University of Groningen

Clinical pharmacology and therapeutic drug monitoring of first-line anti-tuberculosis drugsSturkenboom, Marieke Gemma Geertruida

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1INTRODUCTION

2 Chapter 1. Introduction

Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis. It is oneof the infectious diseases with the highest morbidity and mortality in the world. In2014, an estimated 9.6 million people were infected with TB and 1.5 million peopledied due to TB [1].

Patients with active pulmonary TB are the main source of transmission of M. tuber-culosis. The disease is spread in the air when people, who are sick with pulmonaryTB, expel bacteria, for example by coughing. A relatively small proportion of peopleinfected with M. tuberculosis will develop active TB disease. In more than 90% ofpersons infected with M. tuberculosis, the pathogen is contained as asymptomaticlatent infection [2]. Worldwide, one third of the population, approximately twobillion people, have latent infection and are at risk for reactivation [2].

TB typically affects the lungs (pulmonary TB), but can affect other sites as well (ex-trapulmonary TB). Symptoms of active disease are a productive cough often withother respiratory symptoms like shortness of breath, chest pain or haemoptysisand fever with night sweats, fatigue and loss of appetite and body weight [3]. Ex-trapulmonary TB can affect virtually any organ in the body, with a variety of clinicalmanifestations and therefore it requires a high index of clinical suspicion [2].

The most common method for diagnosing TB worldwide is sputum smear micro-scopy. The use of rapid molecular tests to diagnose TB and drug-resistant TB isincreasing. In countries with more developed laboratory facilities, cases of TB arealso diagnosed via culture methods, which is currently the reference standard [1].

Without adequate treatment, TB mortality rates are high [1]. Drug-susceptible TBis treated with the first-line anti-TB drugs, isoniazid, rifampicin (rifampin), pyrazi-namide and ethambutol, during the first two months, continued with isoniazidand rifampicin for another four months [3, 4]. In general, treatment success ratecontinues to be high among new TB cases [1]. However, healthcare providers arestill confronted with treatment failure on a regular basis. In multidrug-resistantTB (MDR-TB), M. tuberculosis is resistant to isoniazid and rifampicin. In 2014, anestimated 480.000 people developed MDR-TB [1]. MDR-TB is difficult and costly totreat, as first-line treatment is not effective. Besides, treatment takes much longerthan six months in drug-susceptible TB, generally it takes 20 months.

1.1 First-line anti-TB treatment

Isoniazid and rifampicin are still the cornerstones of treatment in drug-susceptibleTB. Both drugs are cheap and readily available worldwide. Rifampicin is bacter-icidal, by inhibition of the β-subunit of RNA polymerase of M. tuberculosis. It ishighly effective and extremely valuable in TB treatment, as rifampicin is capable of

1.2. Pharmacology and therapeutic drug monitoring 3

killing both actively dividing and ‘dormant’ bacilli [5].

Isoniazid is a prodrug that is activated by the mycobacterial enzyme KatG [5, 6].It exerts its activity by inhibiting mycolic acid synthesis, which is essential formycobacterial cell wall integrity. If M. tuberculosis lacks the katG enzyme, it showsresistance to isoniazid. Isoniazid is mostly active in the first few days of therapy asit exhibits the most potent early bactericidal activity (EBA), the decrease in numberof bacilli in sputum in the first two treatment days, among the anti-TB drugs.

Pyrazinamide is a prodrug that is bio-activated by the pyrazinamidase enzymeinside M. tuberculosis. The mechanism of action for pyrazinamide is not clearlyunderstood. It has been suggested to act by inhibiting fatty acid synthase I [5]. Butalso inhibition of protein translation or depletion of cellular adenosine triphosphatehave been proposed [5]. Pyrazinamide is an essential component in the treatmentof M. tuberculosis and is supposed to play an important role in new multidrugregimens which focus on shortening treatment duration [7].

Ethambutol acts by inhibiting the synthesis of arabinogalactan, which is part ofthe mycobacterial cell wall. It is used to protect rifampicin from acquired drugresistance and is the least potent of the four first-line anti-TB drugs [5].

