68

Journal of The Association of Physicians of India Vol. 64 August 2016

Review Article

Importance of Therapeutic Drug Monitoring of

Rifampicin
Prerna K Chawla1, Zarir F Udwadia2, Rajeev Soman3, Ashok A Mahashur2,
Rohit A Amale 2, Alpa J Dherai1,4, Rohan V Lokhande4, Prasad R Naik4,
Tester F Ashavaid1,4
Abstract
Therapeutic Drug Monitoring (TDM) is a routinely practised clinical
laboratory technique which aids the clinicians with a clear clinical
judgement of the drug therapy and optimize the doses if necessary.
Rifampicin is the most important and potent component of first line
therapy of tuberculosis (TB). Several factors like age, weight, gender,
doses and formulations, gastro-intestinal disorders, ethnicity etc alter
the absorption and bioavailability of rifampicin thus altering the drug
levels. Low plasma levels of rifampicin may play a plausible role in
slow response to therapy, treatment failure or relapse or acquired drug
resistance. TB Patients with further complicated conditions like diabetes
or HIV are at an increased risk for poor drug absorption and drug-drug
interactions. A standard treatment regimen may be inadequate for some
cases as the clinical status of patients vary from case to case. TDM can be
used as a clinical tool for identifying patients at high risk of treatment
failure, delayed response, drug-drug interactions and help optimization
of therapy. In the past two decades numerous reports of TDM of antituberculosis drugs have been reported wherein low rifampicin levels
have been a major concern. Rifampicin exhibit concentration dependent
killing of mycobacteria. A 2 hour post-dose sample approximates the peak
plasma rifampicin concentration (Cmax) and is recommended for TDM of
rifampicin. An additional 6 hour sample may be collected to distinguish
between delayed absorption and malabsorption. Combined with clinical
and bacteriological data, TDM can help clinicians treat slow response /
complicated TB patients.

Introduction

uberculosis (TB) is one of

the oldest known infectious
disease and is a leading cause of
mortality in developing countries.
India has a high prevalence of TB
accommodating 11% of the total TB
cases worldwide.1 Treatment for TB
requires good patient adherence
to combination chemotherapy
for an extended period. Despite
directly observed therapy (DOT)
in TB programs, treatment

failure, relapse, acquired drug

resistance, multi-drug resistance,
drug toxicities and extended
treatment duration remain as
o n g o i n g c o m p l i c a t i o n s . 2,3 T h e
bioavailability, pharmacokinetics
and plasma levels of the orally
administered anti-TB drugs vary
differently and are influenced by

patient age, sex, gastro-intestinal

disorders, drug formulations or
drug interactions. 3-6 In such cases
performing therapeutic drug
monitoring (TDM) may benefit TB
patients.

Rifampicin: Kinetics and

Mechanisms of Action
Rifampicin is a critical and
potent component of first-line TB
therapy having unique properties
of a rapid onset action once in
contact with M. tuberculosis. 7 It is
absorbed from the gastro-intestinal
(GI) tract and the rate of absorption
is most variable among all TB
drugs. Following an oral dose,
the peak levels (time to attain
maximum concentration tmax)
are attained within 2 hours with a
Cmax ranging between 4 32 mg/l
as widely reported in literature.8-10,13
Rifampicin is better absorbed in an
acidic condition than in neutral
or alkaline conditions. The peak
levels (Cmax) and Tmax is delayed
in presence of high-fat meals, so
the drug should be given empty
stomach whenever possible. Its
absorption is fairly reduced in fixed
dose combinations with isoniazid
and pyrazinamide. 9-11 A 2 hour
drug level is usually preferred to
estimate peak rifampicin levels.
If delayed absorption (Late peak
levels) or malabsorption (low levels
at all-time points) is suspected, an

1
Research Laboratories, 2Dept of Pulmonary Medicine, 3Dept of Internal Medicine, 4Dept. of Lab Medicine, P.D.
Hinduja Hospital and MRC, Mumbai, Maharashtra
Received: 05.03.2016; Accepted: 26.04.2016

