AAC Accepted Manuscript Posted Online 18 May 2015 Antimicrob. Agents Chemother. doi:10.1128/AAC.00354-15 Copyright © 2015, American Society for Microbiology. All Rights Reserved.

1

1

Pharmacokinetics of Second-line Anti-Tuberculosis Drugs after Multiple

2

Administrations in Healthy Volunteers

3 4

Sang-In Park,a Jaeseong Oh,a Kyungho Jang,a Jangsoo Yoon,a Seol Ju Moon,a Jong Sun Park,b

5

Jae Ho Lee,b Junghan Song,c In-Jin Jang,a Kyung-Sang Yu,a Jae-Yong Chung,d,#

6 7

a

8

of Medicine and Hospital, Seoul, Republic of Korea

9

b

Department of Clinical Pharmacology and Therapeutics, Seoul National University College

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul

10

National University College of Medicine, Seoul National University Bundang Hospital,

11

Gyeonggi-do, Republic of Korea

12

c

13

National University Bundang Hospital, Gyeonggi-do, Republic of Korea

14

d

15

Hospital, Gyeonggi-do, Republic of Korea.

16

Running title: Second-line Anti-Tuberculosis Drugs Pharmacokinetics

17

#

18

Department of Clinical Pharmacology and Therapeutics, Seoul National University, College

19

of Medicine and Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea

20

Phone: 82-31-787-3955

21

Fax: 82-31-787-4045

22

E-mail: [email protected]

Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul

Department of Clinical Pharmacology and Therapeutics, Seoul National University Bundang

Address correspondence to: Jae-Yong Chung, MD, PhD

2

23

Abstract

24

Therapeutic drug monitoring (TDM) of second-line anti-tuberculosis (TB) drugs

25

would allow for optimal individualized dosage adjustments and improve drug safety and

26

therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically

27

relevant, multi-drug treatment regimens and improve the viability of TDM, we conducted an

28

open-label, multiple-dosing study on 16 healthy subjects who were divided into two groups.

29

Cycloserine 250 mg, p-aminosalicylic acid (PAS) 5.28 g, prothionamide 250 mg twice daily

30

and pyrazinamide 1500 mg once daily were administered to both groups. Additionally,

31

levofloxacin 750 mg and streptomycin 1 g once daily were administered to group 1, and

32

moxifloxacin 400 mg and kanamycin 1 g once daily to group 2. Blood samples for PK

33

analysis were collected up to 24 h following the 5 days of drug administration. The PK

34

parameters, including maximum concentration (Cmax) and the area under the plasma

35

concentration-time curve (AUCτ), were evaluated. The correlation between the PK parameters

36

and the concentration at each time-point was conducted. The mean Cmax (mg/L) and AUCτ

37

(mg·h/L) of each drug were as follows: cycloserine (24.9, 242.3), PAS (65.9, 326.5),

38

prothionamide (5.3, 22.1), levofloxacin (6.6, 64.4), moxifloxacin (4.7, 54.2), streptomycin

39

(42.0, 196.7), and kanamycin (34.5, 153.5). The results indicated that sampling at 1, 2.5, and

40

6 h post-dose is needed for TDM when all seven drugs are administered concomitantly. This

41

study indicates that PK characteristics must be considered when prescribing optimal

42

treatments for patients.

43 44

Key words: multidrug-resistant, anti-tuberculosis drugs, therapeutic drug monitoring (TDM)

3

45

Introduction

46

Tuberculosis (TB) that is resistant to isoniazid and rifampicin is considered to be

47

multidrug-resistant (MDR)—regardless of whether or not it is resistant to other first-line

48

drugs. MDR TB has become a major global health concern and, according to the Global

49

Project on Anti-Tuberculosis Drug Resistance Surveillance, MDR TB accounts for more than

50

3% of new TB cases in at least one country in every one of the six World Health Organization

51

(WHO) regions (1).

52

WHO guidelines, recommend the use of at least four different drugs to treat MDR

53

TB; it is recommended that regimens include pyrazinamide along with several second-line

54

drugs—specifically, a later-generation fluoroquinolone, ethionamide or prothionamide, an

55

injectable parenteral agent (kanamycin, amikacin or capreomycin), and either cycloserine or

56

p-aminosalicylic acid (PAS) (2). However, these treatment regimens are less effective, cause

57

more frequent side effects, and have a narrower therapeutic/toxic effect ratio than first-line

58

anti-TB drugs (3). Fortunately, therapeutic drug monitoring (TDM) can be used to overcome

59

variations in patient response and improve the success of second-line therapeutics by

60

allowing individualized therapies to be designed (4).

