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Tuberculosis (Edinb). Author manuscript; available in PMC 2019 January 01.
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Published in final edited form as:

Tuberculosis (Edinb). 2018 January ; 108: 77–82. doi:10.1016/j.tube.2017.11.004.

THE UTILITY OF PHARMACOKINETIC STUDIES FOR THE

EVALUATION OF EXPOSURE-RESPONSE RELATIONSHIPS FOR
STANDARD DOSE ANTI-TUBERCULOSIS DRUGS
Christine Sekaggya-Wiltshire1, Mohammed Lamorde1, Agnes N Kiragga1, Kelly E Dooley3,
Moses R Kamya4, Andrew Kambugu1, Jan Fehr2, Yukari C Manabe3, and Barbara
Castelnuovo1
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1InfectiousDiseases Institute, College of Health Sciences, Makerere University, Kampala,

Uganda 2Division of Infectious Diseases and Infection Control, University Hospital of Zurich,
University of Zurich, Zurich, Switzerland 3Division of Infectious Diseases, Department of
Medicine, Johns Hopkins University School of Medicine, Baltimore, U.S.A 4School of Medicine,
College of Health Sciences, Makerere University, Kampala, Uganda

Abstract
Tuberculosis (TB) is a major public health problem. Many countries still fall below the minimum
World Health Organization (WHO) TB treatment target success rate. There is conflicting evidence
about whether concentrations of anti-tuberculosis drugs given at standard doses have an effect on
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treatment outcomes. The current data correlating anti-TB drug concentrations and treatment
outcome is limited. This article summarized the existing literature and their utility in evaluating
the association between each anti-TB drug’s concentrations using current target concentrations
and treatment outcomes in patients with pulmonary tuberculosis receiving standard WHO-
recommended dosing.

Keywords
anti-tuberculosis drugs; concentrations; treatment outcomes

INTRODUCTION
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In 2015, 10.4 million people were diagnosed with tuberculosis (TB) worldwide and 1.5
million died. Only 8 out of the 30 high-burden countries have achieved the World Health
Organization (WHO) minimum target TB treatment success rates of 90%.1 Several factors
may contribute to this low success rate including failure to achieve the optimal concentration

Address correspondence to C. Sekaggya-Wiltshire, Infectious Diseases Institute, College of Health Sciences, Makerere University,
Kampala ([email protected]).
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 Sekaggya-Wiltshire et al. Page 2

of anti-TB drugs due to poor adherence, insufficient absorption, drug-drug interactions and
other factors.2, 3
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Standard TB treatment includes 2 months of rifampicin, isoniazid, ethambutol and

pyrazinamide followed by 4 months of rifampicin and isoniazid. Rifampicin and isoniazid
both demonstrate concentration-dependent killing of Mycobacterium tuberculosis.4, 5 For
ease of collection, the concentration at 2 hours (C2hr) is frequently used to estimate the
maximum drug concentration (Cmax) during therapeutic drug monitoring (TDM). In some
cases, the concentration at 6 hours is also collected to identify patients with delayed/poor
absorption.6, 7 The Area under the concentration-time curve (AUC) which describes the drug
exposure better, is expensive and tedious to perform in clinical practice. However, limited
sampling strategies using appropriately timed blood draws (for example at 1, 2 and 6 hours
post dose) can be used to predict the AUC.8, 9
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Reference ranges (targets) for the Cmax of first line anti-TB drugs were derived primarily
from phase I clinical trials in healthy volunteers; rifampicin: 8–24mg/L, isoniazid: 3–6mg/L,
pyrazinamide: 20–60mg/L and ethambutol: 2–6mg/L.6 Several studies have highlighted the
pharmacokinetic (PK) properties of first-line drugs in patients with TB, however, many
patients have drug concentrations below the respective cut-offs.2, 10, 11 It is still unclear
whether these low concentrations actually lead to a higher risk of unfavorable TB treatment
outcomes and/or delay in sputum culture conversion to negative, specifically 2-month
culture conversion.

