meta-analysis concluded that the addition or substitu- MFX and rifampicin (RMP).11–13 More specifically, tion of quinolones for (INH) or the co-administration of these two components has in the first-line regimen is not associated with been reported to result in a 30% reduction in the 11–13 increased culture conversion at 8 weeks of treatment MFX AUC24 in several studies. It is noteworthy or a reduction in the rates of relapse or death.7 that these studies were performed either in healthy Furthermore, according to a large double-blind volunteers or in patients at the end of their first-line placebo-controlled trial, the non-inferiority of MFX- regimen. However, given the complexity of routine containing regimens could not be shown, as 4-month MFX-containing anti-tuberculosis regimens and the 2 regimens including MFX resulted in higher rates of large variability of MFX AUC24, an important failure or relapse than the standard first-line regimen.8 clinical question has been raised as to the impact of Regardless of its role in the treatment of uncom- this interaction in a real-life setting. plicated drug-susceptible cases, it is evident that MFX As MFX is currently only recommended in is a promising and valuable drug in the treatment of ‘difficult’ TB cases, and not as part of the routine TB. As for other fluoroquinolones, the ratio of the first-line regimen, the aim of the present pharmaco- area under the plasma concentration time curve from kinetic study was to study the MFX-RMP interaction 0to24h(AUC24) to the minimal inhibitory in patients receiving MFX with or without RMP as

Correspondence to: Katerina Manika, Pulmonary Department, Aristotle University of Thessaloniki, G Papanikolaou Hospital, Exohi, Thessaloniki 57010, Greece. Tel: (þ30) 231 330 7253. Fax: (þ30) 231 035 8477. e-mail: [email protected] Article submitted 9 December 2014. Final version accepted 15 June 2015. 1384 The International Journal of Tuberculosis and Lung Disease part of their guidelines-based anti-tuberculosis regi- those weighing ,55 kg (3 patients) received 450 mg. men. For this purpose, MFX levels were compared RMP was administered 2 h before MFX. between two groups of patients with pulmonary TB (PTB), one receiving RMP and the other not. Drug estimation and pharmacokinetic analysis MFX concentration in plasma was determined using high-performance liquid chromatography with fluo- STUDY POPULATION AND METHODS rescence detection according to the method described Patients by Liang et al.,14 with modifications. Analytical Adult PTB patients who were receiving MFX as part separation was performed using the Nucleosil of their anti-tuberculosis treatment were included in 100C18 250 3 4.6 mm, 5-lm column (M-Z the study. All patients fulfilling the above inclusion Analysentechnic, Mainz, Germany), protected by a criterion who were followed up by the Out-patient guard column (20 3 4.6 mm; 5 mm) of the same Clinic for Tuberculosis, Pulmonary Department, composition. Aristotle University of Thessaloniki, Thessaloniki, The detector was set at an excitation wavelength of Greece, during the period 1 May 2012–30 April 2014 293 nm and at an emission wavelength of 500 nm. and again between 1 January and 31 March 2015 The mobile phase consisted of 10 mM sodium were asked to participate. Patients were divided into dodecyl , 25 mM citric acid, 10 mM tetrabu- two groups according to whether they were receiving tylammonium hydrogen sulfate with 43% (vol/vol) RMP (Group 1) or not (Group 2). In Group 1, acetonitrile at pH 3.5 adjusted with sodium hydrox- patients were under treatment with MFX either due ide (1 N). (CFX; Elpen Pharmaceuti- to resistance to INH (nine cases) or to empirical cals, Athens, Greece) was used as the internal expansion of the anti-tuberculosis regimen due to standard. The isocratic flow rate was 1 ml/min, the treatment failure (three cases). Group 2 patients were column temperature was set at 378C, the total run undergoing treatment with MFX due to multi- or time was 7 min, and the retention times of CFX and extensively drug-resistant TB (MDR-/XDR-TB) (n ¼ MFX were respectively 4.4 and 6.1 min. Coefficients 5), RMP intolerance (n ¼3) or resistance to RMP (n¼ of determination (r2) for MFX and CFX over the 2). In all cases, the introduction of MFX was decided standard curve concentrations of 0.05 to 10 g/l fluid based on international guidelines and before the were 0.999 for the entire study. Intra- and interday patients were recruited in the study. MFX was not coefficients of variation were 5%. The rates of administered to patients who were pregnant or recovery of MFX and CFX in plasma were greater lactating, had disturbances in heart rhythm, history than 100%. The AUC24 was calculated according to of seizures, glucose 6-phoshate-dehydrogenase defi- the trapezoidal rule. ciency or hypersensitivity to quinolones. Patients continued their medication for chronic diseases Statistical analysis during the study period, but MFX was not adminis- Data are expressed as median (range) for continuous tered to patients already receiving Class IA or Class variables or as percentages for quantitative variables. III antiarrhythmic agents or other drugs that can Biostatistical analysis was performed using Predictive cause QT interval prolongation, such as antipsychot- Analytics SoftWare (PASW) version 19.0 for Windows ics and tricyclic antidepressants. In addition, study XP (IBM SPSS, Armonk, NY, USA). Group compar- patients did not concomitantly receive non-steroid isons for continuous variables were conducted using anti-inflammatory drugs due to the increased risk of the Mann-Whitney U-test, while for quantitative convulsions. Multivalent cation-containing products variables the v2 or Fisher’s exact test were used, as and iron supplements were administered at least 6 h appropriate. P , 0.05 was considered significant. before MFX to avoid a reduction in .