61

When planning TDM of second-line anti-TB drugs in a clinical setting, ease-of-use

62

and availability should be considered as well as clinical and bacteriological data. For instance,

63

for anti-TB drugs such as moxifloxacin and levofloxacin, the area under the concentration

64

versus time curve from time 0 to 24 h (AUC0-24h)/minimum inhibitory concentration (MIC) is

65

one of the most important pharmacodynamic parameters along with maximum plasma

66

concentration (Cmax)/MIC (5). However, estimation of AUC requires a minimum of six to

67

seven blood samples and is therefore impractical as a routine measure (4). A more practical

68

alternative to full pharmacokinetic (PK) sampling is the use of only a few sampling time-

69

points that are strongly correlated with Cmax or AUC. Furthermore, since second-line anti-TB

4

70

drugs are administered concomitantly in most cases, the possibility of multi-drug interactions

71

should always be considered. For this reason, it would be more useful to estimate the PK

72

characteristics of second-line anti-TB drugs in the context of a therapeutically relevant

73

dosage regimen.

74 75

Objectives

76

The objective of this study is to evaluate the PK characteristics of second-line anti-

77

TB drugs in MDR TB patients with a view to applying the results to clinical practice,

78

including prescribing. In addition, to reduce the number of sampling time-points required to

79

estimate AUC or Cmax, the most reliable sampling time-points were determined.

80 81

Methods

82

Study subjects and study design

83

Healthy male volunteers who had no history of renal or hepatic impairment and who

84

passed a rigorous on-site physical examination and clinical laboratory tests, which included

85

urine screening and a 12-lead electrocardiogram, were enrolled in the study. Written informed

86

consent was obtained prior to starting the procedures described in this study. This study was

87

approved by the Institutional Review Board (B-1309/219-003) of the Seoul National

88

University Bundang Hospital located in Seongnam, Korea, and was conducted in accordance

89

with the principles of the Declaration of Helsinki and Good Clinical Practice

90

(clinicaltrials.gov registration number: NCT02128308).

91

A randomized, open-label, parallel-group, multiple-dosing study was conducted in

92

the Seoul National University Bundang Hospital Clinical Trials Centre. The patients were

93

divided into two groups so that as many second-line anti-TB drugs as possible could be

94

studied with two different dosing regimens. The two regimens were chosen to reflect

5

95

treatments that are currently used clinically. Group 1 received cycloserine, p-aminosalicylic

96

acid (PAS), and prothionamide twice daily per os (PO); pyrazinamide and levofloxacin PO

97

once daily; and streptomycin intramuscular (IM) once daily from day 1 to day 5. For group 2,

98

the same regimen was applied, except that levofloxacin and streptomycin were replaced with

99

moxifloxacin and kanamycin, respectively (Table 1).

100 101

Pharmacokinetic assessment

102

Serial blood samples were collected in heparinized tubes at 0 (i.e., pre-dose), 0.5, 1,

103

1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 h after dosing on day 5. Blood samples were centrifuged for

104

10 min at 4 ºC at approximately 1910 ×g. Then, plasma (1 mL) was aliquoted into a

105

polypropylene tube and stored at -70 ºC until PK analysis.

106

The plasma concentrations of cycloserine, PAS, prothionamide, pyrazinamide,

107

levofloxacin, moxifloxacin, streptomycin, and kanamycin were determined using ultra-

108

performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). This

109

analytical method was previously developed for the simultaneous measurement of the blood

110

concentrations of nine second-line anti-TB drugs (6). In brief, the analytes were separated on

111

a high-strength silica (HSS) T3 column (50.0 × 2.1 mm, 1.8 μm; Waters, Watford, UK) at a

112

flow rate of 200 μL/min. The mobile phases were 10 mM ammonium formate in 0.1% formic

113

acid (mobile phase A) and acetonitrile in 0.1% formic acid (mobile phase B). Separation was

114

achieved using a gradient program. Detection was performed using MS/MS. The inter-assay

115

calibration variability was evaluated using concentrations of 5.0–100 μg/mL for streptomycin,

116

kanamycin, cycloserine, and PAS; 0.5–10 μg/mL for prothionamide; and 1.0–20 μg/mL for

117

moxifloxacin and levofloxacin. The lower limits of quantification (LLOQ), defined as the

118

lowest concentration with a precision < 20% and an accuracy within ± 20% for each drug,

119

were as follows: 5.0 μg/mL for cycloserine, 5.0 μg/mL for PAS, 0.5 μg/mL for prothionamide,

6

120

1.0 μg/mL for levofloxacin, 2.5 μg/mL for streptomycin, 0.5 μg/mL for moxifloxacin, and 2.5

121

μg/mL for kanamycin.