This article summarizes the existing literature that reports the association between anti-TB
drug concentrations and treatment outcomes in patients with pulmonary tuberculosis and
receiving standard WHO-recommended dosing.
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METHODS
Literature Search Strategy
We carried out a systematic review of studies among adults with TB in which
pharmacokinetic data and TB treatment outcomes were reported and which evaluated the
association between drug pharmacokinetics and outcomes (either TB treatment outcomes or
sputum culture conversion) in patients on standard doses of first line anti-TB treatment. We
searched English-language databases including PubMed/Medline, Embase and Cochrane
reviews for publications up to 31st June 2016. The search strategy included the following
Medical Subject Heading (MeSH) terms: “antituberculous drug” OR “isoniazid” OR
“pyrazinamide” OR “rifampicin” AND “pharmacokinetics” OR “concentration” OR
“kinetics” AND “treatment outcomes” “OR “pharmacodynamics” OR “sputum conversion”
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OR “culture conversion”. We searched for abstracts from targeted conferences including

Conference on Retroviruses and Opportunistic Infections (CROI), International AIDS
Society (IAS), European Congress of Clinical Microbiology and Infectious Diseases
(ECCMID), the International Workshop on Pharmacology of Tuberculosis Drugs and the
Union World Conference on Lung Health. We also searched referenced studies from
publications.

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Inclusion and Exclusion criteria

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We included all retrospective and prospective observational studies as well as clinical trials
in patients with pulmonary TB that met the following criteria: 1) Studies involving standard
dose first-line anti-TB drugs: rifampicin, isoniazid, ethambutol and pyrazinamide with
treatment provided daily according to current WHO guidelines 2) studies whose results
include PK assessments of the anti-TB drugs 3) studies in which TB treatment outcomes
were reported, 4) publications in English. We excluded: 1) studies involving children only 2)
studies involving pregnant women only 3) studies that were categorized as case studies,
commentaries, editorials and reviews 4) studies that did not explore the relationship between
the PK parameters and treatment outcomes 5) studies that specifically enrolled patients with
organ failure.

Data Extraction
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Two researchers (CS and BC) extracted the data from the included studies and entered them
into Excel 2013 (Microsoft Corporation; Redmond, WA, USA). Where discordance on
studies to be included occurred, a third reviewer of (ML) was consulted and consensus
achieved. The following data were extracted: author, year of publication, study
characteristics (location, sample size, study design); population (sex, HIV status); PK
parameters (Cmax, AUC, concentration at 2hrs (C2h)); microbiologic outcomes (proportions
of patients with sputum culture conversion at two months) and treatment outcomes (as
defined by WHO).

RESULTS
We identified 3670 studies from our initial database search and search of referenced studies.
From these, 18 articles were identified for full review after screening by title and abstracts
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(Figure 1). Eight articles were excluded following full review: 4 did not explore the
relationship between anti-TB drug PK and treatment outcomes, 2 carried out dose
adjustment before the sputum conversion was assessed, 1 had no outcome data, and 1
reported drug concentrations only in slow responders and not for the rest of the study
population. In addition, dose adjustment was performed prior to assessment of treatment
outcome. Dates of included studies ranged from 2007 to July 2016. Out of the 10 identified
publications, 7 were prospective2, 12–17, 2 retrospective18, 19, and 1 case control study.20 One
study excluded participants who were HIV-infected20, 1 study reported the proportion of
patients on ART (18%)13 and 6 studies reported that anti-TB treatment was given under
directly observed therapy (DOT).2, 12, 13, 15, 18, 20 Three studies defined the Cmax as the
highest of the measured time points,15, 18, 20 4 studies used a single time point12, 14, 17 and 3
studies used non-compartmental analysis (NCA) to determine the PK parameters.2, 13, 16
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Four studies carried out blood sampling after 8 weeks of TB treatment (Table 1).13, 17, 18, 20
For all studies low concentrations were defined as Cmax or C2hr values below the reference
ranges for Cmax previously defined.6