Journal of The Association of Physicians of India Vol. 64 August 2016

additional 6 hour drug level can be

estimated.
Rifampicin inhibits bacterial
DNA-dependent RNA synthesis
by inhibiting bacterial DNAdependentRNA polymerase.
Rifampicin binds to the RNA
polymerase at a site adjacent to the
RNA polymerase active center and
blocks RNA synthesis by physically
blocking the formation of the
phosphodiester bond in the RNA
backbone, preventing extension of
RNA products beyond a length of
2-3 nucleotides (steric-occlusion
m e c h a n i s m ) . 14 R e s i s t a n c e t o
rifampicin arises from mutations
that alter residues of the rifampicin
binding site on RNA polymerase,
resulting in decreased affinity for
rifampicin.Resistant mutations
map to therpoBgene, encoding
RNA polymerase beta subunit. 14
The half-life of rifampicin is
2- 3 hours. 8 Rifampicin induces
its own hepatic metabolism
and hence the Cmax and t 1/2 of
rifampicin decrease over the first
two weeks of therapy. 7,11 Therefore,
patients on longer than 3 weeks
of rifampicin levels tend to have
lower rifampicin levels than their
initial baseline values. Therapeutic
drug monitoring (TDM) of plasma
levels of rifampicin is performed
since decades and a huge interindividual variability is observed
among several ethnic groups. Some
patients are slow to respond to the
standard treatment and TDM may
help identifying this and provide
the clinicians a justified reason to
increase the respective doses or
decrease / increase the treatment
duration. 12,13

Performing TDM and its

Interpretation
Therapeutic drug monitoring
(TDM) involves a clinical laboratory
measurement of a chemical
parameter which with appropriate
medical interpretation helps better
patient management and influence
drug dose prescribing procedures.
The general approach for TDM

in various patient populations is

the same. In case of rifampicin,
measurement of peak levels after
the steady state attainment is
recommended. Therapeutic peak
plasma concentration for rifampicin
has been established in literature
and ranges from 8 24 mg/l.13,15 Drug
concentration at the site of action
cannot be routinely measured,
but the desired or adverse effects
may be correlated better with
the plasma concentrations. In
most cases, rifampicin attains its
peak level after about 2 hours
post dose ingestion and hence a
blood collection at 2 hour post
dose is usually recommended for
TDM. Given the variability of oral
absorption, a single time point may
miss the actual peak concentration.
Therefore, a second sample,
typically 6-hours post-dose, will
help provide to a better judgement
on the rate and completeness of
absorption. The normal pattern for
serum concentrations is that the
2-hour value is substantially higher
than the 6-hour. Malabsorption
may be seen if the 2-hour and
6 - h o u r va l u e s a r e r o u g h l y t h e
same, while delayed absorption is
seen if the 6-hour values are higher
than the 2-hour drug levels. In
these situations, it is possible that
the actual peak occurred between
the two blood collections. Cases
of malabsorption, wherein the
rifampicin levels are below the
therapeutic range, warrant the need
for dose increment and a follow-up
drug level to judge the achievement
of the targeted therapeutic value.
Rifampicin exhibits concentration
dependent killing of mycobacteria
and hence Cmax < 4 mg/l prompt
the need for dose increment. 15,16
Detailed pharmacokineticpharmacodynamic (PK-PD) data
from human studies are lacking
for the TB drugs. Precise targets for
peak serum concentrations (Cmax)
relative to the minimal inhibitory
concentration (MIC) [Cmax : MIC],
or time above MIC, are scarce
from human studies. While few
studies have looked at Cmax as