122 123

Pharmacokinetic data analyses

124

We used the linear-up and log-down trapezoidal method to estimate the AUC during

125

a dosing interval when the concentrations reached the steady state on day 5 of the dosing

126

administration (AUCτ). The observed values were used to estimate the steady-state Cmax for

127

each drug. The apparent clearance at steady state (CL/F) was calculated as the dose divided

128

by the AUC from time 0 to infinity at steady state (AUCinf). The terminal elimination rate

129

constant (λz) was estimated from the regression line of the log-transformed plasma

130

concentrations versus time over the terminal log-linear portion. The terminal half-life at

131

steady state (t1/2) was calculated as the natural logarithm of 2 divided by λz. A non-

132

compartmental analysis using Phoenix® V1.3 (Certara, MO, USA) was used to calculate the

133

PK parameters.

134 135

Statistical analysis

136

The PK parameters of second-line anti-TB drugs were summarized using descriptive

137

statistics. Possible differences in drug exposure were determined based on the differences in

138

Cmax and AUCτ of cycloserine, PAS, and prothionamide between group 1 and group 2, and the

139

geometric mean ratio (GMR) and its 90% confidence interval (CI) for group 2 compared with

140

group 1 were estimated. Unpaired t-tests were used to compare the differences in CL/F

141

between group 1 and group 2. Analysis was performed using SAS software version 9.3 (SAS

142

Institute Inc., Cary, NC, USA). Statistical significance was confirmed if a p-value was less

143

than 0.05.

144

7

145

Selection of sampling time-points for the limited-sampling TDM strategy

146

After obtaining full PK profiles, the most reliable sampling time-point for each

147

second-line anti-TB drug was determined by correlation analyses between Cmax or AUCτ and

148

the concentrations of the drugs measured in the samples collected at each time-point after

149

dosing on day 5. This Pearson’s correlation analysis was repeated for each sampling time-

150

points from 0 to 24 h for each of the studied second-line anti-TB drugs, using R version 3.1.0

151

(R Foundation for Statistical Computing, Vienna, Austria). The optimal sampling time-points

152

were determined based on the adjusted r2 and p-value using the correlation analysis.

153 154

Results

155

Demographic characteristics

156

A total of 16 subjects were enrolled and completed the study; seven subjects for

157

group 1, and nine subjects for group 2. As the purpose of this study was to explore and

158

describe the PK characteristics of second-line anti-TB drugs, it was desirable to set the

159

minimum number of subjects based on experience from previous studies rather than on the

160

calculation required for a hypothesis study. As such, the required number of subjects for this

161

study was determined to be at least six for each dose group. The demographic characteristics

162

of the subjects are presented in Table 2. There were no significant differences in demographic

163

characteristics such as age, height, weight, and BMI between the two randomized treatment

164

groups (all p-values > 0.05, Student’s t-test).

165 166

PK analysis

167

The PK characteristics of each second-line anti-TB drug regimen after concomitant

168

administration are presented in Table 3 and were generally consistent with the previously

169

reported values for separate administration. Cmax and AUCτ were estimated after the five-day

8

170

dosings of each second-line anti-TB drug according to the regimens presented in Table 1.

171

Relatively larger inter-individual variation was observed for cycloserine, PAS, and

172

prothionamide than for the other second-line anti-TB drugs (Table 3, Figure 1). The observed

173

Cmax of cycloserine, moxifloxacin, streptomycin, and kanamycin was consistent with the

174

available literature data (Table 4). Prothionamide and levofloxacin showed similar t1/2 to the

175

reported t1/2 of each drug. The Tmax and t1/2 of streptomycin and kanamycin were consistent

176

with previously reported data and showed rapid absorption after IM injection (Table 3, Figure

177

2).

178

Sub-group analysis showed higher mean concentrations of cycloserine and

179

prothionamide in group 2 compared with group 1 (Figures 1A and 1C). The GMR was greater

180

than 1.0 (90% CI) for the Cmax and AUCτ values in group 2 compared with group 1 for

181

cycloserine and prothionamide (Table 5). For cycloserine, the mean CL/F rates of the two

182

groups were significantly different, with (p = 0.010) or without (p = 0.026) normalization for

183

body weight. For prothionamide, the CL/F rates of the two groups were significantly different

184

(p = 0.046), but the difference was not significant after normalization for body weight (p =

185

0.100). On the other hand, for PAS, although the mean concentrations were higher in group 2

186

than in group 1 until 3 h after dosing, the 90% CI of the GMR crossed 1.0, indicating no

187

significant differences between the two groups (Table 5, Figure 1B). For PAS, there was no

188

significant difference between the two groups with respect to CL/F rate with (p = 0.873) or

189

without (p = 0.925) normalization for body weight.