Rifampicin
Mah et al. found a trend towards increase in month 2 sputum culture positivity among
patients with low rifampicin Cmax (estimated from 2hr and 6hr blood draws) compared to

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those with adequate concentrations, however this did not reach statistical significance (39%
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vs. 21%, P=0.073). This study was a retrospective study where serum drug concentrations
were measured in patients with diabetes mellitus, HIV and those whom clinicians deemed to
have poor clinical response to TB treatment.18 Prahl et al. found that a higher proportion of
patients with a low C2hr of both rifampicin and isoniazid experienced treatment failure
compared to those with concentrations of at least one of the drugs within the reference range
(5/13 versus 0/15, P=0.013). However, this study had a few limitations: the sample size was
small (N=62), 9 patients received a fluoroquinolone in addition to the standard therapy and it
included a group of patients who were undergoing TDM for various clinical reasons. There
was however no difference in drug concentrations and the occurrence of failure between
those who had TDM and those who did not.14

Van Crevel et al. found no association between rifampicin concentrations and time to sputum
conversion. In this study, patient with rifampicin concentrations at C2hr <4mg/L had a cure
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rate of 74% while those with C2hr >4mg/L had a cure rate of 95%; however, the latter group
had a high default rate and therefore this difference was not reported to be significant.17

Isoniazid
Mah et al. found a significant increase in month 2 sputum culture positivity among patients
with a low Cmax of isoniazid compared to those with adequate concentrations (42.5% vs.
18.3%, P= 0.0084).18 Using 3 sampling time points (0hr, 2hr and 6hr), Sloan et al
demonstrated that a low AUC of isoniazid was associated with a lower likelihood of month 2
sputum culture conversion (P=0.045) and a higher likelihood of failure or relapse (P=0.035).
16 Burhan et al evaluated for the association between C
2hr of isoniazid and treatment
outcome, however, no association was found. Although outcomes were generally good,
Burhan demonstrated low concentrations of isoniazid especially among fast acetylators
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when compared with the slow acetylators (0.9 mg/liter versus 2.2 mg/liter, P<0.001).12 In
Prahl’s study, patients with treatment failure had a significantly lower C2hr of isoniazid than
those who were cured (P=0.004).14 Park et al found no association between C2hr of isoniazid
and sputum conversion or treatment outcome, however, TDM with dose adjustment was
carried out in 85% of the participants.19 Requena-Mendez et al found no association
between the low isoniazid concentrations found in 30% of the study population and
treatment outcomes despite deliberately including patients with diabetes mellitus and HIV,
which are risk factors for poor outcomes.15, 21, 22

Pyrazinamide
Burhan et al. evaluated the relationship between the Cmax of pyrazinamide and month 2
sputum conversion. This study did not find an association when looking at month 2 sputum
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conversion alone however following a post hoc analysis including weeks 4, 8 and 24 sputum
culture conversion as a composite outcome, patients with low pyrazinamide concentrations
were less likely to have a negative cultures at either week 4, 8 or 24 sputum culture (Odds
ratio (OR): 0.59; 95% Confidence Interval (CI): 0.37 to 0.93).12 Chideya et al. found an
association between low pyrazinamide Cmax and treatment failure, these findings were more
pronounced in HIV-infected patients with a CD4 cell count ≤ 200cells/μl (P=0.01).2 On the
other hand, Park et al. found no association between C2hr of pyrazinamide and treatment

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outcomes or sputum conversion.19 Sloan et al. and Mcllleron et al. investigated the
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association between the AUC of pyrazinamide, month 2 sputum conversion and treatment
outcomes and found no association.13, 16