69

a marker for PK-PD target, 16-19

others have considered the area
under curve of rifampicin (AUC)
i.e the complete concentration
of rifampicin from the time of
ingestion to the elimination or
infinity (AUC 0-). Several studies
a l s o c o r r e l a t e A U C ( a t va r i e d
timepoints) and MIC of rifampicin
suggesting as a better predictor
of the PK-PD target of rifampicin
in hollow fibre models. 19-21 The
A U C 24/ M I C r a t i o r e q u i r e d f o r
a 1-log 10 CFU reduction in vivo
a n d i n s i d e m a c r o p h a g e s we r e
271 and 665, respectively, while
that required in vitro was 30. 19
Attainment of the PK-PD target may
also reflect the therapeutic effect.
In rare situations, with severely
ill patients, higher concentrations
may be warranted with proper
clinical judgements.
Several assay s are available
for estimation of rifampicin drug
levels however, sensitivity and
specificity of assays play a vital
role. In general, high-performance
liquid chromatography (HPLC)
and g as chromat ography (GC)
with the commonly used detection
systems (ultraviolet or fluorescence
detection for HPLC, mass
spectrometry for HPLC or GC)
are preferred. Several precautions
like extensive interference checks,
sample stability should be
performed prior to validating the
assays. 22
For precise interpretation of the
results it is important to record
the time of sample collection, the
time of the last dose, the dosage
regimen and the indication for drug
monitoring. Drug concentrations
need to be interpreted in the context
of the individual patient without
rigid adherence to a target range.
Before making dose adjustments,
it is important to consider if the
sample was taken at the correct
time with respect to the last dose, if
a steady state has been reached and
whether the patient has adhered to
their treatment. 13,23
Change in drug dosage is a
function of patient assessment and

70

Journal of The Association of Physicians of India Vol. 64 August 2016

Table 1: Rifampicin TDM studies worldwide

Country

Author, Year Sample size

Turkey

Kayhan et al,
2011

Turkey

Babalik et al,
2013
Canada Van Tongeren
et al, 2013
Iran
Fahimi F et al,
2013
Tanzania Tostmann et
al, 2013
Korea
Um S.W. et al,
2007
India
Gurumurthy
et al, 2004
India
Prakash J et
al, 2003

India

Arya A et al,
2015

America

Mehta J et al,
2001

India

Present
authors #

% with subInference
therapeutic levels
49
75.50%
Diabetes an independent risk factor ;
Dose adjustments necessary to attain
therapeutic level
21
81%
Acetylator status strongly influenced
absorption of drugs
52
8.40%
Low levels responsible for high rate
of treatment failure and relapse
60
92.50%
Auto induction of rifampicin
metabolism
20
35%
Food interaction; low drugs levels
correlated with treatment failure.
69
23.50%
Low rifampicin levels tend to
increase risk of drug resistance
41
NA
Malabsorption of rifampicin is
common in HIV infected patients
77
NA
Rifampicin levels are increased in
presence of PGP/CYP3A4 blocker;
PGP/CYP3A4 plays an important
role in rifampicin absorption
20 (children
100%
Patients were receiving <10 mg/kg
only)
dose and auto-induction could be
reasons for low drug levels
124
4.80%
Only 6 patients were Slow
responders in view of co conditions.
Follow-up analysis on increasing
drug dose showed increase in
rifampicin level
100
59%
Majority patients were in subtherapeutic range. 50% of the
population were partial responders
to the therapy.

NA: Data unavailable; #: Laboratory data manuscript under publication

clinical judgment. TDM provides

objective laboratory data that is
incorporated into the decision but
is not the sole basis for change in
treatment strategy.

TDM Studies Worldwide

Over 95% of TB deaths occur in
low- and middle-income countries,
and it is among the top 5 causes
of death for women aged 15 to 44
years. 1 The incidence of TB is more
common in developing countries
with India bearing the second
l a r g e s t b u r d e n o f T B . S e ve r a l
studies in varied ethnic groups have
reported low plasma rifampicin
levels and hence the role of TDM
of rifampicin in clinical practise.12-21
The pharmacokinetics of rifampicin
varies in different ethnic groups
especially in countries or territories
with low incidence of TB like
Canada, United States of America
etc as compared to countries with

high incidences like India.24 A recent

study by Prahl et al 25 reported the
clinical significance of 2 hour
plasma levels of first line drugs.
In this prospective observational
study of 32 adults, about 58% of
the population had rifampicin
levels below the therapeutic range.
The authors measured the drug
levels of all four first line drugs
(rifampicin, isoniazid, ethambutol
and pyrazinamide) wherein 86%
patients had atleast one drug below
the normal range. A median plasma
rifampicin level of only 6.5mg/L
was observed in this study group. 25
A similar study reported by Fahimi
et al 12 in 60 TB patients reported
a median peak Cmax of 4.0 mg/L
and that 92% of the patients were
in the sub-therapeutic range for
rifampicin and 81% of the study
group had either of the first line
anti-TB drugs below the normal
ranges. 12 The authors reported
auto-induction of rifampicin as the

