University of Groningen
Therapeutic drug monitoring
Pranger, Anna Diewerke
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Pranger, A. D. (2018). Therapeutic drug monitoring: How to improve moxifloxacin exposure in tuberculosis
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Therapeutic drug monitoring:
how to improve moxifloxacin exposure
in tuberculosis patients
Pranger, A.D.
Therapeutic drug monitoring: how to improve moxifloxacin exposure in tuberculosis patients
Thesis, University of Groningen, Groningen, the Netherlands
The work described in this thesis was performed at the department of Clinical Pharmacy and Pharmacology of the University Medical Center Groningen.
Publication of this thesis was financially supported by the Graduate School of Medical Sciences and the University Medical Center Groningen.
Cover image Marijke van Zuilen, http://marijkeengerjannevanzuilen.nl
Lay-out Jeffrey Grashof, Gildeprint & Arianna Pranger
Printed by Gildeprint
ISBN: 978-94-034-0987-0 (printed version) ISBN: 978-94-034-0986-3 (digital version) © A.D. Pranger 2018
Copyright of the published articles is with the corresponding journal or otherwise with the author. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing from the author or the copyright-owing journal.
Therapeutic drug monitoring:
how to improve moxifloxacin
exposure in tuberculosis patients
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op woensdag 31 oktober 2018 om 11.00 uur
door
Anna Diewerke Pranger
geboren op 26 november 1985 te Leeuwarden
Pranger, A.D.
Therapeutic drug monitoring: how to improve moxifloxacin exposure in tuberculosis patients
Thesis, University of Groningen, Groningen, the Netherlands
The work described in this thesis was performed at the department of Clinical Pharmacy and Pharmacology of the University Medical Center Groningen.
Publication of this thesis was financially supported by the Graduate School of Medical Sciences and the University Medical Center Groningen.
Cover image Marijke van Zuilen, http://marijkeengerjannevanzuilen.nl
Lay-out Jeffrey Grashof, Gildeprint & Arianna Pranger
Printed by Gildeprint
ISBN: 978-94-034-0987-0 (printed version) ISBN: 978-94-034-0986-3 (digital version) © A.D. Pranger 2018
Copyright of the published articles is with the corresponding journal or otherwise with the author. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing from the author or the copyright-owing journal.
Therapeutic drug monitoring:
how to improve moxifloxacin
exposure in tuberculosis patients
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op woensdag 31 oktober 2018 om 11.00 uur
door
Anna Diewerke Pranger
geboren op 26 november 1985 te Leeuwarden
Promotores
Prof. dr. J.G.W. Kosterink Prof. dr. T.S. van der Werf Em. prof. dr. D.R.A. Uges
Copromotor
Dr. J.W.C. Alffenaar
Beoordelingscommissie
Prof. dr. F.G.J. Cobelens Prof. dr. H.J. Guchelaar Prof. dr. H.A.M. Kerstjens
Paranimfen
N.M. Pranger, MSc Dr. K.C.M. van der Elst
Promotores
Prof. dr. J.G.W. Kosterink Prof. dr. T.S. van der Werf Em. prof. dr. D.R.A. Uges
Copromotor
Dr. J.W.C. Alffenaar
Beoordelingscommissie
Prof. dr. F.G.J. Cobelens Prof. dr. H.J. Guchelaar Prof. dr. H.A.M. Kerstjens
Paranimfen
N.M. Pranger, MSc Dr. K.C.M. van der Elst
Voor opa & oma, pake & beppe ♥
Contents
Chapter 1 9
Introduction and scope of thesis
Chapter 2a 21
Fluoroquinolones, the cornerstone of treatment of drug-resistant tuberculosis: a pharmacokinetic and pharmacodynamic approach
Chapter 2b 103
The role of fluoroquinolones in the treatment of tuberculosis anno 2018
Chapter 3 123
Determination of moxifloxacin in human plasma, plasma ultrafiltrate, and cerebrospinal fluid by a rapid and simple liquid chromatography-tandem mass spectrometry method
Chapter 4a 143
Evaluation of moxifloxacin for the treatment of tuberculosis: 3 years of experience
Chapter 4b 161
Low moxifloxacin exposure in male tuberculosis patients and the need for monitoring
in early stages of treatment
Chapter 4c 179
Rifampicin and moxifloxacin for tuberculous meningitis
Chapter 5 183
Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin
in patients with tuberculosis
Chapter 6 199
Thin layer chromatography to support therapeutic drug monitoring of moxifloxacin
in resource-limited settings
Chapter 7 217
General discussion and future perspectives
Chapter 8 231
Summary
Epilogue
Nederlandse samenvatting 243
Dankwoord 252
Voor opa & oma, pake & beppe ♥
Contents
Chapter 1 9
Introduction and scope of thesis
Chapter 2a 21
Fluoroquinolones, the cornerstone of treatment of drug-resistant tuberculosis: a pharmacokinetic and pharmacodynamic approach
Chapter 2b 103
The role of fluoroquinolones in the treatment of tuberculosis anno 2018
Chapter 3 123
Determination of moxifloxacin in human plasma, plasma ultrafiltrate, and cerebrospinal fluid by a rapid and simple liquid chromatography-tandem mass spectrometry method
Chapter 4a 143
Evaluation of moxifloxacin for the treatment of tuberculosis: 3 years of experience
Chapter 4b 161
Low moxifloxacin exposure in male tuberculosis patients and the need for monitoring
in early stages of treatment
Chapter 4c 179
Rifampicin and moxifloxacin for tuberculous meningitis
Chapter 5 183
Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin
in patients with tuberculosis
Chapter 6 199
Thin layer chromatography to support therapeutic drug monitoring of moxifloxacin
in resource-limited settings
Chapter 7 217
General discussion and future perspectives
Chapter 8 231
Summary
Epilogue
Nederlandse samenvatting 243
Dankwoord 252
1
Chapter
Introduction and
1
Chapter
Introduction and
Chapter 1 Introduction & scope
10
Tuberculosis today
In 1993, tuberculosis (TB) was for the first time named a global emergency by the World Health Organization (WHO) requiring immediate action in order to prevent expansion of a TB pandemic. At that time, 2.5 million people died from TB annually (1990) (1). Today, the global TB death rate has fallen (2). But still the TB pandemic is killing 1.3 million people according to the latest WHO Global tuberculosis report – and this staggering number excludes another 374,000 people dying from TB in the context of HIV co-infection (2017) (2). In perspective, HIV was responsible for 1.0 million deaths in 2016 (3), more than a third of whom actually died from TB (2). Therefore, even to win the battle against HIV/AIDS, we do have to fight TB (adapted from Nelson Mandela, International AIDS conference, Bangkok 2004).
Like HIV-infected patients, diabetes mellitus (DM) patients have a high lifetime risk of developing TB compared to non-HIV or non-DM patients, respectively, due to a weakened immune system (4). Especially, hyperglycemia is associated with a high risk of falling ill from TB as well as with a poor TB treatment response (5,6). In addition, altered pharmacokinetics in DM could contribute to inadequate drug exposure (7,8). Ageing of the world population and a rising unhealthy lifestyle are important perpetrators for the increasing number of people living with DM, especially in low- and middle-income countries (9). This new and emerging DM epidemic is a challenge for TB control as well.
Historically, TB is a poverty-related disease. Today, the incidence rates are still lower in high-income countries, e.g. 5.9 per 100,000 residents in The Netherlands versus 724/100,000 in Lesotho, Southern Africa (2). However, the downtrend of notified TB cases in the Netherlands was interrupted in 2015 and this is primarily due to the influx of asylum seekers originally from Eritrea and Ethiopia (10). New TB cases in low-incidence countries result from global migration. Therefore, global TB control ought to be a concern of high-income countries as well, as is underlined by WHO’s End TB Strategy (11).