190 191

Sampling time-points For TDM of second-line anti-TB drugs

192

Table 6 shows the most reliable sampling time-points for each second-line anti-TB

193

drug. These represent the time-points at which the drug concentrations were found to have

194

the strongest correlation with Cmax or AUCτ. Based on the adjusted r2 and p-values, the

9

195

concentrations measured in samples collected at 2–3 h after dosing on day 5 correlated most

196

strongly with the Cmax values of cycloserine, PAS, prothionamide, and levofloxacin than

197

samples collected at other time-points. For levofloxacin, the concentrations of levofloxacin

198

sampled 2 h and 1.5 h after dosing were most strongly correlated with Cmax and AUCτ,

199

respectively. In the case of moxifloxacin, the concentration in the sample collected 6 h after

200

dosing was most strongly correlated with both Cmax and AUCτ. For streptomycin and

201

kanamycin, the concentrations in samples collected 1 h after dosing were most strongly

202

correlated with the Cmax of both drugs.

203 204

Discussion

205

This study shows that the measured PK characteristics of the tested second-line anti-

206

TB drugs after concomitant administration were consistent those reported for separate

207

administration (4, 7, 8). Correlation analysis between the PK parameters and the observed

208

concentrations at each time-point suggested that the time-points 1, 2.5, and 6 h post-dosing

209

are required for accurate limited-sampling TDM when all seven drugs are administered

210

concomitantly. To the best of our knowledge, the present study is the first clinical study to

211

evaluate the PK characteristics of second-line anti-TB drugs in the context of the commonly

212

used regimens for MDR TB with multiple doses.

213

In general, the results of this study correspond with the PK characteristics previously

214

reported for single drug administrations (4, 7, 8). However, compared to single drug

215

administration, some differences in PK characteristics were observed when concomitantly

216

administering the drugs. For example, although the observed mean Cmax for cycloserine

217

corresponded with the literature data (9), the median Tmax was 2 h later than the known range

218

of Tmax (4). For PAS, the mean Cmax in all of the subjects was ~ 28% greater than the reported

219

mean Cmax (10), which is thought to be due to the 32% larger dose used in this study;

10

220

however, the mean AUCτ was ~ 11% smaller than the reported value of AUC0-12hr after the

221

administration of 4 g twice daily (10). In the case of prothionamide, the observed mean Cmax

222

and AUCτ in all subjects was ~ 2-fold greater than the previously reported values of each

223

parameter, although the mean dose used in the previous literature was 55.3% larger than in

224

the present study (11). For levofloxacin, the mean Cmax was more than 17.5% smaller than the

225

reference Cmax (4), though for moxifloxacin, the mean Cmax was consistent with previous data

226

(4). The mean Cmax, Tmax, and t1/2 of streptomycin and kanamycin were within the previously

227

reported ranges (4, 8).

228

Several factors may have contributed to the fact that the mean concentrations of

229

cycloserine and prothionamide, and the GMRs (90% CI) of the Cmax and AUCτ of cycloserine

230

and prothionamide were higher in group 2 than in group 1 (Table 5, Figure 1). For example,

231

the estimated CL/F (oral clearance) for cycloserine in group 1 was 2-fold larger than for

232

group 2; as the elimination of cycloserine is dependent on renal clearance (8), differences in

233

the bioavailability could be a possible explanation considering both groups consisted of

234

healthy subjects without any abnormalities in renal functions. Additionally, the apparent

235

volume of distribution (Vd/F) for cycloserine was 1.6-fold larger in group 1 than in group 2.

236

Likewise, the CL/F and the Vd/F of prothionamide in group 1 were 1.5 and 1.4-fold larger

237

than those in group 2, respectively. Therefore, the difference in the bioavailability of

238

cycloserine and prothionamide was most likely caused by the different drugs in each group.

239

In the case of PAS, the mean concentrations in group 2 were higher than in group 1 until 3 h

240

after dosing, although the 90% CI of the Cmax and AUCτ suggests no significant differences

241

between the two groups. The absorption of PAS granules, which are enteric coated and

242

designed for sustained release, might have been affected by the concomitantly administered

243

drugs (8), although further studies with a larger number of subjects are needed for precise

244

comparisons.

11

245

Drug interactions among second-line anti-TB drugs are not well-known, and this

246

study was not designed to assess these interactions; nonetheless, it is possible to speculate on

247

the possibility of drug interactions based on the reported PK mechanisms of the

248

concomitantly administered second-line anti-TB drugs. The PK characteristics of

249

aminoglycosides, such as streptomycin and kanamycin, are known to be similar, and more

250

than 90% is excreted unchanged in the urine (7, 8). Therefore, it is more likely that it is the

251

PK characteristics of levofloxacin and moxifloxacin that were responsible for the observed

252

differences between the two groups. However, the reported differences between moxifloxacin

253

and levofloxacin mainly concern the mechanism of metabolism rather than the effects on the

254

absorption process or bioavailability of the other drugs. Levofloxacin is primarily excreted

255

unchanged in the urine, with < 5% metabolized in the liver (12). In contrast, moxifloxacin

256

has multiple routes of elimination, with approximately 50% undergoing glucuronide and

257

sulfate conjugation in the liver, 25% excreted unchanged in the feces, and 20–25% excreted

258

unchanged in the urine (5, 13-15). Further studies on the factors that could have affected the

259

drug interactions focusing on the absorption process or bioavailability are necessary as

260

knowledge of the mechanism of metabolism is not sufficient to explain the differences

261

observed here.