plausible reason of low drug levels

in the study group. In another
study, 5 68% of the study group
had low rifampicin levels among
a t ot al of 52 pat ient s en rol l ed
in the study. About 90% of the
study group had either of the first
line drugs in the lower range. A
follow-up drug level in patients
with a low baseline level and dose
increase reflected an increase in
t h e d r u g l e ve l s . H o we ve r , t h e
s a m p l e s i z e o f t h e g r o u p wa s
small to represent and explain the
pharmacokinetics of these drugs.
Table 1 summarizes the various
TDM studies performed worldwide
with respect to rifampicin.
While several studies are
reported for low rifampicin levels
in various ethnic groups, a few
have focussed on understanding
the pharmacokinetics of these
drugs. The ratio of Cmax : MIC
of rifampicin is evaluated in a
study reported by Van Crevel et
al wherein an estimated ratio of
30 was targeted with a Cmax of >
8 mg/l and MIC 0.25 of rifampicin
[16]. In the same study more than
50% of the study group had Cmax
: MIC < 10. The PK-PD targets
h a ve n o t ye t b e e n e s t a b l i s h e d
in human while several studies
report varied target points like 271
in vitro, 665 in macrophages etc.
using the AUC:MIC ratio. 18,19 The
differences in the target points are
dependent on the MIC of rifampicin
c o n s i d e r e d . 2 8 A va r i e d M I C o f
rifampicin for susceptible strains of
mycobacterium have been reported
so far and also it would change
on individual case to case. It is
advisable to evaluate a laboratory
based MIC for susceptible strains
to be used in pharmacokinetic
measurements. 29
Till date no direct association
of a particular factor for low
rifampicin levels have been
established however, differences
in patient characteristics,
dosing formulations, methods
of pharmacokinetic evaluation,
ethnicity, auto-induction of
rifampicin etc have been suggested

Journal of The Association of Physicians of India Vol. 64 August 2016

to account for the discrepancies

reported in literature.
Gender based differences in the
absorption and bioavailability of the
drug have been widely reported. 30,31
Literature reports suggest the
delay in diagnosis of TB symptoms
among females as compared to
males due to several factors like
(i) biological factors (occurrence
of symptoms, severity of disease);
(ii) health care system factors
(availability of health care service,
accessibility of service, quality of
service); and (iii) socio-economic
a n d c u l t u r a l f a c t o r s ( p o ve r t y ,
social stigma, isolation, cultural
behaviour and belief). 31 However,
once diagnosed and started on
treatment, females clinically
improve faster as compared to
males. These findings are further
supported by the low rifampicin
levels in males as compared to
females. 16,20,30 This could possibly
be due to good compliance, nonalcoholic or non-smoker status in
women.
In India, studies on plasma
rifampicin levels are limited to the
patients with HIV, 32 or amongst
c h i l d r e n 35 a n d o n d r u g - d r u g
interactions. 11,33,34 The authors in
the present review article have
performed TDM of rifampicin in
Indian patients suffering from
active tuberculosis wherein
low plasma rifampicin levels is
observed in majority patients and is
a major concern. (Manuscript under
preparation).

Patients with Complicated

Co-conditions
Patients with Diabetes Mellitus:
Gastro-intestinal (GI) problems
including gastroparesis is common
among Diabetics and hence these
patients are at an increased risk
of delayed or malabsorption of
drugs. Heysell et al have reported
among 350 patients, 14% (n=42/350)
o f t h e s t u d y g r o u p we r e s l o w
responders to the therapy. Among
these, 52% (n=22/42) had rifampicin
levels below the reference range.