In one-out-of-five previously treated TB patients that relapse, resistance emerges against rifampicin (RIF), the most important drug in TB treatment (2). Furthermore, from 2007 onwards, the first extremely drug-resistant or “ totally-drug resistant” cases were reported in Italy, Iran and India (12-14). In general, drug resistance is a result of improper use of medication regarding the dose, the combination of drugs, treatment compliance and/or the availability of drugs. Also, in some parts of the world where drug susceptibility cannot be tested, the epidemic of drug-resistant TB cannot be curbed (2).
11 In consecutive reports, the WHO have argued that the TB pandemic is declining, but even if the current global trend of estimated new TB cases continues to decline, additional interventions are needed to end TB by 2035, which is the target elaborated on the United Nations Sustainable Development Goals (15). Intensified efforts are needed now, as it appears that the actual TB incidence in recent years has rather plateaued than decreased (16) which is likely explained by the emergence of multi-drug resistant TB (MDR-TB) among all new TB cases. In case of MDR-TB, M. tuberculosis is resistant against RIF and isoniazid (INH), the two most powerful first-line agents (17). And next to TB-HIV co-infected patients and current topics as global migration and changing co-morbidity profiles (e.g. diabetes), the spread of drug resistance is therefore the biggest threat of today’s TB burden (18,19).
Mycobacterium tuberculosis
TB is an air borne disease and transmission occurs via inhalation of droplets, loaded with Mycobacterium tuberculosis, which are dispersed by sneezing or coughing of pulmonary TB patients. Major TB outbreaks have revealed that a substantial proportion of supposedly newly infected people eradicate M. tuberculosis before the adaptive immune response is put in motion, whereas in others, M. tuberculosis settles, primarily in alveolar macrophages. The underlying cause of this distinction could be important for the development of new vaccines and therapies, including immunotherapy (20).
Once settled in the lungs, M. tuberculosis has a genetically determined program that can be switched on toward a low metabolic and low replication rate. This “on” mode of the dormancy survivor regulator (DosR) is driven by certain stress factors, e.g. host immune defense, drug treatment and hypoxia (21). An infected individual therefore either develops TB or only becomes ‘latently’ infected with dormant TB bacilli. Once the immune defense of the host weakens, the dormant mycobacteria may start replicating, e.g. in ageing individuals with immunosenescence, hosts co-infected with HIV, those that develop DM, or with declining vitamin D levels. Almost one quarter of the world’s population is latently infected and therefore a pending threat for the TB burden (22).
Also, for TB patients, to ensure elimination of the slowly replicating or ‘persister’ population of TB bacilli, treatment lasts 6 months for drug-susceptible, and up to 20 months for advanced stages of drug-resistant TB. In 2016, based on clinical outcome data, the WHO justified the use of shorter drug regimens than 18-20 months – but still, 9-12 months - with current established 2nd line anti-TB agents, for drug resistant TB, under stringent conditions (17). Therefore, next to the dire need to develop new vaccines and immunotherapies, novel anti-TB agents are needed that directly act on the dormant mycobacterial population.
Chapter 1 Introduction & scope
Chapter
1
10
Tuberculosis today
In 1993, tuberculosis (TB) was for the first time named a global emergency by the World Health Organization (WHO) requiring immediate action in order to prevent expansion of a TB pandemic. At that time, 2.5 million people died from TB annually (1990) (1). Today, the global TB death rate has fallen (2). But still the TB pandemic is killing 1.3 million people according to the latest WHO Global tuberculosis report – and this staggering number excludes another 374,000 people dying from TB in the context of HIV co-infection (2017) (2). In perspective, HIV was responsible for 1.0 million deaths in 2016 (3), more than a third of whom actually died from TB (2). Therefore, even to win the battle against HIV/AIDS, we do have to fight TB (adapted from Nelson Mandela, International AIDS conference, Bangkok 2004).
Like HIV-infected patients, diabetes mellitus (DM) patients have a high lifetime risk of developing TB compared to non-HIV or non-DM patients, respectively, due to a weakened immune system (4). Especially, hyperglycemia is associated with a high risk of falling ill from TB as well as with a poor TB treatment response (5,6). In addition, altered pharmacokinetics in DM could contribute to inadequate drug exposure (7,8). Ageing of the world population and a rising unhealthy lifestyle are important perpetrators for the increasing number of people living with DM, especially in low- and middle-income countries (9). This new and emerging DM epidemic is a challenge for TB control as well.
Historically, TB is a poverty-related disease. Today, the incidence rates are still lower in high-income countries, e.g. 5.9 per 100,000 residents in The Netherlands versus 724/100,000 in Lesotho, Southern Africa (2). However, the downtrend of notified TB cases in the Netherlands was interrupted in 2015 and this is primarily due to the influx of asylum seekers originally from Eritrea and Ethiopia (10). New TB cases in low-incidence countries result from global migration. Therefore, global TB control ought to be a concern of high-income countries as well, as is underlined by WHO’s End TB Strategy (11).
In one-out-of-five previously treated TB patients that relapse, resistance emerges against rifampicin (RIF), the most important drug in TB treatment (2). Furthermore, from 2007 onwards, the first extremely drug-resistant or “ totally-drug resistant” cases were reported in Italy, Iran and India (12-14). In general, drug resistance is a result of improper use of medication regarding the dose, the combination of drugs, treatment compliance and/or the availability of drugs. Also, in some parts of the world where drug susceptibility cannot be tested, the epidemic of drug-resistant TB cannot be curbed (2).
11 In consecutive reports, the WHO have argued that the TB pandemic is declining, but even if the current global trend of estimated new TB cases continues to decline, additional interventions are needed to end TB by 2035, which is the target elaborated on the United Nations Sustainable Development Goals (15). Intensified efforts are needed now, as it appears that the actual TB incidence in recent years has rather plateaued than decreased (16) which is likely explained by the emergence of multi-drug resistant TB (MDR-TB) among all new TB cases. In case of MDR-TB, M. tuberculosis is resistant against RIF and isoniazid (INH), the two most powerful first-line agents (17). And next to TB-HIV co-infected patients and current topics as global migration and changing co-morbidity profiles (e.g. diabetes), the spread of drug resistance is therefore the biggest threat of today’s TB burden (18,19).
Mycobacterium tuberculosis
TB is an air borne disease and transmission occurs via inhalation of droplets, loaded with Mycobacterium tuberculosis, which are dispersed by sneezing or coughing of pulmonary TB patients. Major TB outbreaks have revealed that a substantial proportion of supposedly newly infected people eradicate M. tuberculosis before the adaptive immune response is put in motion, whereas in others, M. tuberculosis settles, primarily in alveolar macrophages. The underlying cause of this distinction could be important for the development of new vaccines and therapies, including immunotherapy (20).
Once settled in the lungs, M. tuberculosis has a genetically determined program that can be switched on toward a low metabolic and low replication rate. This “on” mode of the dormancy survivor regulator (DosR) is driven by certain stress factors, e.g. host immune defense, drug treatment and hypoxia (21). An infected individual therefore either develops TB or only becomes ‘latently’ infected with dormant TB bacilli. Once the immune defense of the host weakens, the dormant mycobacteria may start replicating, e.g. in ageing individuals with immunosenescence, hosts co-infected with HIV, those that develop DM, or with declining vitamin D levels. Almost one quarter of the world’s population is latently infected and therefore a pending threat for the TB burden (22).
Also, for TB patients, to ensure elimination of the slowly replicating or ‘persister’ population of TB bacilli, treatment lasts 6 months for drug-susceptible, and up to 20 months for advanced stages of drug-resistant TB. In 2016, based on clinical outcome data, the WHO justified the use of shorter drug regimens than 18-20 months – but still, 9-12 months - with current established 2nd line anti-TB agents, for drug resistant TB, under stringent conditions (17). Therefore, next to the dire need to develop new vaccines and immunotherapies, novel anti-TB agents are needed that directly act on the dormant mycobacterial population.