262

Finally, the effects of weight can be considered as one of the factors affecting group

263

differences. Although no statistically significant difference was observed, the mean difference

264

in body weight between the two groups was 5.4 kg (p = 0.057) (Table 2). However, even after

265

normalizing the GMRs of the Cmax and AUCτ of cycloserine and prothionamide for weight,

266

the values remained larger in group 2 than in group 1. This demonstrates that weight

267

differences are less likely to be responsible for the differences in mean concentrations among

268

the studied drugs.

269

Although further studies are needed to clarify the factors responsible for the

12

270

difference between the two groups shown in this study, the work demonstrates that the

271

possibility of inter-patient differences in absorption/elimination PK characteristics should be

272

considered when treating MDR TB patients. In addition, such differences are one of the

273

reasons that TDM should be performed to confirm the presence of PK interactions and to

274

help prevent toxicity resulting from an interaction.

275

Another objective of this study was to determine the optimal sampling time-points

276

when using limited-sampling TDM. Among the second-line anti-TB drugs studied,

277

cycloserine, PAS, and prothionamide had relatively larger inter-individual variation than the

278

other drugs (Figure 1, Table 3). This suggests there is a greater need for TDM of cycloserine,

279

PAS, and prothionamide to improve the chance of safe successful therapy. For cycloserine,

280

PAS and prothionamide, target Cmax values of serum levels have been proposed (5, 8).

281

Additionally, serious central nervous system toxicity may be associated with elevated serum

282

concentrations of cycloserine (4). The activity of aminoglycosides such as streptomycin and

283

kanamycin relies on a high Cmax-to-MIC ratio due to concentration-dependent antibiotic and

284

post-antibiotic effects (7). In contrast, based on the known PK parameters and MICs of

285

fluoroquinolones, the expected pharmacodynamic parameters of moxifloxacin and

286

levofloxacin can be derived from Cmax/MIC and AUC/MIC (5). In this respect, the sampling

287

time-points can be suggested based on the adjusted r2 and p-values as presented in Table 6.

288

When using cycloserine, PAS, and prothionamide together, the sampling time-points should

289

be set at 2–3 h after dosing in regards to Cmax. When adding aminoglycosides such as

290

streptomycin and kanamycin, an additional sampling at 1 h after dosing can be helpful to

291

predict the efficacy. Adding a 6-h sampling point after dosing is needed for TDM when using

292

moxifloxacin. A 6-h sampling time-point is also useful in distinguishing between

293

malabsorption and late absorption of the other TB agents, and in regimens including

294

moxifloxacin an additional later time point might be considered. Therefore, when

13

295

administering all seven drugs evaluated in this study, at least three sampling time-points are

296

needed: 1 h, 2.5 h, and 6 h after dosing.

297

Extrapolating the results of this study to larger MDR TB patient populations may be

298

difficult due to the small number of healthy, relatively young male subjects who participated

299

in the study. However, in conjunction with the PK characteristics described in other studies,

300

the PK profiles of the second-line anti-TB drugs described here could be used to develop

301

basic guidelines for TDM.

302 303

Conclusion

304

This study provides valuable information concerning the PK characteristics of second-line

305

anti-TB drugs in commonly used multiple dosing regimens for MDR TB. Possible drug

306

interactions were observed when co-administering fluoroquinolones with cycloserine, PAS,

307

and prothionamide, and this may warrant further study in MDR TB patients. Based on the

308

results of this study it is also possible to recommend sampling time-points for use in reduced-

309

sampling TDM of second-line anti-TB drugs. It is envisaged that when treating patients in a

310

complex clinical setting such a procedure will enable optimal adjustments of dosing regimens

311

in order to overcome problems such as slow response to treatment, toxicity, or suspicious

312

drug interactions.

313 314

Funding

315

This work was supported by a grant from the Korean Health Technology R&D Project of the

316

Ministry of Health & Welfare, Republic of Korea (HI13C0892).

317 318

Transparency declarations

14

319

The funders had no role in the study’s design, its data collection and analysis, its decision to

320

publish or in any preparation of the manuscript. None of the authors of the study have any

321

conflict of interest to disclose.