Diabetes was an independent risk

factor (p=0.03) for low rifampicin
levels in this study. A follow-up
after increase in dose improved
t h e d r u g l e ve l s a s we l l a s t h e
clinical outcome. 6,37 In a similar
study reported by Babalik et al, the
diabetics had half the rifampicin
levels than the non-diabetics. After
30 days of therapy, all the diabetic
p a t i e n t s h a d r i f a m p i c i n l e ve l s
below the reference range. 4 These
studies suggest diabetics need close
monitoring in terms of drug levels
and clinical outcome.
Patients co-infected with HIV:
HIV-positive patients are more
likely to progress to active disease
if exposed to or previously infected
w i t h T B . 3 2 Pa t i e n t s w i t h H I V
infection have an increased risk
of other concurrent opportunistic
infections and due to large intake
of heavy dose drugs, they are at
an increased risk of malabsorption
or drug drug interactions. 32-34,38-40
In an Indian study reported by
Gurumurthy et al, a decreased
bioavailability of rifampicin was
seen in HIV infected TB patients
than the non-HIV TB patients. 32
Similar trends were reported in
other ethnic groups as well. Both
diseases require long durations of
treatment thus demanding correct
dosing and appropriate care taken
in the treatment regimen. Also,
when one considers the cost of the
HIV drugs, TDM appears to be a
relatively inexpensive way to verify
the correct doses.
Patients with Renal Failure or
Hepatic Dysfunction: Chronic renal
failure compromises the immune
system. Patients receiving dialysis
are far more likely to go on to have
active TB disease than those with
normal renal function, whether
they are latently infected or newly
exposed to TB. 13,15,41 Rifampicin is
cleared via the hepatic route. Toxic
drug levels or one of the major
side-effects of rifampicin include
hepatotoxicity. Patients with either
hepatic or renal dysfunction often
experience nausea and vomiting.
This can produce the dual problems

71

of malabsorption and reduced drug

clearance. Therefore, it is reasonable
to check serum concentrations
in patients with significant renal
or hepatic dysfunction, so that
each patient gets the correct,
individualised dose. 15

Conclusion
Thus to conclude, TDM may
not be mandatory for all patients
however, slow responders,
patients with further complicated
conditions warrant the need of
TDM. The alternate to TDM is to
watch, wait and hope for the best.
Serum concentrations is just one
of the several factors needed to be
considered for clinical judgement
and it is important to treat the
individual patient and not the
l a b o r a t o r y va l u e . T h e c l i n i c a l
condition of the patient, the extent
of disease, the susceptibility of
the organisms once it becomes
a va i l a b l e , a n d t h e r a p i d i t y o f
the clinical and bacteriological
response are also important
parameters needing consideration.
Drug concentrations may be used
as surrogates for drug effects so
therapeutic drug monitoring may
assist with dose individualisation.
It can also be used to detect toxicity,
so therapeutic drug monitoring can
optimise patient management and
improve clinical outcomes.
Disclosures

All authors declare that they

have no conflict of interest.

References
1.

Global tuberculosis report 2014 WHO

Library Cataloguing-in-Publication Data,
ISBN 978 92 4 156480 9

2.

Heysell S, Moore J, Keller S, Houpt E.

Therapeutic Drug Monitoring for Slow
Response to Tuberculosis Treatment in a
State Control Program, Virginia, USA. Emerg
Infect Dis 2010; 16:1546-1553.

3.

Kayhan S. Therapeutic monitoring of

isoniazid, rifampicin, ethambutol and
pyrazinamide serum levels in the treatment
of ac tive pulmonar y tuberculosis
a n d d e te r mi n a nts of thei r ser um
concentrations. African Journal of Pharmacy
and Pharmacology 2011; 5:2035-2041.

4.

Babalk A, Ulus I, Bak irci N, et al.

72

Journal of The Association of Physicians of India Vol. 64 August 2016

Pharmacokinetics and serum

concentrations of antimycobacterial drugs
in adult Turkish patients. The International
Journal of Tuberculosis and Lung Disease
2013; 17:1442-1447.
5.

6.

Van Tongeren L, Nolan S, Cook V, et al.

