Pharmacometric Optimization of Second Line Drugs for MDR Tuberculosis Treatment
Pharmacometric Optimization of Second Line Drugs for MDR Tuberculosis Treatment
Multidrug-resistant (MDR) tuberculosis (TB), defined as simultaneous resistance to isoniazid
 and rifampin, has been declared a global emergency. Treatment outcomes are poor, driven by
 toxicity and limited efficacy of the 2nd-line anti-TB drugs.

 Although there is evidence that both anti-TB activity and most of the toxicity of the key
 drugs are related to drug exposure, the pharmacokinetic/pharmacodynamic (PK/PD) relationships
 in patients with MDR-TB are poorly characterized. Moreover potential synergy of drug
 combinations has not been identified in the context of MDR-TB, dosing has not taken into
 account the concentrations needed to suppress resistance, and the role of minimum inhibitory
 concentrations (MICs) in dosing is poorly studied.

 There are therefore opportunities to optimize drug doses and combinations to improve
 efficacy, and reduce toxicity. Based on this observational study of patients on standard
 treatment for MDR-TB, our proposal builds on novel methodologies we have developed, largely
 for drug sensitive TB:

 1. The application of computational analytical techniques to tease out the individual
 contributions of anti-TB drugs used in combination

 2. The development of a treatment response biomarker model based on time-to-positivity in
 liquid culture of serial sputum samples.

 3. The in vitro determination of PK targets for anti-TB activity and the suppression of
 resistance using the hollow fiber models of Mycobacterium tuberculosis (Mtb) (HFM-TB).

 Thus the research will enhance our understanding of current modalities of TB treatment, while
 contributing research approaches for future regimen optimization.

 This protocol describes the clinical research component (points 1&2).

 Aim 1: To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB
 patients. The 2nd-line drugs to be examined are those comprising the standardized regimen
 used in South Africa: kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone.

 Hypothesis: Amongst patients on standard MDR-TB treatment, variation in drug exposure has a
 quantifiable impact on the rates at which viable Mtb are cleared from the sputum.

 Aim 2: To identify drug exposures associated with the risk of treatment-related toxicities in
 patients on a standard 2nd-line regimen for MDR-TB.

 Hypothesis: The risks of specific toxicities associated with kanamycin, pyrazinamide,
 moxifloxacin, ethionamide and terizidone are linked to drug concentrations.
Aim 1: To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB
 patients. The 2nd-line drugs to be examined are those comprising the standardized regimen
 used in South Africa: kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone.

 Hypothesis: Amongst patients on standard MDR-TB treatment, variation in drug exposure has a
 quantifiable impact on the rates at which viable Mtb are cleared from the sputum.

 Rationale: There is substantial variability in the PK parameters of the 2nd-line drugs
 between patients, and in the susceptibility of individual Mtb isolates to those drugs.
 Concentration-dependent activity has been demonstrated for moxifloxacin, pyrazinamide and
 aminoglycosides, and higher doses of moxifloxacin and pyrazinamide have been proposed.
 Studies are needed to identify the most important determinants of treatment response and to
 describe the optimal drug exposures in MDR-TB, taking MICs into account. We will describe the
 exponential decline of viable Mtb in the sputum of MDR-TB patients in a treatment response
 model based on time-to-positivity in liquid culture, thus furthering the field of TB
 biomarker research. We will then define the relationship between PK and the rates of
 eradication of viable Mtb from the sputum of patients on the standard MDR-TB regimen to
 identify the more potent drugs driving treatment response, and to identify synergism or
 antagonism between individual drugs. Examples of specific questions that will be addressed
 include: What is the impact of pyrazinamide resistance on treatment response?; What is the
 impact of inhA mutations on the effect of ethionamide?; and, Should a higher doses of
 moxifloxacin and pyrazinamide be considered?

 Aim 2: To identify drug exposures associated with the risk of treatment-related toxicities in
 patients on a standard 2nd-line regimen for MDR-TB.

 Hypothesis: The risks of specific toxicities associated with kanamycin, pyrazinamide,
 moxifloxacin, ethionamide and terizidone are linked to drug concentrations.

 Rationale: Treatment limiting adverse drug effects are common in patients on MDR-TB treatment
 regimens. Although several common toxicities are linked to specific drugs and are thought to
 be dose-related, the relationship between PK and toxicity has not been adequately studied.
 Overlapping toxicity of antiretroviral drugs in HIV-infected patients, amongst other risk
 factors, may be contributory. Minimum drug concentration thresholds associated with increased
 toxicity would allow optimization of doses by targeting concentrations below which toxicity
 is common, but above which there is optimal efficacy.
Inclusion Criteria:

 Age > 18 years Current diagnosis of pulmonary MDR-TB or rifampicin-monoresistant TB

 Baseline sputum sample with positive Gene Xpert MTB/RIF test, or confirmed positive
 Mycobacterium tuberculosis culture displaying resistance to rifampicin with or without
 isoniazid resistance on standard DST.

 Eligible for standard MDR-TB treatment regimen (see Table 1), or, started on standard
 MDR-TB regimen within the past 1 month.

 Written confirmation of informed consent to participate.

 Pregnant women satisfying all other eligibility criteria may be enrolled.

 Exclusion Criteria:

 Critically ill or medically unstable* e.g. organ failure - on ventilator, receiving
 dialysis for acute renal failure, fulminant hepatitis (*can be recruited once stabilized if
 still eligible), or severe haemoptysis.

 Unwilling to participate, or unable to understand the Participant information and provide
 full informed consent.

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