Chapter 1 Introduction & scope
12
Treatment of tuberculosis and optimization of treatment
A treatment regimen has to be effective, well tolerated, but also preferably short and simple to ensure patient’s compliance and good quality of life. TB treatment is assumed to be effective if the patient is successfully treated with subsequent negative cultures (cured), or at least, successfully treated without failure or relapse, without development of drug resistance and without transmission of the disease in the community (23). In this perspective, in general, even treatment for drug-susceptible TB is less than ideal, while treatment for MDR-TB is not nearly as successful as it should be.
To treat drug-susceptible TB, the WHO recommends a six-month regimen of INH, RIF, pyrazinamide (PZA) and ethambutol (23). As explained, there is at best marginal decline in new TB cases, and especially the proportion of MDR/RIF resistant (RR) cases among new and among previously treated TB cases is worrisome (2). On the opposite side of the therapeutic window, drug tolerability might be a problem. Drug-induced liver injury is a well-known side effect of INH, and especially, PZA, while RIF is the least hepatotoxic 1st line TB drug (24). In case of drug-resistance or drug-intolerability, the physician may have to switch to less studied, and thus probably less effective, more toxic, less simple (e.g. intravenous) second-line agents as part of a longer treatment regimen.
According to the WHO there are four classes of drugs for TB if RIF, the most important 1st line agent, is not suitable (Table 1). Efficacy and tolerability of the drugs forced to the latter
class (D) is less substantiated than the evidence for the core agents in class A, B and C. Bedaquiline, the first drug ever FDA-approved for MDR-TB in 2012, is one of the ‘add on’ drugs of class D. Class D drugs are recommended to add-on to the regimen in case not enough class A, B and/or C drugs will fit an individual MDR/RR-TB case. Nowadays, fluoroquinolones are defined as most valuable agents in case of intolerability or resistance of 1st line anti-TB agents (17). Moxifloxacin is the scope of this thesis.
13 Table 1. Medicines recommended for the treatment of multi-drug resistant/rifampicin-resistant TB.
Medicine
Class A Fluoroquinolones Levofloxacin
Moxifloxacin Gatifloxacin
Class B Second-line injectable agents Amikacin
Capreomycin Kanamycin (Streptomycin)
Class C Other core second-line agents Ethionamide/ Prothionamide
Cycloserine/ Terizidone Linezolid
Clofazimine
Class D Add-on agents D1 Pyrazinamide
Ethambutol High-dose isoniazid D2 Bedaquiline Delamanid D3 p-amino-salicylic acid Imipenem-cilastatin Meropenem Amoxicillin-clavulanate (Thioacetazone)
Adapted from the WHO treatment guidelines for drug-resistant tuberculosis. 2016 update (Table 6) via URL http://apps.who.int/iris/bitstream/10665/250125/1/9789241549639-eng.pdf?ua=1.
Chapter 1 Introduction & scope
Chapter
1
12
Treatment of tuberculosis and optimization of treatment
A treatment regimen has to be effective, well tolerated, but also preferably short and simple to ensure patient’s compliance and good quality of life. TB treatment is assumed to be effective if the patient is successfully treated with subsequent negative cultures (cured), or at least, successfully treated without failure or relapse, without development of drug resistance and without transmission of the disease in the community (23). In this perspective, in general, even treatment for drug-susceptible TB is less than ideal, while treatment for MDR-TB is not nearly as successful as it should be.
To treat drug-susceptible TB, the WHO recommends a six-month regimen of INH, RIF, pyrazinamide (PZA) and ethambutol (23). As explained, there is at best marginal decline in new TB cases, and especially the proportion of MDR/RIF resistant (RR) cases among new and among previously treated TB cases is worrisome (2). On the opposite side of the therapeutic window, drug tolerability might be a problem. Drug-induced liver injury is a well-known side effect of INH, and especially, PZA, while RIF is the least hepatotoxic 1st line TB drug (24). In case of drug-resistance or drug-intolerability, the physician may have to switch to less studied, and thus probably less effective, more toxic, less simple (e.g. intravenous) second-line agents as part of a longer treatment regimen.
According to the WHO there are four classes of drugs for TB if RIF, the most important 1st line agent, is not suitable (Table 1). Efficacy and tolerability of the drugs forced to the latter
class (D) is less substantiated than the evidence for the core agents in class A, B and C. Bedaquiline, the first drug ever FDA-approved for MDR-TB in 2012, is one of the ‘add on’ drugs of class D. Class D drugs are recommended to add-on to the regimen in case not enough class A, B and/or C drugs will fit an individual MDR/RR-TB case. Nowadays, fluoroquinolones are defined as most valuable agents in case of intolerability or resistance of 1st line anti-TB agents (17). Moxifloxacin is the scope of this thesis.
13 Table 1. Medicines recommended for the treatment of multi-drug resistant/rifampicin-resistant TB.
Medicine
Class A Fluoroquinolones Levofloxacin
Moxifloxacin Gatifloxacin
Class B Second-line injectable agents Amikacin
Capreomycin Kanamycin (Streptomycin)
Class C Other core second-line agents Ethionamide/ Prothionamide
Cycloserine/ Terizidone Linezolid
Clofazimine
Class D Add-on agents D1 Pyrazinamide
Ethambutol High-dose isoniazid D2 Bedaquiline Delamanid D3 p-amino-salicylic acid Imipenem-cilastatin Meropenem Amoxicillin-clavulanate (Thioacetazone)
Adapted from the WHO treatment guidelines for drug-resistant tuberculosis. 2016 update (Table 6) via URL http://apps.who.int/iris/bitstream/10665/250125/1/9789241549639-eng.pdf?ua=1.
Chapter 1 Introduction & scope
14
A TB regimen contains multiple active drugs, i.e. five or six for MDR/RR-TB (17), during a longer period of time, which is not conducive for treatment compliance and a good quality of life. At this moment, phase III trials investigate the value of shorter regimes for drug-susceptible and drug-resistant TB. New (delamanid and bedaquiline) and ‘old’ anti-TB agents (e.g. moxifloxacin) are part of this investigation (25). As mentioned above, for MDR/RR-TB patients with no history of second line-drug use and/or second-line drug resistance, the WHO recently for the first time justified the use of a shorter, standardized regimen (17). The global focus is on minimizing treatment duration. However, the exposure to individual drugs and the drug susceptibility of the M. tuberculosis isolate settled in an individual patient might be as important for treatment success, especially, when factors like the pathophysiology of other diseases or conditions (diabetes, HIV, malnutrition) or interactions with other drugs accounts for variability of exposure to the anti-TB drug, or if the clinical isolate is less susceptible against the drug (7,8, 26-30). Finally, as is an important note for TB as well, there is no established target to estimate efficacy and/or tolerability of treatment for each individual drug. In the end, improvement of the global availability of tests for drug-susceptibility, including important second-line drugs, and simple point-of-care tests for measuring drug exposure in body fluids is of utmost importance to maximize the effect of each individual drug instead of (only) shortening the treatment duration (31,32).
Scope of the thesis
The above-mentioned findings suggest that the spread of rifampicin resistance is the biggest threat of today’s TB burden. Although this epidemic cannot be curbed without successful treatment, of the treatment-experienced MDR/RR-TB patients, only 54% was successfully treated (i.e. cured or treatment completed) in 2016 (2). Unfortunately, TB resistant against most 2nd line drugs is increasingly common (12-14).