DISCUSSION
There is insufficient evidence to suggest that achieving current anti-TB drug targets
correlates with a higher chance of favorable treatment outcomes or two-month sputum
culture conversion in patients on the standard dose anti-TB treatment. Our main finding was
the paucity of studies linking PK to TB treatment outcomes, despite the existence of PK
target concentrations that are used commonly by TB programs around the world. We
concluded that there is limited data to support these target concentrations. Some of the
studies were retrospective or were designed to include patients that were at a high risk of
unfavorable treatment outcomes. This clearly reflects on the quality of the studies and their
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ability to answer the question at hand. The small sample size of most of these studies limits
their ability or statistical power to sufficiently evaluate the multiple factors that may affect
outcomes. In addition, use of a single C2h, which is not very representative of the typical
drug exposure of an individual, may also affect the power to relate PK to treatment
outcomes. The studies included applied highly variable blood sampling time points and
analytical methods and therefore a meta-analyses of this type of heterogeneous information
would be extremely difficult unless there is standardization of both laboratory and
pharmacometric methodologies. Assessment of the proportion of patients who experienced
sputum culture conversion also differed, for example use of different culture methods and
variable definitions of culture conversion, in some instances more than one negative culture
was required to ascertain culture conversion.
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Population PK modeling which includes compartmental analysis is very useful in studies

like these with sparse blood sampling and explains inter-individual PK variability by
exploring several demographic or clinical factors where relationships between exposure and
outcome are non-linear. However, very few studies were able to use this method.

That drug concentrations do not clearly appear to have an effect on outcome is somewhat
counterintuitive. It is possible, though, that the cut-offs are poorly defined and are not
‘targets’. Specifically, average concentrations are not necessarily optimal concentrations.
Indeed, antimicrobial effect seems to be enhanced among patients receiving higher than
standard-dose rifampicin in clinical trials, and the dosing of rifampicin has been called into
question.23, 24

Other pharmacodynamic (PD) markers have been described including the minimum
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inhibitory concentration (MIC) which takes into account the heterogeneity in the
susceptibility of the mycobacteria isolates to the antimicrobial effect. Other authors have
demonstrated that the Cmax/MIC or AUC/MIC ratios may be more useful PK- PD markers
for prediction of treatment outcomes.25, 26

The validity of the commonly used reference ranges for first-line anti-TB drugs needs to be
further investigated. Pasipanodya et al. used a CART analysis to develop new AUC and Cmax

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 Sekaggya-Wiltshire et al. Page 6

cut-offs that predict >91% of the outcomes.27 These Cmax cut-offs were higher than
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currently used cut-offs for isoniazid (8.8mg/L vs 3mg/L) and pyrazinamide (58.3mg/L vs 20
mg/Lf) but lower for rifampicin (6.6 mg/L vs 8 mg/L) and an association between Cmax of
pyrazinamide and 2 month sputum conversion was evident when using these new cut-offs.
These new cut-offs need to be validated in other populations.

For TDM to be of value, the PK parameter that is more closely associated with TB treatment
outcomes (AUC and Cmax) must be defined. Because the Cmax and AUC are strongly
correlated, either of these parameters may be useful and clinicians need to determine which
one would be easier and more practical for clinical use during TDM. The ‘target’ for that PK
parameter must be established, and the optimal sampling times for estimating the parameter
must be determined. It is important to deliver doses that result in concentrations that
maximize microbiologic activity, giving all patients, even hard-to treat patients, the best
chance at cure. It is also essential to optimize dosing of a given drug to prevent emergence of
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resistance to companion drugs.28 What exposures of first-line drugs are required to protect
other drugs in the regimen? Since acquired drug resistance (DR) during treatment is
relatively uncommon (and is often not identified because, in most settings, drug
susceptibility testing is not performed pre-treatment), studying the relationship between PK
and prevention of acquired DR is challenging.