Therapeutic drug monitoring in the
treatment of tuberculosis: a retrospective
analysis. The International Journal of
Tuberculosis and Lung Disease 2013; 17:221224.
Heysell S, Moore J, Staley D, et al. Early
Therapeutic Drug Monitoring for Isoniazid
and Rifampin among Diabetics with Newly
Diagnosed Tuberculosis in Virginia, USA.
Tuberculosis Research and Treatment 2013;
2013:1-6.

of rifampicin in tuberculosis patients in

Indonesia. Internat J Tuberculosis Lung Dis
2002; 6:497-502.
17. Tostmann A, Mtabho C, Semvua H, et al.
Pharmacokinetics of First-Line Tuberculosis
Drugs in Tanzanian Patients. Antimicrobial
Agents Chemotherapy 2013; 57:3208-3213.
18. Gumbo T, Louie A, Deziel M, et al.
Concentration-Dependent Mycobacterium
tuberculosis Killing and Prevention of
Resistance by Rifampin. Antimicrobial
Agents Chemotherapy 2007; 51:3781-3788.
19. Jayaram R, Gaonkar S, Kaur P, et al.
Pharmacokinetics-Pharmacodynamics of
Rifampin in an Aerosol Infection Model
of Tuberculosis. Antimicrobial Agents
Chemotherapy 2003; 47:2118-2124.

7.

Peloquin CA. Antituberculosis Drugs:

Pharmacokinetics. In Heifets, L, ed. Drug
Susceptibility in the Chemotherapy of
Mycobacterial Infections. CRC Press, Boca
Raton, 1991; 59-88.

20. McIlleron H, Wash P, Burger A. Determinants

of Rifampin, Isoniazid, Pyrazinamide, and
Ethambutol Pharmacokinetics in a Cohort
of Tuberculosis Patients. Antimicrobial
Agents Chemotherapy 2006; 50:1170-1177.

8.

http://www.fda.gov/Safety/MedWatch/
SafetyInformation/ucm234017.htm

9.

E l l a rd G A , Fo u r i e P B. R i f a m p i c i n
bioavailability: a review of its pharmacology
and the chemotherapeutic necessity for
ensuring optimal absorption. Int J Tuberc
Lung Dis 1999; 3(11 Suppl 3):S301-8;
discussion S317-21.

21. Pasipanodya J, McIlleron H, Burger A, et al.

Serum Drug Concentrations Predictive of
Pulmonary Tuberculosis Outcomes. J Infect
Dis 2013; 208:1464-1473.

10. Blomberg B, Spinaci S, Fourie B, Laing R.

The rationale for recommending fixeddose combination tablets for treatment of
tuberculosis. Bull World Health Organ 2001;
79:61-8. Epub 2003 Nov 5.
11. Agrawal S, Singh I, Kaur K, et al. Comparative
bioavailability of rifampicin, isoniazid and
pyrazinamide from a four drug fixed dose
combination with separate formulations at
the same dose levels. International Journal
of Pharmaceutics 2004; 276:41-49.
12. Fahimi F, Tabarsi P, Kobarfard F, et al.
Isoniazid, rifampicin and pyrazinamide
plasma concentrations 2 and 6 h post dose
in patients with pulmonary tuberculosis.
The International Journal of Tuberculosis and
Lung Disease 2013; 17:1602-1606.
13. Peloquin C. Therapeutic Drug Monitoring
in the Treatment of Tuberculosis. Drugs
2002; 62:2169-2183.
14. Campbell EA, Korzheva N, Mustaev A, et
al. Structural mechanism for rifampicin
inhibition of bacterial RNA polymerase.
Cell 2001;104:90112.
15. Alsultan A, Peloquin C. Therapeutic
Drug Monitoring in the Treatment of
Tuberculosis: An Update. Drugs 2014;
74:839-854.
16. Van Crevel R, Alisjahbana B, de Lange
WC, et al. Low plasma concentrations