From 2016 onwards, a short regimen – still 9 to 12 months – is solely reserved for MDR/RR-TB patients that fulfill a large set of criteria including full susceptibility to class A (fluoroquinolone) and class B (injectable) drugs (17). Unfortunately, not many patients qualify for this shortened regimen (32-34). Shortening of treatment duration will reduce pill burden, which is in the interest of both the health care system (costs, patients’ compliance) and the patient. However, regardless of the duration of treatment, for each regimen inadequate (inefficient or toxic) dosing of individual drugs will or may have implications for treatment success. Therefore, the main objective of this thesis is to gain insight in the pharmacokinetics (PK), pharmacodynamics (PD) and safety of moxifloxacin, one of the core agents in
15 MDR/RR-TB treatment. The second objective is to develop strategies and methods for concentration measurement in countries or areas with and without centralized laboratories.
In chapter 2A, we review the literature evaluating the value of fluoroquinolones as part of
drug-resistant TB treatment by using a PK and PD approach. The anti-mycobacterial or PD effect of fluoroquinolones is assumed to be at maximum when there is a perfect alignment of PK (absorption, distribution, metabolism, elimination) and drug susceptibility of M. tuberculosis. Co-prescribed agents can influence both PK and PD (synergistic or antagonistic effect). Integrating PK and PD properties, we aimed to select the most important (novel) fluoroquinolone for drug-resistant TB treatment. Several years thereafter, in chapter 2B, we
summarized and discussed clinical and/or bacteriological outcome of drug-resistant and (short-course) drug-susceptible TB regimens based on the most valuable 2nd line anti-TB agents, i.e. moxifloxacin, levofloxacin and gatifloxacin.
A few years before the start of the studies described in this thesis, moxifloxacin was introduced in our TB center (Beatrixoord, UMCG), one of the two TB referral centers in the Netherlands, based on promising data of in vitro and in vivo bactericidal activity (35,36). However, treatment success, or the right dose, seems to be driven by individualized treatment as both drug exposure and drug susceptibility of M. tuberculosis may vary (26,27). The goal of chapter 3 and 4 was therefore to gain better insight in the PK, PD and exposure
of moxifloxacin. In chapter 3 we describe the development and validation of a simple and
rapid bio-analytical method to measure the moxifloxacin exposure in plasma, plasma ultrafiltrate (i.e. the protein-unbound fraction) and cerebrospinal fluid. In chapter 4A we
retrospectively review the medical charts of TB patients, receiving 400mg once daily, on drug-drug interaction and safety data, and determined drug exposure and drug susceptibility, in order to estimate efficacy and safety of the standard dosage, used off-label in TB treatment. In the second part of chapter 4 (4B), we further retrospectively explore time
dependency of drug exposure during TB treatment. In this study we hypothesize that TB patients during the intensive phase of treatment differ clinically from TB patients in the continuation phase of treatment in order to explain the observed PK variability. In chapter 4C, in a letter to the editor, we challenge the authors to find out to what extent cumulative
drug exposures of high-dose rifampicin, moxifloxacin and isoniazid predict TB meningitis outcome, using an alternative analysis.
The focus of chapter 5 and 6 is development of less-invasive strategies or analytical methods for therapeutic drug monitoring (TDM). In chapter 5 we aim to develop and validate a limited
Chapter 1 Introduction & scope
Chapter
1
14
A TB regimen contains multiple active drugs, i.e. five or six for MDR/RR-TB (17), during a longer period of time, which is not conducive for treatment compliance and a good quality of life. At this moment, phase III trials investigate the value of shorter regimes for drug-susceptible and drug-resistant TB. New (delamanid and bedaquiline) and ‘old’ anti-TB agents (e.g. moxifloxacin) are part of this investigation (25). As mentioned above, for MDR/RR-TB patients with no history of second line-drug use and/or second-line drug resistance, the WHO recently for the first time justified the use of a shorter, standardized regimen (17). The global focus is on minimizing treatment duration. However, the exposure to individual drugs and the drug susceptibility of the M. tuberculosis isolate settled in an individual patient might be as important for treatment success, especially, when factors like the pathophysiology of other diseases or conditions (diabetes, HIV, malnutrition) or interactions with other drugs accounts for variability of exposure to the anti-TB drug, or if the clinical isolate is less susceptible against the drug (7,8, 26-30). Finally, as is an important note for TB as well, there is no established target to estimate efficacy and/or tolerability of treatment for each individual drug. In the end, improvement of the global availability of tests for drug-susceptibility, including important second-line drugs, and simple point-of-care tests for measuring drug exposure in body fluids is of utmost importance to maximize the effect of each individual drug instead of (only) shortening the treatment duration (31,32).
Scope of the thesis
The above-mentioned findings suggest that the spread of rifampicin resistance is the biggest threat of today’s TB burden. Although this epidemic cannot be curbed without successful treatment, of the treatment-experienced MDR/RR-TB patients, only 54% was successfully treated (i.e. cured or treatment completed) in 2016 (2). Unfortunately, TB resistant against most 2nd line drugs is increasingly common (12-14).
From 2016 onwards, a short regimen – still 9 to 12 months – is solely reserved for MDR/RR-TB patients that fulfill a large set of criteria including full susceptibility to class A (fluoroquinolone) and class B (injectable) drugs (17). Unfortunately, not many patients qualify for this shortened regimen (32-34). Shortening of treatment duration will reduce pill burden, which is in the interest of both the health care system (costs, patients’ compliance) and the patient. However, regardless of the duration of treatment, for each regimen inadequate (inefficient or toxic) dosing of individual drugs will or may have implications for treatment success. Therefore, the main objective of this thesis is to gain insight in the pharmacokinetics (PK), pharmacodynamics (PD) and safety of moxifloxacin, one of the core agents in
15 MDR/RR-TB treatment. The second objective is to develop strategies and methods for concentration measurement in countries or areas with and without centralized laboratories.
In chapter 2A, we review the literature evaluating the value of fluoroquinolones as part of
drug-resistant TB treatment by using a PK and PD approach. The anti-mycobacterial or PD effect of fluoroquinolones is assumed to be at maximum when there is a perfect alignment of PK (absorption, distribution, metabolism, elimination) and drug susceptibility of M. tuberculosis. Co-prescribed agents can influence both PK and PD (synergistic or antagonistic effect). Integrating PK and PD properties, we aimed to select the most important (novel) fluoroquinolone for drug-resistant TB treatment. Several years thereafter, in chapter 2B, we
summarized and discussed clinical and/or bacteriological outcome of drug-resistant and (short-course) drug-susceptible TB regimens based on the most valuable 2nd line anti-TB agents, i.e. moxifloxacin, levofloxacin and gatifloxacin.
A few years before the start of the studies described in this thesis, moxifloxacin was introduced in our TB center (Beatrixoord, UMCG), one of the two TB referral centers in the Netherlands, based on promising data of in vitro and in vivo bactericidal activity (35,36). However, treatment success, or the right dose, seems to be driven by individualized treatment as both drug exposure and drug susceptibility of M. tuberculosis may vary (26,27). The goal of chapter 3 and 4 was therefore to gain better insight in the PK, PD and exposure
of moxifloxacin. In chapter 3 we describe the development and validation of a simple and
rapid bio-analytical method to measure the moxifloxacin exposure in plasma, plasma ultrafiltrate (i.e. the protein-unbound fraction) and cerebrospinal fluid. In chapter 4A we
retrospectively review the medical charts of TB patients, receiving 400mg once daily, on drug-drug interaction and safety data, and determined drug exposure and drug susceptibility, in order to estimate efficacy and safety of the standard dosage, used off-label in TB treatment. In the second part of chapter 4 (4B), we further retrospectively explore time
dependency of drug exposure during TB treatment. In this study we hypothesize that TB patients during the intensive phase of treatment differ clinically from TB patients in the continuation phase of treatment in order to explain the observed PK variability. In chapter 4C, in a letter to the editor, we challenge the authors to find out to what extent cumulative
drug exposures of high-dose rifampicin, moxifloxacin and isoniazid predict TB meningitis outcome, using an alternative analysis.