Study design RESULTS This was a single-centre open-label two-arm study; it The characteristics of patients in both groups are was approved by the hospital’s ethics committee of presented in Tables 1 and 2. Two patients declined to Aristotle University of Thessaloniki, Thessaloniki, participate for practical reasons. Twelve patients (11 Greece. The participants received oral MFX (Ave- males, 1 female; age 53 years [range 29–78]; body loxw; , Leverkusen, Germany) for at least 4 days mass index [BMI] 20.1 kg/m2 [range 17.4– 25.9]) to achieve steady state, and were admitted to the were receiving MFXþRMP as part of their anti- ward 1 day before the study. On the day of the study, tuberculosis regimen (Group 1), while 10 patients (8 plasma samples were collected via a peripheral males, 2 females; age 36.5 years [range 25–61]; BMI venous catheter immediately before and 1, 1.5, 2, 3, 21.5 kg/m2 [range 17.3–29.2]) were receiving MFX 4, 6, 9, 12 and 24 h after MFX administration. but not RMP (Group 2). The participants did not Samples were stored at 208C until analysis. Group 2 significantly differ by sex, weight, BMI, days of MFX patients with weight 755 kg received 600 mg RMP; treatment or MFX dose per body weight (Table 3). MFX-RMP interaction 1385

Table 1 Characteristics of patients receiving MFX and RMP

Patient Anti-tuberculosis Age Weight BMI Type of drugs at the time of Sex years kg kg/m2 MFX days tuberculosis MFX measurement 1 Male 47 55 21.48 141 Treatment failure R, H, CS, AMK 2 Male 49 75 24.49 161 Resistance to H R, E, AMK 3 Male 35 60 19.59 169 Resistance to H R, E, AMK 4 Male 62 58 20.55 34 Treatment failure R, E, H, CS, CPM 5 Male 38 54 17.84 64 Resistance to H R, E, AMK 6 Male 78 57 22.83 14 Resistance to H R, E, Z, AMK 7 Male 75 55 17.76 178 Resistance to H R, AM, CS 8 Male 29 52 17.58 12 Resistance to H R, E, Z, AMK 9 Female 61 54 18.25 186 Resistance to H R, E, AMK 10 Male 56 56 21.08 74 Treatment failure R, H, E, Z, CPM 11 Male 50 73 25.86 83 Resistance to H R, E, Z, AMK 12 Male 74 55 17.36 26 Resistance to H R, E, Z

MFX ¼ moxifloxacin; RMP, R ¼ rifampicin; BMI ¼ body mass index; H ¼ isoniazid; CS ¼ ; AMK ¼ amikacin; E ¼ ethambutol; CPM ¼ ; Z ¼ .