322 323

Author contributions

324

S.-I.P., J.O., K.J, K.-S.Y., J.-Y.C. wrote the manuscript; J.Y., K.J., J.S.P., J.H.L., I.-J.J., J.-Y.C.

325

designed the research; S.-I.P., J.O., S.J.M., J.S. J.-Y.C. performed the research; and S.-I.P.,

326

J.O., J.-Y.C. analyzed the data.

327

15

328

References

329

1.

Gandhi NR, Nunn P, Dheda K, Schaaf HS, Zignol M, Van Soolingen D, Jensen P,

330

Bayona J. 2010. Multidrug-resistant and extensively drug-resistant tuberculosis: a

331

threat to global control of tuberculosis. Lancet 375:1830-1843.

332

2.

Falzon D, Jaramillo E, Schunemann HJ, Arentz M, Bauer M, Bayona J, Blanc L,

333

Caminero JA, Daley CL, Duncombe C, Fitzpatrick C, Gebhard A, Getahun H,

334

Henkens M, Holtz TH, Keravec J, Keshavjee S, Khan AJ, Kulier R, Leimane V,

335

Lienhardt C, Lu C, Mariandyshev A, Migliori GB, Mirzayev F, Mitnick CD,

336

Nunn P, Nwagboniwe G, Oxlade O, Palmero D, Pavlinac P, Quelapio MI,

337

Raviglione MC, Rich ML, Royce S, Rusch-Gerdes S, Salakaia A, Sarin R, Sculier

338

D, Varaine F, Vitoria M, Walson JL, Wares F, Weyer K, White RA, Zignol M.

339

2011. WHO guidelines for the programmatic management of drug-resistant

340

tuberculosis: 2011 update. Eur Respir J 38:516-528.

341

3.

Dartois V, Barry CE. 2010. Clinical pharmacology and lesion penetrating properties

342

of second- and third-line antituberculous agents used in the management of

343

multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis. Curr

344

Clin Pharmacol 5:96-114.

345

4.

346 347

Alsultan A, Peloquin CA. 2014. Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs 74:839-854.

5.

Garcia-Prats AJ, Donald PR, Hesseling AC, Schaaf HS. 2013. Second-line

348

antituberculosis drugs in children: a commissioned review for the World Health

349

Organization 19th Expert Committee on the Selection and Use of Essential Medicines.

350

World Health Organization, Geneva.

351

6.

Han M, Jun SH, Lee JH, Park KU, Song J, Song SH. 2013. Method for

16

352

simultaneous analysis of nine second-line anti-tuberculosis drugs using UPLC-

353

MS/MS. J Antimicrob Chemother 68:2066-2073.

354

7.

355 356

Douglas JG, McLeod M-J. 1999. Pharmacokinetic factors in the modern drug treatment of tuberculosis. Clinical pharmacokinetics 37:127-146.

8.

357

Peloquin CA. 2002. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 62:2169-2183.

358

9.

Anonymous. 2008. Cycloserine. Tuberculosis 88:100-101.

359

10.

Liwa AC, Schaaf HS, Rosenkranz B, Seifart HI, Diacon AH, Donald PR. 2013.

360

Para-aminosalicylic acid plasma concentrations in children in comparison with adults

361

after receiving a granular slow-release preparation. J Trop Pediatr 59:90-94.

362

11.

Lee HW, Kim DW, Park JH, Kim SD, Lim MS, Phapale PB, Kim EH, Park SK,

363

Yoon YR. 2009. Pharmacokinetics of prothionamide in patients with multidrug-

364

resistant tuberculosis. Int J Tuberc Lung Dis 13:1161-1166.

365

12.

Chien SC, Rogge MC, Gisclon LG, Curtin C, Wong F, Natarajan J, Williams RR,

366

Fowler CL, Cheung WK, Chow AT. 1997. Pharmacokinetic profile of levofloxacin

367

following once-daily 500-milligram oral or intravenous doses. Antimicrob Agents

368

Chemother 41:2256-2260.

369

13.

Tachibana M, Tanaka M, Masubuchi Y, Horie T. 2005. Acyl glucuronidation of

370

fluoroquinolone antibiotics by the UDP-glucuronosyltransferase 1A subfamily in

371

human liver microsomes. Drug Metab Dispos 33:803-811.

372

14.

Senggunprai L, Yoshinari K, Yamazoe Y. 2009. Selective role of sulfotransferase

373

2A1 (SULT2A1) in the N-sulfoconjugation of quinolone drugs in humans. Drug

374

Metab Dispos 37:1711-1717.

375 376

15.

Anonymous. 2008. Moxifloxacin. Tuberculosis 88:127-131.

17

377

Table and Figure Legends

378

Table 1. Dosing regimen for each study group from the day 1 morning dose to the day 5

379

morning dose.