The focus of chapter 5 and 6 is development of less-invasive strategies or analytical methods for therapeutic drug monitoring (TDM). In chapter 5 we aim to develop and validate a limited
Chapter 1 Introduction & scope
16
adequately predicts moxifloxacin exposure with limited samples in case it is not possible or not desired to obtain a full blood curve. However, in TB endemic areas, with a low density of laboratories, the required transport conditions might not always be met, and in addition, the analytical method to be used is often too expensive. In chapter 6 we strive to develop a
simple, affordable and non-invasive point-of-care test for TDM of moxifloxacin in oral fluid. In addition, we describe the first statistically robust analytical validation of a semi-quantitative thin-layer-chromatography method.
In chapter 7, we discuss the clinical impact of these findings and speculate on the role of
moxifloxacin in the treatment of TB. In chapter 8, a summary of the findings of this thesis is
presented.
17
References
1. World Health Organization (WHO) (ed.). 1993. A review of current epidemiological data and estimation of future tuberculosis incidence and mortality. World Health Organization, Geneva, Switzerland.
2. World Health Organization (WHO) (ed.). 2017. Global tuberculosis report 2017. World Health Organization, Geneva, Switzerland.
3. World Health Organization (WHO) (ed.). 2017. Factsheet Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS): updated November 2017. World Health Organization, Geneva, Switzerland.
4. World Health Organization (WHO) (ed.). 2016. Factsheet Tuberculosis and Diabetes. World Health Organization, Geneva, Switzerland.
5. Yoon Y.S., Jung J.W., Jeon E.J., Seo H., Ryu Y.J., Yim J.J., Kim Y.H., Lee B.H., Park Y.B., Lee B.J., Kang H., and Choi J.C. 2017. The effect of diabetes control status on treatment response in pulmonary tuberculosis: a prospective study. Thorax. 72(3):263-270.
6. Lee P.H, Fu H., Lai T.C., Chiang C.Y., Chan C.C., and Lin H.H. 2016. Glycemic control and the risk of tuberculosis: a cohort study. Plos Med.13(8):e1002072.
7. Nijland H.M.J, Ruslami R., Stalenhoef J.E., Nelwan E.J., Alisjahbana B., Nelwan R.H.H., van der Ven A.J.A.M., Danusantoso H., Aarnoutse R.E., and van Grevel R. 2006. Exposure to Rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin. Infect. Dis. 43(7):848-54.
8. Kumar A.K., Chandrasekaran V., Kannan T., Murali A.L., Lavanya J., Sudha V., Swaminathan S., and Ramachandran G. 2017. Anti-tuberculosis drug concentrations in tuberculosis patients with and without diabetes mellitus. Eur J Clin Pharmacol. 73(1):65-70..
9. World Health Organization (WHO) (ed.). 2016. Global report on diabetes. World Health Organization, Geneva, Switzerland.
10. National Institute for Public Health and the Environment (RIVM) (ed.). 2017. State of Infectious Diseases in the Netherlands, 2016. National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
11. World Health Organization (WHO) (ed.). 2014. Towards tuberculosis elimination: an action framework for low-incidence countries. World Health Organization, Geneva, Switzerland. 12. Migliori G.B., De Iaco G., Besozzi G., Centis R., and Cirillo D.M. 2007. First tuberculosis cases
in Italy resistant to all tested drugs. Eurosurveillance. 12(5):E070517.1.
13. Velyati A.A., Masjedi M.R., Farnia P., Tabarsi P., Ghanavi J., Ziazarifi A.H., and Hoffner S.E. 2009. Emergence of new forms of totally drug-resistent tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran. Chest. 136(2):420-5. 14. Udwadia Z.F., Amale R.A., Ajbani K.K., and Rodrigues C. 2012. Totally drug-resistant
Chapter 1 Introduction & scope
Chapter
1
16
adequately predicts moxifloxacin exposure with limited samples in case it is not possible or not desired to obtain a full blood curve. However, in TB endemic areas, with a low density of laboratories, the required transport conditions might not always be met, and in addition, the analytical method to be used is often too expensive. In chapter 6 we strive to develop a
simple, affordable and non-invasive point-of-care test for TDM of moxifloxacin in oral fluid. In addition, we describe the first statistically robust analytical validation of a semi-quantitative thin-layer-chromatography method.
In chapter 7, we discuss the clinical impact of these findings and speculate on the role of
moxifloxacin in the treatment of TB. In chapter 8, a summary of the findings of this thesis is
presented.
17
References
1. World Health Organization (WHO) (ed.). 1993. A review of current epidemiological data and estimation of future tuberculosis incidence and mortality. World Health Organization, Geneva, Switzerland.
2. World Health Organization (WHO) (ed.). 2017. Global tuberculosis report 2017. World Health Organization, Geneva, Switzerland.
3. World Health Organization (WHO) (ed.). 2017. Factsheet Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS): updated November 2017. World Health Organization, Geneva, Switzerland.
4. World Health Organization (WHO) (ed.). 2016. Factsheet Tuberculosis and Diabetes. World Health Organization, Geneva, Switzerland.
5. Yoon Y.S., Jung J.W., Jeon E.J., Seo H., Ryu Y.J., Yim J.J., Kim Y.H., Lee B.H., Park Y.B., Lee B.J., Kang H., and Choi J.C. 2017. The effect of diabetes control status on treatment response in pulmonary tuberculosis: a prospective study. Thorax. 72(3):263-270.
6. Lee P.H, Fu H., Lai T.C., Chiang C.Y., Chan C.C., and Lin H.H. 2016. Glycemic control and the risk of tuberculosis: a cohort study. Plos Med.13(8):e1002072.
7. Nijland H.M.J, Ruslami R., Stalenhoef J.E., Nelwan E.J., Alisjahbana B., Nelwan R.H.H., van der Ven A.J.A.M., Danusantoso H., Aarnoutse R.E., and van Grevel R. 2006. Exposure to Rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin. Infect. Dis. 43(7):848-54.
8. Kumar A.K., Chandrasekaran V., Kannan T., Murali A.L., Lavanya J., Sudha V., Swaminathan S., and Ramachandran G. 2017. Anti-tuberculosis drug concentrations in tuberculosis patients with and without diabetes mellitus. Eur J Clin Pharmacol. 73(1):65-70..
9. World Health Organization (WHO) (ed.). 2016. Global report on diabetes. World Health Organization, Geneva, Switzerland.
10. National Institute for Public Health and the Environment (RIVM) (ed.). 2017. State of Infectious Diseases in the Netherlands, 2016. National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
11. World Health Organization (WHO) (ed.). 2014. Towards tuberculosis elimination: an action framework for low-incidence countries. World Health Organization, Geneva, Switzerland. 12. Migliori G.B., De Iaco G., Besozzi G., Centis R., and Cirillo D.M. 2007. First tuberculosis cases
in Italy resistant to all tested drugs. Eurosurveillance. 12(5):E070517.1.
13. Velyati A.A., Masjedi M.R., Farnia P., Tabarsi P., Ghanavi J., Ziazarifi A.H., and Hoffner S.E. 2009. Emergence of new forms of totally drug-resistent tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran. Chest. 136(2):420-5. 14. Udwadia Z.F., Amale R.A., Ajbani K.K., and Rodrigues C. 2012. Totally drug-resistant
Chapter 1 Introduction & scope
18
15. World Health Organization (WHO) (ed.). 2014. The end TB strategy: Global strategy and targets for tuberculosis prevention, care and control after 2015. World Health Organization, Geneva, Switzerland.
16. Murray C.J., Ortblad K.F., and Guinovart C. et al., 2014. Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 384(9947):1005-70.
17. World Health Organization (WHO) (ed.). 2016. WHO treatment guidelines for drug-resistant tuberculosis (2016 update). World Health Organization, Geneva, Switzerland.