Patients in Group 2 were younger than those in does not appear to significantly affect MFX levels in Group 1. The dose per body weight of RMP in Group patients with resistant TB or drug intolerance in the 1 was 9.7 6 10.2 mg/kg. MFX was well tolerated in routine setting. Although a decrease in MFX expo- all patients, and no significant adverse effects on renal sure was noted in Group 1 (AUC 29.1 vs. 36.5 mgh/ or hepatic function were observed. Gastrointestinal l), this did not reach statistical significance, and was complaints and arthralgias were the most common lower than the previously reported 30%.11–13 side effects, reported by respectively three and two Several studies have investigated MFX-RMP inter- patients, but these did not lead to discontinuation of action. RMP is the most potent known inducer of the drug. cytochrome P450 isoenzymes, but it also induces The main pharmacokinetic variables of MFX are phase II metabolic processes of glucuronidation and presented in Table 4. The mean concentration-time sulfation. Cytochrome P450 does not play a role in curves for the two groups are shown in the Figure. MFX metabolism, which entirely undergoes phase II 11,12 Although both peak concentration (Cmax) and AUC24 biotranformation. The effect of RMP on MFX were lower in Group 1 (Cmax 3.9 mg/l [range 1.9–4.5] levels appears to be mediated in part by the induction in Group 1 vs. 4.1 mg/l [2–6.4] in Group 2; P¼0.187; of the sulphate conjugation pathway of the MFX 12 AUC24 29.1 mgh/l [range 10–47.4] in Group 1 vs. metabolism. 36.5 mgh/l [14.6–54.2] in Group 2; P ¼ 0.644), these In experimental models, it seems that the combi- differences were not statistically significant. Tmax was nation of these two drugs enhances suppression of marginally shorter in Group 1 (1.3 h [range 1–2] vs. 2 resistance but also results in antagonism for cell h [range 1–3]; P ¼ 0.046). kill.15,16 In humans, MFX levels were found to be reduced by around 30% when RMP was adminis- tered in two two-period studies in healthy volun- DISCUSSION teers.12,13 These results were also confirmed by the Based on our study results, interaction with RMP study by Nijiland et al.,11 which was conducted in TB

Table 2 Characteristics of patients receiving MFX but not RMP

Patient Age Weight BMI MFX Anti-tuberculosis drugs at the Sex years kg kg/m2 days Type of TB time of MFX measurement 1 Male 37 88 29.2 124 MDR-TB Z, CPM, ETH, CS 2 Male 40 51 19.43 88 Resistance to RMP H, E, Z, CS 3 Male 26 52 17.99 154 Intolerance to RMP H, E, Z 4 Female 26 58 21.2 12 Resistance to RMP H, E, Z, AMK 5 Female 25 45 18.3 54 MDR-TB Z, AMK, ETH, LZD 6 Female 36 57 22.27 93 XDR-TB Z, CPM, PAS, CS, LZD, IMP/CLN 7 Male 61 71 24.1 84 Intolerance to RMP H, E, Z, AMK 8 Male 60 56 21.87 21 MDR-TB E, Z, AMK, PAS, ETH 9 Male 52 53 17.31 91 Intolerance to RMP H, E, Z 10 Male 28 83 27.10 83 XDR-TB Z, CPM, ETH, IMP/CLN, LNZ, CS