1991.
30. Requena-Mendez A, Davies G, Ardrey
A, et al. Pharmacokinetics of Rifampin
in Peruvian Tuberculosis Patients with
and without Comorbid Diabetes or HIV.
Antimicrobial Agents Chemotherapy 2012;
56:2357-2363.
31. Thorson A. G ender differences in
tuberculosis. Internat J Infectious Dis 2014;
21:65-66.
32. Gurumurthy P, Ramachandran G, Hemanth
KA, et al. Decreased Bioavailability of
Rifampin and Other Antituberculosis Drugs
in Patients with Advanced HIV Disease.
Antimicrobial Agents Chemotherapy 2004;
48:4473-4475.
33. Ramachandran G, Kumar AKH, Srinivasan
R, et al, Effect of rifampicin and isoniazid
on the steady state pharmacokinetics
of moxifloxacin. Indian J Med Res 2012;
136:979-984.
34. Prakash J, Velpandian T, Pande J, et al.
Serum Rifampicin Levels in Patients with
Tuberculosis. Clinical Drug Investigation
2003; 23:463-472.

22. Desai D. A Review: Validated Analytical

Methods Developed on Antitubercular
Drug, Rifampicin. J Pharm Sci Bioscientific
Res 2015; 5:254-265.

35. Arya A, Roy V, Lomash A, et al. Rifampicin

pharmacokinetics in children under the
Revised National Tuberculosis Control
Programme, India, 2009. Int J Tuberc Lung
Dis 2015; 19:440-445.

23. Noemi Astuti A. The Role of Therapeutic

Drug Monitoring and Pharmacogenetic
Testing in the Management of HIV
Infection: A Review. J AIDS Clin Res 2015; 06.

36. Tappero J, Bradford W, Agerton T, et al. Serum

Concentrations of Antimycobacterial Drugs
in Patients with Pulmonary Tuberculosis in
Botswana. Clin Infect Dis 2005; 41:461-469.

24. Abou-Auda HS. Possible Interethnic

Differences in Rifampin Pharmacokinetics:
Comparison of Middle Eastern Arabs With
Other Populations. Adv Tech Biol Med 2014;
1:112.

37. Mehta J. Utility of rifampin blood levels

in the treatment and follow-up of active
pulmonary tuberculosis in patients who
were slow to respond to routine directly
observed therapy. Chest 2001; 120:1520.

25. Prahl J, Johansen I, Cohen A, et al. Clinical

significance of 2 h plasma concentrations
of first-line anti-tuberculosis drugs:
a prospective observational study. J
Antimicrobial Chemotherapy 2014; 69:2841.

38. Gengiah T, Botha J, Soowamber D, et al. Low

rifampicin concentrations in tuberculosis
patients with HIV infection. J Infect Dev
Ctries 2014; 8.

26. Kimerling M. Low Serum Antimycobacterial

D r u g Le ve l s i n N o n - H I V- I n fe c t e d
Tuberculosis Patients. Chest 1998; 113:1178.
27. Um SW, Lee SW, Kwon YS, et al. Low serum
concentrations of anti-tuberculosis drugs
and determinants of their serum levels.
Internat J Tuberculosis Lung Dis 2007;
11:972-978.
28. Peloquin CA, Jaresko GS,Yong CL, et al.
Population pharmacokinetic modeling
of isoniazid, rifampin, and pyrazinamide.
Antimicrob Chemother 1997; 41:2670-9.
29. Heifets L, Cynamon M. Drug susceptibility
in the chemotherapy of mycobacterial
infections. Boca Raton, Fla.: CRC Press;

39. Perlman D, Segal Y, Rosenkranz S, et al. The

Clinical Pharmacokinetics of Rifampin and
Ethambutol in HIV-Infected Persons with
Tuberculosis. Clinical Infectious Diseases
2005; 41:1638-1647.
40. McIlleron H, Rustomjee R, Vahedi M,
et al. Reduced Antituberculosis Drug
Concentrations in HIV-Infected Patients
Who Are Men or Have Low Weight:
Implications for International Dosing
G u i d e l i n e s . A n t i m i c r o b i a l Ag e n t s
Chemotherapy 2012; 56:3232-3238.
41. Peloquin CA. Pharmacological issues in the
treatment of tuberculosis. Ann NY Acad
Sci2001; 953:157-64.