18. Sharma A., Hill A., Kurbatova E., van der Walt M., Kvasnovsky C., Tupasi T.E., Caoili J.C., Gler M.T., Volchenkov G.V., Kazennyy B.Y., Demikhova O.V., Bayona J., Contreras C., Yagui M., Leimane V., Cho S.N., Kim H.J., Kliiman K., Akksilp S., Jou R., Ershova J., Dalton T., Cegielski P.; Global Preserving Effective TB Treatment Study Investigators. 2017. Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study. Lancet Infect Dis. 17(7):707-715.
19. Mariandyshev A. and Eliseev P. 2017. Drug-resistant tuberculosis threatens WHO’s End-TB strategy. Lancet Infect Dis. 17(7):674-675.
20. Verrall A.J., Netea M.G., Alisjahbana B., Hill P.C., and van Grevel R. 2014. Early clearance of
Mycobacterium tuberculosis: a new frontier in prevention. Immunology. 141(4):506-513.
21. Boon C. and Dick T. 2012. How Mycobacterium tuberculosis goes to sleep: the dormancy survival regulator DosR a decade later. Future Microbiol. 7(4):513-8.
22. Houben R.M. and Dodd P.J. 2016. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 13(10):e1002152.
23. World Health Organization (WHO) (ed.). 2017. Guidelines for treatment of drug-susceptible tuberculosis and patient care. 2017 Update. World Health Organization, Geneva, Switzerland. 24. National Institute of Health (NIH) (ed.). Clinical and research information on drug-induced liver-injury. U.S. National Library of Health, Bethesda, United States of America. Accessed: March 16th 2018 via www.livertox.nih.gov.
25. Stop TB Partnership (ed.). Drug pipeline. Stop TB Partnership. Accessed: March 16th 2018 via www.newtbdrugs.org.
26. Pasipanodya J.G., Srivastava S., and Gumbo T. 2012. Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy. CID. 55(2):169-77.
27. Pasipanodya J.G., Srivastava S., and Gumbo T. 2012. New susceptibility breakpoints and the regional variability of MIC distribution in Mycobacterium tuberculosis isolates. AAC. 56(10):5428.
28. Daskapan A., de Lange W.C.M., Akkerman O.W., Kosterink J.G.W., van der Werf T.S., Stienstra Y., and Alffenaar J.W.C. 2015. The role of therapeutic drug monitoring in individualized drug dosage and exposure measurement in tuberculosis and HIV co-infection. Eur. Respir. J. 45(2):569-571.
19 29. Newman M., Foissy M.M., and Ahmed R.A.. 2015. The use of therapeutic drug monitoring in complex antituberculous and anitretroviral drug dosing in HIV/tuberculosis-coinfected patients. J. Int. Assoc. Provid. AIDS Care. 14(4):295-9.
30. Nijland H.M., Ruslami R., Suroto A.J., Burger D.M., Alisjahbana B., van Crevel R., and Aarnoutse R.E. 2007. Rifampicin reduces plasma concentrations of moxifloxacin in patients with tuberculosis. Clin. Infect. Dis. 45(8):1001-7.
31. Ghimire S., Bolhuis M.S., Sturkenboom M.G.G., Akkerman O.W., de Lange W.C.M., van der Werf T.S., and Alffenaar J.W.C. 2016. Incorporating therapeutic drug monitoring into the World Health Organization hierarchy of tuberculosis diagnostics. Eur. Respir. J. 47(6):1867-1869.
32. Sotgiu G., Tiberi S., D’Ambrosio L., Centis R., Alffenaar J.W., Caminero J.A., Abdo Arbex M., Alarcon Guizado G., Aleksa A., Dore S., Gaga M., Gualano G., Kunst H., Payen M.C., Roby Arias A.J., Skrahina A., Solovic I., Sulis G., Tadolini M., Zumla A., Migliori G.B.; International Carbapenem Study Group. 2016. Faster for less: the new “shorter” regimen for multidrug-resistant tuberculosis. Eur Respir. J. 48(5):1503-1507.
33. Van Altena R., Akkerman O.W., Alffenaar J.C., Kerstjens H.A., Magis-Escurra C., Boeree M.J., van Soolingen D., de Lange W.C., Bolhuis M.S., Hoefsloot W., de Vries G., and van der Werf T.S. 2016. Shorter treatment for multidrug-resistant tuberculosis: the good, the bad and the ugly. Eur Respir J. 48(6):1800-1802.
34. Lange C., Duarte R., Fréchet-Jachym M., Guenther G., Guglielmetti L., Olaru I.D., Oliveira O., Rumetshofer R., Veziris N., van Leth F.;European MDR-TB database collaboration. 2016. Limited benefit of the new shorter multidrug-resistant tuberculosis regimen in Europe. Am J Respir Crit Care Med. 194(8):1029-1031.
35. Nuermberger E.L., Yoshimatsu T., Tyagi S., O’Brien R.J., Vernon A.N., Chaisson R.E., Bishai W.R., and Grosset J.H. 2004. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am. J. Respir. Crit. Care Med. 169(3):421-426.
36. Ginsburg A.S., Grosset J.H., and Bishai W.R. 2003. Fluoroquinolones, tuberculosis and resistance. Lancet Infect. Dis. 3(7):432-442.
Chapter 1 Introduction & scope
Chapter
1
18
15. World Health Organization (WHO) (ed.). 2014. The end TB strategy: Global strategy and targets for tuberculosis prevention, care and control after 2015. World Health Organization, Geneva, Switzerland.
16. Murray C.J., Ortblad K.F., and Guinovart C. et al., 2014. Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 384(9947):1005-70.
17. World Health Organization (WHO) (ed.). 2016. WHO treatment guidelines for drug-resistant tuberculosis (2016 update). World Health Organization, Geneva, Switzerland.
18. Sharma A., Hill A., Kurbatova E., van der Walt M., Kvasnovsky C., Tupasi T.E., Caoili J.C., Gler M.T., Volchenkov G.V., Kazennyy B.Y., Demikhova O.V., Bayona J., Contreras C., Yagui M., Leimane V., Cho S.N., Kim H.J., Kliiman K., Akksilp S., Jou R., Ershova J., Dalton T., Cegielski P.; Global Preserving Effective TB Treatment Study Investigators. 2017. Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study. Lancet Infect Dis. 17(7):707-715.
19. Mariandyshev A. and Eliseev P. 2017. Drug-resistant tuberculosis threatens WHO’s End-TB strategy. Lancet Infect Dis. 17(7):674-675.
20. Verrall A.J., Netea M.G., Alisjahbana B., Hill P.C., and van Grevel R. 2014. Early clearance of
Mycobacterium tuberculosis: a new frontier in prevention. Immunology. 141(4):506-513.
21. Boon C. and Dick T. 2012. How Mycobacterium tuberculosis goes to sleep: the dormancy survival regulator DosR a decade later. Future Microbiol. 7(4):513-8.
22. Houben R.M. and Dodd P.J. 2016. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 13(10):e1002152.
23. World Health Organization (WHO) (ed.). 2017. Guidelines for treatment of drug-susceptible tuberculosis and patient care. 2017 Update. World Health Organization, Geneva, Switzerland. 24. National Institute of Health (NIH) (ed.). Clinical and research information on drug-induced liver-injury. U.S. National Library of Health, Bethesda, United States of America. Accessed: March 16th 2018 via www.livertox.nih.gov.
25. Stop TB Partnership (ed.). Drug pipeline. Stop TB Partnership. Accessed: March 16th 2018 via www.newtbdrugs.org.
26. Pasipanodya J.G., Srivastava S., and Gumbo T. 2012. Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy. CID. 55(2):169-77.
27. Pasipanodya J.G., Srivastava S., and Gumbo T. 2012. New susceptibility breakpoints and the regional variability of MIC distribution in Mycobacterium tuberculosis isolates. AAC. 56(10):5428.