MFX¼moxifloxacin; RMP¼rifampicin; BMI¼body mass index; TB¼tuberculosis; MDR-TB¼multidrug-resistant TB; Z¼ pyrazinamide; CPM ¼ capreomycin; ETH ¼ ; CS ¼ cycloserine; H ¼ isoniazid; E ¼ ethambutol; AMK ¼ amikacin; LZD ¼ linezolid; IPM/CLN ¼ imipenem/cilastatin; PAS: para-aminosalycilic acid; XDR-TB ¼ extensively drug- resistant TB. 1386 The International Journal of Tuberculosis and Lung Disease

Table 3 Characteristics of patients receiving and not receiving RMP

MFXþRMP MFX, no RMP (n ¼ 12) (n ¼ 10) Characteristic median (range) median (range) P value Age, years 53 (29–78) 36.5 (25–61) 0.032 Weight, kg 55.5 (52–75) 56.5 (45–88) 0.895 Body mass index, kg/m2 20.1 (17.4–25.9) 21.5 (17.3–29.2) 0.356 Male sex, % 80 91.7 0.427 Duration of MFX treatment, days 78.5 (12–186) 86 (12–154) 0.668 MFX dosage, mg/kg 7.2 (5.3–7.7) 7.1 (4.6–8.9) 0.895