380

Table 2. Subject demographics and characteristics

381

Table 3. Summary of pharmacokinetic parameters of second-line anti-tuberculosis drugs

382

Table 4. Summary of literature data of pharmacokinetic parameters of second-line anti-

383

tuberculosis drugs

384

Table 5. Comparison of pharmacokinetic parameters of cycloserine, PAS, and prothionamide

385

between group 1 and group 2

386

Table 6. Recommended sampling time-points as estimated by correlation analysis between

387

Cmax or AUCτ and the concentration of second-line anti-TB drugs measured in the samples at

388

each time-point on day 5

389

Figure 1. Mean plasma concentration-time profiles of (A) cycloserine, (B) p-aminosalicylic

390

acid, and (C) prothionamide after multiple administrations in group 1 (closed circles), in

391

group 2 (open circles), and in all subjects (open squares) on day 5. The error bars denote

392

standard deviations.

393

Figure 2. Mean plasma concentration-time profiles of (A) levofloxacin, (B) moxifloxacin, (C)

394

streptomycin, and (D) kanamycin after multiple administrations on day 5. The error bars

395

denote standard deviations.

1

Table 1. Dosing regimen for each study group from the day 1 morning dose to the day 5 morning dose.

Group

Regimen common to both groups

Part of regimen different between groups

1 (n = 7)

cycloserine 250 mg PO twice daily

levofloxacin 750 mg PO once daily

PAS 5.28 g PO twice daily

streptomycin 1 g IM once daily

prothionamide 250 mg PO twice daily

moxifloxacin 400 mg PO once daily

pyrazinamide 1500 mg PO once daily

kanamycin 1 g IM once daily

2 (n = 9)

IM, intramuscular; PAS, p-aminosalicylic acid; PO, per os.

2

Table 2. Subject demographics and characteristics All

Group 1

Group 2

(n = 16)

(n = 7)

(n = 9)

Age (years)

26 (21–40)

25 (22–32)

28 (21–40)

Weight (kg)

66.3 (57.9–81.0)

69.3 (61–81)

63.9 (57.9–68.7)

Height (cm)

171.3 (161.0–178.0)

173.0 (167.0–178.0)

170.0 (161.0–177.0)

BMI (kg/m2)

22.5 (19.6–25.9)

23.2 (20.6–25.9)

22.0 (19.6–24.0)

Characteristic

Data are presented as arithmetic mean (range) except for age, for which median (range) is presented.

3

Table 3. Summary of pharmacokinetic parameters of second-line anti-tuberculosis drugs cycloserine

PAS

prothionamide

levofloxacin

moxifloxacin

streptomycin

kanamycin

Tmax (h)

4.0 [2.0-6.0]

2.5 [0.5-6.0]

3.0 [1.5-6.0]

4.0 [3.0-6.0]

4.0 [1.0-6.0]

1.0 [0.5-1.5]

1.0 [0.5-2.5]

Cmax (mg/L)

24.9 ± 9.9

65.9 ± 32.2

5.3 ± 1.9

6.6 ± 1.0

4.7 ± 1.5

42.0 ± 10.8

34.5 ± 4.3

(CV %)

(39.8)

(48.9)

(35.9)

(15.2)

(31.7)

(25.8)

(12.5)

242.3 ± 99.8

326.5 ± 152.5

22.1 ± 7.9

64.4 ± 19.0

54.2 ± 14.0

196.7 ± 25.6

153.5 ± 25.7

(41.2)

(46.7)

(35.8)

(29.6)

(25.9)

(13.0)

(16.7)

20.7 ± 11.9

12.8 ± 4.7

12.3 ± 2.8 7.8 ± 1.9 (23.9)

5.2 ± 0.7 (12.9)

6.7 ± 0.9 (14.2)

(57.6)

(36.7)

(22.8)

AUCτ (mg·h/L) (CV %) CL/F (L/h)

1.2 ± 0.5 (41.6)

t1/2 (h)

20.3 ± 13.9

1.8 ± 0.5

2.4 ± 0.5

8.2 ± 3.3

13.7 ± 2.6

3.1 ± 0.4

3.2 ± 1.0

Vd/F (L)

10.7 ± 4.4

16.6 ± 13.9

41.0 ± 14.6

117.1 ± 23.9

103.8 ± 25.7

22.6 ± 2.8

30.4 ± 9.8

Data are presented as arithmetic mean ± SD except for Tmax, for which median [min–max] is presented. AUCτ, area under the plasma concentration-time curve within a dosing interval at steady state; CL/F, apparent clearance at steady state; Cmax,

4

maximum plasma concentration at steady state; CV, coefficient of variation; PAS, p-aminosalicylic acid; t1/2, terminal elimination half-life; Tmax, time to reach maximum blood concentration at steady state; Vd/F, apparent volume of distribution.