In a meta-analysis by Pasipanodya et al., investigators found that pharmacokinetic variability

of isoniazid, genetically mediated, has an important role in the development of acquired DR
and TB treatment failure.29 In in vitro testing on moxifloxacin, the exposures required to
suppress the drug resistance were different from the exposures needed for maximal
antimicrobial activity. This may apply to other anti-TB drugs.30
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This review demonstrates the limited number of adequately powered studies and the
difference in the PK parameters used to evaluate the association between anti-TB drug
concentrations and treatment outcomes in patients on the daily standard dose of the
recommended WHO TB treatment regimen. Nevertheless, in reviewing the data to determine
whether the current data supports the target concentrations, we high-light the gap in research
on anti-TB drug pharmacology and its application in clinical practice (TDM). Larger studies,
that do not deliberately include patients at risk of treatment failure need to be performed
using the most suitable and practical pharmacological marker which can be applied in
clinical practice.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
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Acknowledgments
We acknowledge the contribution of Richard Senono of the Infectious Diseases Institute, Makerere University and
the South African Cochrane Center, Medical Research Council who assisted in the literature search. We would also
like to acknowledge Dr. Ekwaro Obuku and the Africa Center for Systematic Reviews and Knowledge Translation,
Makerere University for the support provided during the review process.

FUNDING INFORMATION

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 Sekaggya-Wiltshire et al. Page 7

This work was supported by the National Institutes of Health Office of the Director, Fogarty International Center,
Office of AIDS Research, National Cancer Center, National Heart, Blood, and Lung Institute, and the NIH Office of
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Research for Women’s Health through the Fogarty Global Health Fellows Program Consortium comprised of the
University of North Carolina, John Hopkins, Morehouse and Tulane (R25TW009340). The funders had no role in
study design, data collection and interpretation, or the decision to submit the work for publication.

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Figure 1.
PRISMA flow diagram showing study inclusion
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Table 1

Table demonstrating study characteristics and results.

Author Year Location Design Sample Study PK PK PK Sampling Method for Outcome Correlation of
Size drug parameter sampling time point(s) determination measure drug
occasion of PK parameter concentration
with outcome

Mah 201512 2015 Canada Retrospective 153 (134 for RIF, INH Cmax 8 weeks 1–2, 6 hr (INH) 2, 6 hr Highest of time points Month 2 culture conversion Yes (INH)
outcomes) (RIF)
Sekaggya-Wiltshire et al.

Chang 200823 2008 Hong Kong Case control 36 cases 36 RIF Cmax 8 weeks 2, 4 hr Highest of time points Month 2 culture conversion No
controls

Crevel R. 200224 2002 Indonesia Prospective cohort 62 RIF C2h 4 and 8 weeks 2 hr Single time point Month 2 Culture conversion, cure, No
failure

Chideya 20093 2009 Botswana Prospective cohort 225 All Cmax ≥ 1 week 1, 2, 6 hr NCA Failure, death, cure Yes (PZ)

Sloan 201416 2014 Malawi Prospective cohort 133 All Cmax, AUC(0–6h) 2 or 3 weeks 0, 2, 6 hr NCA Month 2 culture conversion, failure, Yes (INH)
death, cure and

Mcllleron 200717 2007 South Africa Prospective cohort 142 All AUC(0–8h) 8 weeks 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, NCA failure, death, cure relapse at 24 No
and 8 hr months

Burhan 201314 2012 Indonesia Prospective cohort 196 INH, RIF, PZ C2h 4 weeks 2 hr Single time point Month 2 culture conversion No*

Prahl 201413 2014 Denmark Prospective cohort 32 active TB, 3 All C2h After day 6 2 hr Single time point Failure, death, cure, relapse at 12 Yes (RIF and INH)
IPT months

Requena-Mendez 201425 2014 Peru Prospective cohort 107 (41 with INH Cmax, AUC(0–6h) After 15 days 2, 6 hr NCA Failure, death, cure, relapse at 6 No
outcomes) months

Park 201615 2015 Korea Retrospective 413 All C2h After 1 week 2 hr Single time point Month 2 Culture conversion, cure, No
failure, relapse

Cmax: Maximum concentrations, AUC: Area under the concentration-time curve, RIF: Rifampicin, INH: Isoniazid, PZ: Pyrazinamide, NCA: Non-Compartmental analysis
*
Post hoc analysis found patients with low pyrazinamide concentrations were at risk of either positive sputum at week 4/8/24/32

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