MFX ¼ moxifloxacin; RMP ¼ rifampicin. patients at the end of a treatment regimen containing three-times-weekly RMPþINH. However, in the only study evaluating the MFX-RMP interaction in the setting of a real-life anti-tuberculosis regimen, statis- tical significance was not reached, although AUC24 levels were lower in the RMP-treated groups (21.3 vs. 36.8 mgh/l).2 Our results are in agreement with those Figure Mean 6 standard deviation MFX concentration-time by Pranger et al.,2 and an even smaller arithmetical curves in A) patients receiving MFXþRMP, and in B) patients receiving MFX and not RMP. MFX ¼ moxifloxacin; RMP ¼ difference was observed, indicating that the MFX- rifampicin. RMP interaction may not be clinically relevant in the routine setting. patients at the end of treatment (i.e., when these According to international guidelines, patients patients are healthy),11 which is repeatedly higher receiving MFX as part of their anti-tuberculosis than the value observed in TB patients undergoing regimen either have drug-resistant TB or have treatment, regardless of co-administration of experienced intolerance to the first-line regimen. In RMP.2,20 It is possible that not only administration both cases, this means that MFX is administered as of other drugs but also the general status of at least part of a multidrug combination in patients with some more severely ill patients may affect MFX ‘difficult’ disease. In the present study, patients under pharmacokinetics. treatment with the MFX-RMP combination were Another interesting observation on the discrepancy also receiving another 2–4 drugs. INH is only known between our results and those previously reported11–13 to affect cytochrome P450 metabolism, and is thus is the large variability in C and AUC. AUC values not expected to alter MFX levels. However, when max of as low as 14.62 mgh/l and as high as 54.22 mgh/l compared to MFX alone, co-administration of MFX were reported, while the highest C value was 3.28 and INH resulted in a small, non-significant reduc- max tion in AUC.13 Interactions between MFX and other times the corresponding lowest one. This large first- or second-line agents cannot be excluded, variability was also observed in our previous study, 20 although they have not been clearly established in whichonlyincludedMDR-/XDR-TBpatients, and is 2 the literature. in agreement with the results by Pranger et al. These variations will clearly have a significant effect in It is noteworthy that a steady state MFX AUC24 of .40 mgh/l has been reported in several studies clinical practice, as MFX 400 mg may not be sufficient conducted 1) in healthy individuals,13,17,18 2) in TB for some patients, regardless of whether or not they are patients before the start of treatment19 or 3) in TB receiving RMP. A dose of 800 mg MFX has been previously tried in the context of a RMP-containing Table 4 Pharmacokinetic analysis of MFX in the two study regimen in TB , resulting, as expected, in a groups significant increase in AUC24 without any severe adverse effects.21,22 Cmax AUC Tmax mg/l mgh/l h The main limitation of our study is the heterogeneity Study group median (range) median (range) median (range) of the two patient groups in terms of co-administered MFXþRMP drugs. First, the patients receiving MFX but not RMP (n ¼ 12) 3.9 (1.9–4.5) 29.1 (10–47.4) 1.3 (1–2) were significantly younger than those receiving both MFX, no RMP (n ¼ 10) 4.1 (2–6.4) 36.5 (14.6–54.2) 2 (1–3) drugs. This is probably because more patients in Group P value 0.187 0.644 0.046 2 than in Group 1 were immigrants, who generally belong to younger age groups. However, as no dose MFX ¼ moxifloxacin; Cmax ¼ peak concentration; AUC ¼ area under the curve; 23 Tmax ¼ time to Cmax; RMP ¼ rifampicin. adjustment of MFX is required in the elderly, and no MFX-RMP interaction 1387 patients with moderate to severe liver impairment or 5 Lange C, Abubakar I, Alffenaar J W, et al. Management of renal impairment were included, we do not expect this patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement. Eur difference in age to have any significant effect on MFX Respir J 2014; 44: 23–63. pharmacokinetics. Second, in the non-RMP group 6 Takiff H, Guerrero E. Current prospects for the patients had more ‘difficult’ forms of TB, as indicated fluoroquinolones as first-line tuberculosis therapy. Antimicrob by the four MDR-/XDR-TB cases; they thus received a Agents Chemother 2011; 55: 5421–5429. combination of a larger number of drugs. How this 7 Ziganshina L E, Titarenko A F, Davies G R. Fluoroquinolones for treating tuberculosis (presumed drug-sensitive). Cochrane difference affected MFX pharmacokinetics is hard to Database Syst Rev 2013; 6: CD004795. estimate. Nevertheless, it is exactly these differences in 8 Gillespie S H, Crook A M, McHugh T D, et al. Four-month the routine administration of MFX that our study moxifloxacin-based regimens for drug-sensitive tuberculosis. N attempted to investigate. In addition, our sample size Engl J Med 2014; 371: 1577–1587. was relatively