5

Table 4. Summary of literature data of pharmacokinetic parameters of second-line anti-tuberculosis drugs. cycloserine

PAS

prothionamide

levofloxacin

moxifloxacin

streptomycin

kanamycin

reference

(4) a

(9)

(10)

(11)

(4) a

(4) a

(4, 8) a

(4) a

dosage

250–500 mg QD or BIW

250 mg BID

4 g BID

250 mg or 375 mg BID (mean dose 5.9 mg/kg)

500–1,000 mg QD

400 mg QD

15 mg/kg QD

15 mg/kg QD

Tmax (h)

2

5.2

3.4

1–2

1–2

0.5–1.5

0.5–1.5

Cmax (mg/L)

20–35

51.3

2.5

8–13

3–5

35–45 b

35–45 b

368

11.3 9

7

3

3

25–30

AUCτ (mg·h/L) t1/2 (h)

7

10

3

a

‘Normal’ values of the pharmacokinetic parameters for standard doses of drugs.

b

Calculated Cmax using linear regression to 1 h post IM dose.

AUCτ, area under the plasma concentration-time curve within a dosing interval at steady state; BID, twice daily; BIW, twice weekly; Cmax, maximum plasma concentration at steady state; IM, intramuscular; PAS, p-aminosalicylic acid; QD, every day; t1/2, terminal elimination halflife; Tmax, time to reach the maximum blood concentration at steady state.

6

Table 5. Comparison of pharmacokinetic parameters of cycloserine, PAS, and prothionamide between group 1 and group 2 Cycloserine group 1

group 2

Tmax (h)

4.0 [3.0–6.0]

2.5 [2.0–4.0]

Cmax (mg/L)

18.6 ± 7.7

29.9 ± 8.8

PAS GMR

group 1

group 2

4.0 [2.0–6.0]

1.8 [0.5–4.0]

54.9 ± 28.0

75.6 ± 34.3

323.6 ±

327.6 ±

1.66

CL/F (L/h)

0.6 ± 0.3

t1/2 (h) Vd/F (L)

group 1

group 2

3.0 [2.5–4.0]

2.3 [1.5–6.0]

4.3 ± 1.8

6.3 ± 1.5 (1.16–2.04)

1.04

287.2 ± 92.5

1.45 17.8 ± 6.3

(1.18–2.19)

GMR

1.54

(0.83–2.27)

1.61 184.5 ± 81.1

GMR

1.37

(1.24–2.22)

AUCτ (mg·h/L)

Prothionamide

25.7 ± 7.6

186.0

152.7

(0.52–2.06)

(1.08–1.95)

0.3 ± 0.2

6.5 ± 4.5

6.0 ± 3.2

15.3 ± 4.8

10.1 ± 3.8

16.4 ± 5.1

23.3 ± 17.9

1.7 ± 0.2

1.8 ± 0.6

2.2 ± 0.5

2.5 ± 0.6

13.5 ± 4.9

8.6 ± 2.6

15.3 ± 10.0

17.1 ± 15.7

47.7 ± 14.9

35.2 ± 12.5

Data are presented as arithmetic mean ± standard deviations. GMR of group 2 to group 1 (90% confidence interval) AUCτ, area under the plasma concentration-time curve within a dosing interval at steady state; CL/F, apparent clearance at steady state; Cmax, maximum plasma concentration at steady state; CV, coefficient of variation; GMR, geometric mean ratio; PAS, p-aminosalicylic acid; t1/2, terminal elimination half-life; Tmax, time to reach the maximum blood concentration at steady state; Vd/F, apparent volume of distribution.

7

Table 6. Recommended sampling time-points as estimated by correlation analysis between Cmax or AUCτ and the concentration of second-line anti-tuberculosis drugs measured in the samples at each time-point on day 5

cycloserine

PAS

prothionamide

levofloxacin

moxifloxacin

streptomycin

kanamycin

a

p ≤ 0.001

b

p ≤ 0.05

Sample time for Cmax (h)

Sample time for AUCτ (h)

(adjusted r2)

(adjusted r2)

2

4

(0.939) a

(0.968) a

3

3

(0.891) a

(0.906) a

2.5

4

(0.602) a

(0.565) a

2

1.5

(0.917) a

(0.877) a

6

6

(0.523) a

(0.849) a

1

6

(0.928) a

(0.918) a

1

4

(0.858) a

(0.937) a

8

AUCτ, area under the plasma concentration-time curve from time within a dosing interval at steady state; Cmax, maximum plasma concentration of drug at steady state; PAS, p-aminosalicylic acid.

Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers.

Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers. - PDF Download Free
1MB Sizes 0 Downloads 8 Views