1.2 Pharmacology and therapeutic drug monitoring

Pharmacokinetics describes the behaviour of a drug in the patient’s body, includingabsorption, distribution, metabolism and excretion, whereas pharmacodynamicsdescribe the biochemical or pharmacological effect of a drug at the site of actionin the patient’s body. Together, both parameters determine the pharmacologicalprofile of the drug.

In infectious diseases, the pharmacological effect of the drug is directed against thepathogen. The minimum inhibitory concentration (MIC), a measure of potencyof the drug for the microorganism, is the lowest concentration at which the druginhibits growth of M. tuberculosis. In case of first-line anti-TB drugs, actual MICsare often unknown. Critical concentrations or breakpoints have been defined as theMIC above which maximum tolerated doses fail to effectively kill M. tuberculosis[8]. Conventionally, these critical concentrations were 1.0 mg/L for rifampicinand 0.2 mg/L and 1.0 mg/L for low-level and high-level resistance for isoniazid.However, Gumbo et al. advocated the use of much lower critical concentrations,0.0625 mg/L for rifampicin and 0.0312 and 0.125 mg/L for isoniazid, suggestingthat M. tuberculosis is resistant at a much lower level [8].

The efficacy of anti-infective drugs is not only dependent on the pathogens re-lated MIC, but also on the exposure of the drug in the patient. The area under

4 Chapter 1. Introduction

the concentration-time curve (AUC) over 24 h in steady state (AUC0–24) representsthis exposure. Studies in both hollow fiber infection models and murine modelsshowed that the AUC divided by the MIC (AUC/MIC ratio) is the best predictivepharmacokinetic/pharmacodynamic parameter for determination of the efficacyof first-line anti-TB drugs [9–15]. More importantly, these data were recently con-firmed in TB patients, as poor long-term outcome was predicted by low AUC valuesof pyrazinamide, rifampicin and isoniazid [7].

For a long time, it was suggested that poor compliance was the cause of acquireddrug resistance of M. tuberculosis. Now it has become clear that pharmacokineticvariability is much more likely to be the driving force of drug resistance [16]. In thestudy by Pasipanodya et al., low maximum concentrations (Cmax) or peak levelsof rifampicin or isoniazid preceded all (three) cases of acquired drug resistance in142 TB patients [7]. Therefore, both AUC and Cmax are important parameters toinvestigate. This can be done using therapeutic drug monitoring (TDM).

The International Association of Therapeutic Drug Monitoring and Clinical Toxic-ology defined TDM ”as a multi-disciplinary clinical specialty aimed at improvingpatient care by individually adjusting the dose of drugs for which clinical experi-ence or clinical trials have shown it improved outcome in the general or specialpopulations. It can be based on an a priori pharmacogenetic, demographic and clin-ical information and/or on the a posteriori measurement of blood concentrationsof drugs (pharmacokinetic monitoring) and/or biomarkers (pharmacodynamicmonitoring).”

TDM has been used when it is impossible to measure the pharmacodynamic effectof the drug faster or in a more direct way. For antibiotics this is often true, as itis both difficult and time-consuming to observe whether the infection is beingtreated adequately. If the infection is not treated adequately, it may be too late toturn the tide. However, in the case of anti-TB drugs, a therapeutic range or targethas not been established. Until recently, the available data was based mostly onmeasurements in TB patients, rather than target values based on outcome. It haslong been thought that exposure was sufficient and TDM was not indicated. Hence,TDM of first-line anti-TB drugs has not been performed on a regular basis.

Moreover, obtaining a full concentration-time curve to calculate the AUC valuesis a laborious and expensive procedure and it is therefore not feasible in clinicalpractice. Alternative strategies to easily evaluate drug exposure are urgently needed.An optimal sampling procedure based on a population pharmacokinetic modelmay help to overcome these problems. This method implies that a limited numberof appropriately timed blood samples are needed to adequately predict the AUC asa measure for drug exposure [17–19].

1.3. Outline of the thesis 5

However, there are more hurdles to take. Not many laboratories are capable of per-forming bioanalysis, as no commercially available assays exist and thus all methodshave to be developed in-house. As a consequence, TDM has long been thought tobe too costly and too difficult. Finally, once one has decided on performing TDM offirst-line anti-TB drugs, the logistics of the blood samples is complicated by boththe instability of the drugs in blood and the contagiousness of the material.