small. A larger number of patients would 9 Hooper D C. New uses for new and old quinolones and the challenge of resistance. Clin Infect Dis 2000; 30: 243–254. probably have had increased statistical power, and 10 Wright D H, Brown G H, Peterson M L, Rotschafer J C. allowed safer conclusions to be drawn on the Application of fluoroquinolone pharmacodynamics. J significance of the MFX-RMP interaction. However, Antimicrob Chemother 2000; 46: 669–683. as an adequate number of patients is difficult to obtain 11 Nijland H M, Ruslami R, Suroto A J, et al. Rifampicin reduces in pharmacokinetic studies, the application of the plasma concentrations of moxifloxacin in patients with tuberculosis. Clin Infect Dis 2007; 45: 1001–1007. Monte Carlo simulation may prove extremely useful. 12 Weiner M, Burman W, Luo C C, et al. Effects of rifampin and This point will be absolutely crucial in the future if multidrug resistance gene polymorphism on concentrations of MFX is officially included in first-line regimens. moxifloxacin. Antimicrob Agents Chemother 2007; 51: 2861– 2866. 13 Ramachandran G, Hemanth Kumar A K, Srinivasan R, et al. CONCLUSIONS Effect of rifampicin & isoniazid on the steady state pharmacokinetics of moxifloxacin. Indian J Med Res 2012; Although a decrease in MFX exposure was observed 136: 979–984. in the RMP-treated group, in the real-life setting the 14 Liang H, Kays M B, Sowinski K M. Separation of , effect was lower than previously reported. Our results , moxifloxacin, and by HPLC: application to levofloxacin determination in human are in accordance with the results previously reported plasma. J Chromatogr B Analyt Technol Life Sci 2002; 772: 53– by Pranger et al.,2 indicating that the MFX-RMP 63. interaction does not play an important role in TB 15 Drusano G L, Sgambati N, Eichas A, Brown D L, Kulawy R, patients. However, due to the small sample size our Louie A. The combination of rifampin plus moxifloxacin is results cannot safely rule out a significant MFX-RMP synergistic for suppression of resistance but antagonistic for cell kill of tuberculosis as determined in a hollow- interaction. Nevertheless, what seems to be clearly fiber infection model. MBio 2010; 1: pii. relevant in those patients with resistant TB or drug 16 Balasubramanian V, Solapure S, Gaonkar S, et al. Effect of intolerance who receive MFX based on international coadministration of moxifloxacin and rifampin on guidelines is the large variability in MFX pharmaco- Mycobacterium tuberculosis in a murine aerosol infection model. Antimicrob Agents Chemother 2012; 56: 3054–3057. kinetics. Based on this observation, the standard dose 17 Nightingale C H. Moxifloxacin, a new designed to of MFX may need to be readjusted in some patients, treat community-acquired respiratory tract infections: a review and this may also affect the dose of MFX included in of microbiologic and pharmacokinetic-pharmacodynamic first-line regimens if it becomes part of standard characteristics. Pharmacotherapy 2000; 20: 245–256. practice in the future. 18 Pea F, Pavan F, Lugatti E, et al. Pharmacokinetic and pharmacodynamic aspects of oral moxifloxacin 400 mg/day Acknowledgements in elderly patients with acute exacerbation of chronic bronchitis. Clin Pharmacokinet 2006; 45: 287–295. The authors wish to acknowledge the contribution of M Lada, E 19 Peloquin C A, Hadad D J, Molino L P, et al. Population Papadaki and M Kipourou in the collection of blood samples. pharmacokinetics of levofloxacin, gatifloxacin, and Conflicts of interest: none declared. moxifloxacin in adults with pulmonary tuberculosis. Antimicrob Agents Chemother 2008; 52: 852–857. 20 Manika K, Chatzika K, Zarogoulidis K, Kioumis I. References Moxifloxacin in multidrug-resistant tuberculosis: is there any 1 Ginsburg A S, Grosset J H, Bishai W R. Fluoroquinolones, indication for therapeutic drug monitoring? Eur Respir J 2012; tuberculosis, and resistance. Lancet Infect Dis 2003; 3: 432– 40: 1051–1053. 442. 21 Alffenaar J W, van Altena R, Bokkerink¨ H J, et al. 2 Pranger A D, van Altena R, Aarnoutse R E, et al. Evaluation of Pharmacokinetics of moxifloxacin in cerebrospinal fluid and moxifloxacin for the treatment of tuberculosis: 3 years of plasma in patients with tuberculous meningitis. Clin Infect Dis experience. Eur Respir J 2011; 38: 888–894. 2009; 49: 1080–1082. 3 American Thoracic Society/Centers for Disease Control and 22 Ruslami R, Ganiem A R, Dian S, et al. Intensified regimen Prevention/Infectious Diseases Society of America. Treatment containing rifampicin and moxifloxacin for tuberculous of tuberculosis. Am J Respir Crit Care Med 2003; 167: 603– meningitis: an open-label, randomised controlled phase 2 662. trial. Lancet Infect Dis 2013; 13: 27–35. 4 World Health Organization. Treatment of tuberculosis: 23 Balfour J A, Lamb H M. Moxifloxacin: a review of its clinical guidelines. 4th ed. WHO/HTM/TB/2009.420. Geneva, potential in the management of community-acquired Switzerland: WHO, 2010. respiratory tract infections. Drugs 2000; 59: 115–139. MFX-RMP interaction i