28. Daskapan A., de Lange W.C.M., Akkerman O.W., Kosterink J.G.W., van der Werf T.S., Stienstra Y., and Alffenaar J.W.C. 2015. The role of therapeutic drug monitoring in individualized drug dosage and exposure measurement in tuberculosis and HIV co-infection. Eur. Respir. J. 45(2):569-571.
19 29. Newman M., Foissy M.M., and Ahmed R.A.. 2015. The use of therapeutic drug monitoring in complex antituberculous and anitretroviral drug dosing in HIV/tuberculosis-coinfected patients. J. Int. Assoc. Provid. AIDS Care. 14(4):295-9.
30. Nijland H.M., Ruslami R., Suroto A.J., Burger D.M., Alisjahbana B., van Crevel R., and Aarnoutse R.E. 2007. Rifampicin reduces plasma concentrations of moxifloxacin in patients with tuberculosis. Clin. Infect. Dis. 45(8):1001-7.
31. Ghimire S., Bolhuis M.S., Sturkenboom M.G.G., Akkerman O.W., de Lange W.C.M., van der Werf T.S., and Alffenaar J.W.C. 2016. Incorporating therapeutic drug monitoring into the World Health Organization hierarchy of tuberculosis diagnostics. Eur. Respir. J. 47(6):1867-1869.
32. Sotgiu G., Tiberi S., D’Ambrosio L., Centis R., Alffenaar J.W., Caminero J.A., Abdo Arbex M., Alarcon Guizado G., Aleksa A., Dore S., Gaga M., Gualano G., Kunst H., Payen M.C., Roby Arias A.J., Skrahina A., Solovic I., Sulis G., Tadolini M., Zumla A., Migliori G.B.; International Carbapenem Study Group. 2016. Faster for less: the new “shorter” regimen for multidrug-resistant tuberculosis. Eur Respir. J. 48(5):1503-1507.
33. Van Altena R., Akkerman O.W., Alffenaar J.C., Kerstjens H.A., Magis-Escurra C., Boeree M.J., van Soolingen D., de Lange W.C., Bolhuis M.S., Hoefsloot W., de Vries G., and van der Werf T.S. 2016. Shorter treatment for multidrug-resistant tuberculosis: the good, the bad and the ugly. Eur Respir J. 48(6):1800-1802.
34. Lange C., Duarte R., Fréchet-Jachym M., Guenther G., Guglielmetti L., Olaru I.D., Oliveira O., Rumetshofer R., Veziris N., van Leth F.;European MDR-TB database collaboration. 2016. Limited benefit of the new shorter multidrug-resistant tuberculosis regimen in Europe. Am J Respir Crit Care Med. 194(8):1029-1031.
35. Nuermberger E.L., Yoshimatsu T., Tyagi S., O’Brien R.J., Vernon A.N., Chaisson R.E., Bishai W.R., and Grosset J.H. 2004. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am. J. Respir. Crit. Care Med. 169(3):421-426.
36. Ginsburg A.S., Grosset J.H., and Bishai W.R. 2003. Fluoroquinolones, tuberculosis and resistance. Lancet Infect. Dis. 3(7):432-442.
2A
Chapter
Fluoroquinolones,
the cornerstone of treatment of
drug-resistant tuberculosis:
a pharmacokinetic and
pharmacodynamic approach
A.D. Pranger, J.W.C. Alffenaar, and R.E. Aarnoutse2A
Chapter
Fluoroquinolones,
the cornerstone of treatment of
drug-resistant tuberculosis:
a pharmacokinetic and
pharmacodynamic approach
A.D. Pranger, J.W.C. Alffenaar, and R.E. AarnoutseChapter 2a Fluoroquinolones for tuberculosis: a PK/PD approach
22
Abstract
Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-administered agents on these characteristics, for the currently used FQs (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin) in TB treatment. Future FQs that are being developed may overcome the problems with FQs that are used in daily practice. Therefore PK and pharmacodynamic (PD) properties of novel FQs (clinafloxacin, garenoxacin, lomefloxacin, sitafloxacin, sparfloxacin, trovafloxacin, gemifloxacin, grepafloxacin and DC-159a) were evaluated in TB treatment as well. Integrating both excellent PK and PD properties, moxifloxacin, possibly at a higher dosage, may fulfil a far more important role in the treatment of multi-drug and early-generation FQ resistant TB than proposed in the current WHO guideline. Sparfloxacin, trovafloxacin and sitafloxacin are upcoming novel FQs that may be useful for drug-resistant TB based on their favourable PK properties or microbiological susceptibility against M. tuberculosis. Finally, the 8-methoxy moiety, as present in the chemical structure of MFX, will possibly provide DC-159a with promising PK/PD characteristics and consequently this FQ may develop into a key FQ in future drug-resistant TB treatment.
23
Introduction
The global extent in multidrug resistant tuberculosis (MDR-TB) cases is very alarming (1-6). The proportion of MDR-TB among new TB cases has nearly tripled to about 3% since 2004, with high rates up to 22% in certain countries (7). In addition, it should be recognized that rates of MDR-TB could become even 4-fold higher than currently assumed, if new susceptibility breakpoints for first-line TB drugs were used, based on current pharmacokinetic/pharmacodynamic science and variability in exposure to these drugs (8). Fluoroquinolones (FQs) are key players in the field of MDR-TB treatment (1;9). Unfortunately, FQ resistance or “pre-extensively drug resistant TB” is upcoming and reported worldwide for ciprofloxacin (CFX), levofloxacin (LFX), moxifloxacin (MFX) and particularly for ofloxacin (OFX) (2;4;6;10-30), but a lack of resistance have been reported for aforementioned agents as well (19;31-38). Furthermore, extensively drug-resistant tuberculosis (XDR-TB), is becoming more of a global health concern, predominantly due to inadequate management of MDR-TB (1;2;12;15;17;23;25;39-45).
In daily practice, there are several guidelines and publications on how to manage drug-resistant TB (1;15). According to the current WHO guideline (46), TB drugs are divided into five groups to be of help for a practicing physician to make a choice for the right drug. MDR-TB treatment regimens should be designed with a systematic approach based on a hierarchy in these groups. Together with injectable TB drugs (i.e. group 2), FQs (i.e. designated as group 3) are considered to be the cornerstone of MDR-TB regimens. The further classification of FQs in generations is based on integration of both microbiological susceptibilities and pharmacokinetic (PK) data (47). Drugs that are active against M. tuberculosis belong to the second (CFX and OFX), third (LFX and GFX) and fourth generation (MFX) of FQs. According to the current WHO guidelines for programmatic management of drug-resistant tuberculosis, CFX should be no longer part of an MDR-TB regimen as time to achieve sputum conversion will prolong and the relapse rate will increase (46;48). Despite its moderate anti-mycobacterial activity, the low cost drug OFX is still widely used in resource-limited countries (41;46). OFX resistance seems therefore not surprising. Instead, a later-generation FQ (i.e. LFX) is recommended in the drug-resistant regimen. MFX is not yet recommended by the WHO, with the argument that there is insufficient data to substantiate its long-term safety. GFX should only be used as last remedy, in case there is no other later-generation FQ available (46). In this period of emerging FQ resistance, novel FQs are needed for future drug-resistant TB regimens. Based on their molecular structure, the new FQs, sitafloxacin (STX), sparfloxacin (SFX) and clinafloxacin (CLX) are suggested to be highly active, in contrast to grepafloxacin (GPX), gemifloxacin (GMX), trovafloxacin (TFX)
Chapter 2a Fluoroquinolones for tuberculosis: a PK/PD approach
Chapter
2
a22
Abstract
Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-administered agents on these characteristics, for the currently used FQs (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin) in TB treatment. Future FQs that are being developed may overcome the problems with FQs that are used in daily practice. Therefore PK and pharmacodynamic (PD) properties of novel FQs (clinafloxacin, garenoxacin, lomefloxacin, sitafloxacin, sparfloxacin, trovafloxacin, gemifloxacin, grepafloxacin and DC-159a) were evaluated in TB treatment as well. Integrating both excellent PK and PD properties, moxifloxacin, possibly at a higher dosage, may fulfil a far more important role in the treatment of multi-drug and early-generation FQ resistant TB than proposed in the current WHO guideline. Sparfloxacin, trovafloxacin and sitafloxacin are upcoming novel FQs that may be useful for drug-resistant TB based on their favourable PK properties or microbiological susceptibility against M. tuberculosis. Finally, the 8-methoxy moiety, as present in the chemical structure of MFX, will possibly provide DC-159a with promising PK/PD characteristics and consequently this FQ may develop into a key FQ in future drug-resistant TB treatment.