Treatment with the first-line anti-TB drugs, though usually successful, is increas-ingly challenged by the emergence of drug resistance, toxicity, relapse and non-response. It is believed that for both rifampicin and isoniazid higher doses mightwell be indicated and tolerated [5, 20–22].

We hypothesize that it is necessary to move away from the ‘one size fits all’ approach[23]. The aim of this thesis is to develop methods to facilitate TDM of first-lineanti-TB drugs and to optimize treatment in drug-susceptible TB patients.

1.3 Outline of the thesis

In Chapter 2, a review is presented on the use of liquid chromatography-tandemmass spectrometry (LC-MS/MS) in TDM of anti-infective drugs. Pharmacokineticand pharmacodynamic parameters are discussed. We explore aspects of newmatrices such as saliva and new sampling techniques like dried blood spot (DBS)and their analysis.

The objective of Chapter 3 was to develop a fast, simple and reliable LC-MS/MSmethod for the simultaneous determination of isoniazid, pyrazinamide and etham-butol in human serum for TDM and pharmacokinetic studies.

In Chapter 4, we describe a recently initiated international interlaboratory qualitycontrol (QC) or proficiency testing programme for the measurement of anti-TBdrugs. In the first round of this programme, the four first-line anti-TB drugs and thesecond-line TB drugs moxifloxacin and linezolid were included. The programmeaddresses the utility of an ongoing QC programme in this area of bioanalysis.

The objective of Chapter 5a was to develop an optimal sampling procedure basedon population pharmacokinetics to predict AUC0–24 of rifampicin. In Chapter 5b,we discuss the need of well-designed pharmacokinetic studies to produce reliabledata and relevant outcome.

In Chapter 6, we performed a retrospective study in TB patients in which we determ-ined the correlation of clinical variables with exposure of isoniazid and rifampicin.The aim was to discuss the maximum dose of isoniazid and rifampicin, which isguided by the World Health Organization [3].

6 Chapter 1. Introduction

Concomitant food is known to influence pharmacokinetics of first-line anti-TBdrugs in healthy volunteers. However in treatment-naive TB patients who arestarting with drug treatment, data on the influence of food intake on the phar-macokinetics are absent. In Chapter 7, we performed a prospective randomizedcrossover pharmacokinetic study that aimed to quantify the influence of food onthe pharmacokinetics of isoniazid, rifampicin, ethambutol and pyrazinamide in TBpatients, starting anti-TB treatment.

In Chapter 8, the outcome of the research in this thesis is discussed and future per-spectives are presented. This chapter is based on a letter to the editor in which westress the importance of well-designed randomized controlled trials to investigatethe effectiveness of TDM on outcome.

References

1. World Health Organization. Global Tuberculosis Report 2015 tech. rep. (2015).

2. Zumla A., Raviglione M., Hafner R. & von Reyn C. F. Tuberculosis. N Engl J Med368, 745–755 (2013).

3. World Health Organization. Treatment of tuberculosis guidelines 4th editiontech. rep. (2010).

4. Blumberg H. M. et al. American Thoracic Society/Centers for Disease Controland Prevention/Infectious Diseases Society of America: treatment of tubercu-losis. Am J Respir Crit Care Med 167, 603–662 (2003).

5. Egelund E. F., Alsultan A. & Peloquin C. A. Optimizing the clinical pharmaco-logy of tuberculosis medications. Clin Pharmacol Ther 98, 387–93 (2015).

6. Timmins G. S. & Deretic V. Mechanisms of action of isoniazid. Mol Microbiol62, 1220–1227 (2006).

7. Pasipanodya J. G., McIlleron H., Burger A., Wash P. A., Smith P. & Gumbo T.Serum drug concentrations predictive of pulmonary tuberculosis outcomes. JInfect Dis 208, 1464–1473 (2013).

8. Gumbo T., Pasipanodya J. G., Wash P., Burger A. & McIlleron H. Redefiningmultidrug-resistant tuberculosis based on clinical response to combinationtherapy. Antimicrob Agents Chemother 58, 6111–5 (2014).