RESUME

CONTEXTE : Il aet´ ´ e rapport´e que la rifampicine (RMP) significativement en termes d’index de masse diminuait le taux de moxifloxacine (MFX) et ceci corporelle, de jours de traitement par MFX ou de dose pourrait interf´erer avec l’efficacit´e de la MFX dans le de MFX/kg. Ni la concentration maximale (Cmax)nila traitement de la tuberculose (TB). surface situ´ee sous la courbe de 24 h (AUC24)ne OBJECTIF : Examiner l’interaction MFX-RMP chez des diff´eraient significativement entre les deux groupes patients recevant de la MFX avec ou sans RMP dans le (Groupe 1, Cmax m´ediane 3,9 mg/l [extrˆemes 1,9–4,5] ; cadre de leur protocole antituberculeux. AUC24 29,1 mgh/l [10–47,4] contre Groupe 2, Cmax 4,1 SCHE´ MA : Les patients ayant une TB pulmonaire, suivis mg/l [2–6,4], AUC24 36,5 mgh/l [14,6–54,2]). par le centre de consultation externe de la TB au service CONCLUSION : Bien qu’une diminution de l’exposition de pneumologie de l’universit´e Aristotea ` Thessalonique, a` la MFX aitet´ ´ e observ´ee dans le groupe trait´e par RMP, Gr`ece pour les p´eriodes allant du 1e mai 2012 au 30 avril l’effet aet´ ´ einf´erieura ` ce qui avaitet´ ´ erapport´e 2014 et du 1e janvier au 31 mars 2015 quietaient ´ sous auparavant dans un contexte de vie r´eelle. La grande traitement par MFX, ontet´ ´ e inclus dans l’´etude. Les taux variabilit´e observ´ee dans la pharmacocin´etique de la de MFX ontet´ ´ e compar´es chez 12 patients qui MFX dans les deux groupes pourrait impliquer la recevaient de la RMP (Groupe 1) et 10 patients qui n´ecessit´eder´eajuster les doses chez certains patients n’en recevaient pas (Groupe 2). sans forc´ement tenir compte de l’administration RE´ SULTATS : Les participants ne diff´eraient pas conjointe de RMP.

RESUMEN

MARCO DE REFERENCIA: Se ha descrito que la significativas en los pacientes con respecto al ´ındice de rifampicina (RMP) disminuye las concentraciones de masa corporal, los d´ıas de tratamiento con MFX o su moxifloxacino (MFX) y puede interferir con la eficacia dosis por kilogramo. Ni la concentracion ´ ma´xima del tratamiento de la tuberculosis (TB). (Cmax)niela´rea bajo la curva en 24 h (AUC24) OBJETIVO: Evaluar la interaccion ´ entre el MFX y la difirieron significativamente en ambos grupos (Grupo

RMP en los pacientes que reciben MFX asociado o no 1, Cmax mediano 3,9 mg/l [rango 1,9–4,5] ; AUC24 29,1 con RMP, como parte de su r´egimen antituberculoso. mg/h/l [10–47,4], contra Grupo 2, Cmax 4,1 mg/l [2– ME´ TODO: Participaron en el estudio pacientes con 6,4] ; AUC24 36,5 mg/h/l [14,6–54,2]. diagnostico ´ de TB pulmonar que recib´ıan tratamiento CONCLUSIO´ N: Aunque se observo ´ una disminucion ´ en con MFX, atendidos en la consulta ambulatoria de TB la concentracion ´ de MFX en el grupo que recib´ıa RMP, del Departamento de Neumolog´ıa de la Universidad el efecto fue inferior al comunicado en estudios Aristoteles ´ de Tesal´onica, en Grecia del 18 de mayo del anteriores sobre el terreno. La gran variabilidad de la 2012 al 30 de abril del 2014 y del 18 de enero al 31 de farmacocin´etica observada en ambos grupos puede marzo del 2015. Se compararon las concentraciones de indicar la necesidad de reajustar las dosis en algunos MFX de 12 pacientes que recib´ıan RMP (Grupo 1) y 10 pacientes, independientemente de la coadministracion ´ pacientes que no la recib´ıan (Grupo 2). de RMP. RESULTADOS: No se observaron diferencias