23
Introduction
The global extent in multidrug resistant tuberculosis (MDR-TB) cases is very alarming (1-6). The proportion of MDR-TB among new TB cases has nearly tripled to about 3% since 2004, with high rates up to 22% in certain countries (7). In addition, it should be recognized that rates of MDR-TB could become even 4-fold higher than currently assumed, if new susceptibility breakpoints for first-line TB drugs were used, based on current pharmacokinetic/pharmacodynamic science and variability in exposure to these drugs (8). Fluoroquinolones (FQs) are key players in the field of MDR-TB treatment (1;9). Unfortunately, FQ resistance or “pre-extensively drug resistant TB” is upcoming and reported worldwide for ciprofloxacin (CFX), levofloxacin (LFX), moxifloxacin (MFX) and particularly for ofloxacin (OFX) (2;4;6;10-30), but a lack of resistance have been reported for aforementioned agents as well (19;31-38). Furthermore, extensively drug-resistant tuberculosis (XDR-TB), is becoming more of a global health concern, predominantly due to inadequate management of MDR-TB (1;2;12;15;17;23;25;39-45).
In daily practice, there are several guidelines and publications on how to manage drug-resistant TB (1;15). According to the current WHO guideline (46), TB drugs are divided into five groups to be of help for a practicing physician to make a choice for the right drug. MDR-TB treatment regimens should be designed with a systematic approach based on a hierarchy in these groups. Together with injectable TB drugs (i.e. group 2), FQs (i.e. designated as group 3) are considered to be the cornerstone of MDR-TB regimens. The further classification of FQs in generations is based on integration of both microbiological susceptibilities and pharmacokinetic (PK) data (47). Drugs that are active against M. tuberculosis belong to the second (CFX and OFX), third (LFX and GFX) and fourth generation (MFX) of FQs. According to the current WHO guidelines for programmatic management of drug-resistant tuberculosis, CFX should be no longer part of an MDR-TB regimen as time to achieve sputum conversion will prolong and the relapse rate will increase (46;48). Despite its moderate anti-mycobacterial activity, the low cost drug OFX is still widely used in resource-limited countries (41;46). OFX resistance seems therefore not surprising. Instead, a later-generation FQ (i.e. LFX) is recommended in the drug-resistant regimen. MFX is not yet recommended by the WHO, with the argument that there is insufficient data to substantiate its long-term safety. GFX should only be used as last remedy, in case there is no other later-generation FQ available (46). In this period of emerging FQ resistance, novel FQs are needed for future drug-resistant TB regimens. Based on their molecular structure, the new FQs, sitafloxacin (STX), sparfloxacin (SFX) and clinafloxacin (CLX) are suggested to be highly active, in contrast to grepafloxacin (GPX), gemifloxacin (GMX), trovafloxacin (TFX)
Chapter 2a
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and garenoxacin (GNX) which appear to be moderately active against M. tuberculosis DNA gyrase (49). Therefore, FQs that are promising for future TB treatment may help to overcome the resistance against currently important key FQs.
Despite favourable microbiological and/or pharmacokinetic properties for treatment of (drug-resistant) tuberculosis, most of the FQs are not marketed agents for treatment of tuberculosis. A summary of the currently registered indications and of the clinical development state for TB treatment of the currently used and novel FQs is shown in Table 1.
The aim of this review is to integrate available data on pharmacokinetic (PK) properties with reported microbiological susceptibility against (drug-resistant) M. tuberculosis and eventually to evaluate the pharmacodynamic (PD) parameters, as well as the influence of co-administered agents on both PK and PD characteristics, of currently used and novel FQs in the treatment of drug-resistant TB. Based on available data, it seems prudent to revise or expand the treatment criteria and consider other FQs to be one of the cornerstone drugs in the drug-resistant TB regimen. In addition, this review indentifies FQs for which more clinical research is required along with the need to revise the current state of affaires on the market of some FQs. Table 1 (I) . S ta te of c lini ca l de vel op m en t i n T B tre atm en t a nd g en era l m ar keti ng s tatu s. FQ Ma rk eti ng s tat us oth er t ha n TB 1,7 Regi st ered str en gth (m g) Regi st ered i nd ic at ion 2, 7 Cl ini ca l de vel op m en t stat us for T B trea tm en t 3 Ref erenc es S ec on d g en erat io n CF X (Ci pro®) Ap pr ov ed 100 – 75 0 (c om pl ic ate d) 4 urin ar y trac t i nf ec tion s, py el one ph rit is 4 , ac ute u nc om pl ic ate d c ys tit is , c hroni c ba ct eria l pros tat iti s, l ow er r es pi rato ry trac t i nf ec tio ns , a cut e si nu si tis , S SS I, b on e an d j oi nt inf ec tio ns , c om pl ic ate d intra -a bd om ina l i nf ec tion s, i nf ec tiou s d iarr he a, t yph oi d fev er, unc om pl ic at ed c er vi cal a nd urethra l g on orr ha, inh al ati ona l a nth rax 5 None (408 ) O FX Ap pr ov ed 200 – 40 0 Unk no w n Pha se II (20 8;4 08 ) Thi rd g en er ati on G FX Di sc on tinu ed 8 Unk no w n Unk no w n Pha se III (20 8;4 08 ) LFX (Le va qu in® ) Ap pr ov ed 250 - 7 50 Pne um on ia (nos oc om ial an d c om m un ity ac qu ired ), ac ute b ac teri ca l s in us iti s, a cute ba ct eric al ex ac erba tio n or c hroni c br on chi tis , (u n)c om pl ic ate d SS SI, c hr on ic ba cter ia l pros tat iti s, (u n)c om pl ic ate d u rina ry trac t inf ec tion s, ac ute p ye lon eph riti s, i nh al ati ona l an thrax Pha se III 6 /IV 6 (40 8;4 09 ) 1 The m ar keti ng s tat us is ind ic ate d as the s tat e of the F Q on the m ar ket of the Uni te d Sta tes an d or Euro pe an Uni on ; 2 In di cat ed in ad ul ts ( at lea st 18 y ears ) inf ec ted wi th s us cep tib le m ic ro organ is m s un les s in di cate d oth erw is e; 3 The c lin ic al de ve lo pm en t s tat us w as ind ic at ed as “no ne ” whe n no Ph as e I t o IV c lini ca l trai l r eg is tered on c lini ca ltr ial s.go v or av ai lab le as li ter atu re on P ubm ed ; 4 In c hi ldren; 5 In adu lts a nd c hi ldren; 6 Mu lti drug res is tan t tu be rc ul os is ; 7 The m ar keti ng stat us an d/ or the r eg is tere d ind ic at ion w as ind ic ate d as “ un kno w n” w he n reg is te red da ta was no t a va ila bl e on fda .go v or em ea .eu rop e.e u; 8 D is con tinu ati on du e t o c on si de rat io n o f c om m er ci al po te nti al ; FQ = fl uoroqu ino lo ne , T B = tu be rc ul os is , n .a. = n ot app lic ab le, SS SI = s ki n a nd s ki n s truc ture i nf ec tion s.