9. Gumbo T., Louie A., Deziel M. R., Liu W., Parsons L. M., Salfinger M. & DrusanoG. L. Concentration-dependent Mycobacterium tuberculosis killing and pre-vention of resistance by rifampin. Antimicrob Agents Chemother 51, 3781–3788 (2007).

References 7

10. Jayaram R. et al. Pharmacokinetics-pharmacodynamics of rifampin in anaerosol infection model of tuberculosis. Antimicrob Agents Chemother 47,2118–2124 (2003).

11. Gumbo T., Louie A., Liu W., Brown D., Ambrose P. G., Bhavnani S. M. & DrusanoG. L. Isoniazid bactericidal activity and resistance emergence: integratingpharmacodynamics and pharmacogenomics to predict efficacy in differentethnic populations. Antimicrob Agents Chemother 51, 2329–2336 (2007).

12. Jayaram R. et al. Isoniazid pharmacokinetics-pharmacodynamics in an aero-sol infection model of tuberculosis. Antimicrob Agents Chemother 48, 2951–2957 (2004).

13. Gumbo T., Dona C. S., Meek C. & Leff R. Pharmacokinetics-pharmacodynamicsof pyrazinamide in a novel in vitro model of tuberculosis for sterilizing effect:a paradigm for faster assessment of new antituberculosis drugs. AntimicrobAgents Chemother 53, 3197–3204 (2009).

14. Srivastava S., Musuka S., Sherman C., Meek C., Leff R. & Gumbo T. Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in Myco-bacterium tuberculosis and the pharmacokinetics and pharmacodynamics ofethambutol. J Infect Dis 201, 1225–1231 (2010).

15. Gumbo T. New susceptibility breakpoints for first-line antituberculosis drugsbased on antimicrobial pharmacokinetic/pharmacodynamic science andpopulation pharmacokinetic variability. Antimicrob Agents Chemother 54,1484–1491 (2010).

16. Srivastava S., Pasipanodya J. G., Meek C., Leff R. & Gumbo T. Multidrug-resistant tuberculosis not due to noncompliance but to between-patientpharmacokinetic variability. J Infect Dis 204, 1951–1959 (2011).

17. Alffenaar J. W., Kosterink J. G., van Altena R., van der Werf T. S., Uges D. R. &Proost J. H. Limited sampling strategies for therapeutic drug monitoring oflinezolid in patients with multidrug-resistant tuberculosis. Ther Drug Monit32, 97–101 (2010).

18. Pranger A. D., Kosterink J. G., van Altena R., Aarnoutse R. E., van der Werf T. S.,Uges D. R. & Alffenaar J. W. Limited-sampling strategies for therapeutic drugmonitoring of moxifloxacin in patients with tuberculosis. Ther Drug Monit 33,350–354 (2011).

19. Magis-Escurra C. et al. Population pharmacokinetics and limited samplingstrategy for first-line tuberculosis drugs and moxifloxacin. Int J AntimicrobAgents 44, 229–34 (2014).

8 Chapter 1. Introduction

20. Ruslami R., Nijland H. M., Alisjahbana B., Parwati I., van Crevel R. & AarnoutseR. E. Pharmacokinetics and tolerability of a higher rifampin dose versusthe standard dose in pulmonary tuberculosis patients. Antimicrob AgentsChemother 51, 2546–2551 (2007).

21. Van Ingen J., Aarnoutse R. E., Donald P. R., Diacon A. H., Dawson R., Plem-per van Balen G., Gillespie S. H. & Boeree M. J. Why Do We Use 600 mg ofRifampicin in Tuberculosis Treatment? Clin Infect Dis 52, e194–9 (2011).

22. Boeree M. J. et al. A Dose Ranging Trial to Optimize the Dose of Rifampin inthe Treatment of Tuberculosis. Am J Respir Crit Care Med 191, 1058–65 (2015).

23. Van der Burgt E. P., Sturkenboom M. G., Bolhuis M. S., Akkerman O. W., Kos-terink J. G., de Lange W. C., Cobelens F. G., van der Werf T. S. & Alffenaar J.-W.End TB with precision treatment! Eur Respir J 47, 680–2 (2016).