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INT J TUBERC LUNG DIS 17(12):1602–1606
© 2013 The Union
http://dx.doi.org/10.5588/ijtld.13.0019
Isoniazid, rifampicin and pyrazinamide plasma concentrations
2 and 6 h post dose in patients with pulmonary tuberculosis
F. Fahimi,*† P. Tabarsi,‡ F. Kobarfard,§ B. D. Bozorg,† A. Goodarzi,† F. Dastan,† N. Shahsavari,†
S. Emami,* M. Habibi,* J. Salamzadeh†
* Chronic Respiratory Disease Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD),
Masih Daneshvari Hospital, Tehran, † Clinical Pharmacy Department, School of Pharmacy, Shahid Beheshti University of
Medical Sciences, Tehran, ‡ Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Masih Daneshvari Hospital,
Shahid Beheshti University of Medical Sciences, Tehran, § Department of Medicinal Chemistry, School of Pharmacy,
Shahid Beheshti University of Medical Sciences, Tehran, Iran
SUMMARY
BACKGROUND:
Low concentrations of anti-tuberculosis
drugs are related to drug resistance and treatment
failure.
O B J E C T I V E : To determine the prevalence of low plasma
concentrations of anti-tuberculosis drugs.
M E T H O D S : The study was performed among 60 pulmonary tuberculosis (TB) in-patients at a tertiary care
university-affiliated hospital in Tehran, Iran. Drug samples were drawn 2 and 6 h post dose for isoniazid (INH),
rifampicin (RMP) and pyrazinamide (PZA); related concentrations were determined using high-performance
liquid chromatography. Plasma drug concentrations, duration of treatment, age, sex, liver enzyme levels, administered doses and smoking status were evaluated and
recorded.
R E S U LT S : Among 60 patients recruited to the study, the
mean (±SD) age was 54.2 (±20.9) years; 39 were female.
The median peak plasma concentrations (Cmax) of INH,
RMP and PZA were respectively 2.5, 4.0 and 43.6 μg /
ml; 81% of the patients had drug plasma concentrations
lower than the target ranges for at least one administered
drug. Respectively 49.1%, 92.5% and 8.7% of the patients had low concentrations of INH, RMP and PZA.
C O N C L U S I O N : The results indicate that RMP concentrations are below the reference range in most patients,
while PZA is within the target range of the standard
doses.
K E Y W O R D S : plasma concentrations; therapeutic drug
monitoring
TUBERCULOSIS (TB) is one of the oldest infectious
diseases known to man, and mostly affects groups
of lower socio-economic status.1 It is the second
leading cause of mortality due to an infectious disease
globally.2 According to the World Health Organization, 8.8 million people were infected with TB in 2010,
leading to 1.4 million deaths worldwide.2 Iran has a
high prevalence of TB, with an annual cumulative
incidence of 13 cases per 100 000 population.3 The
increasing global burden of TB is linked to adverse
drug reactions, particularly drug-induced hepatotoxicity, drug resistance and human immunodeficiency
virus (HIV) infection.1,4
Therapeutic drug monitoring (TDM) is an accepted clinical tool used in the management of many
infectious diseases. TDM allows clinicians to make
timely adjustments to drug regimens for patients who
fail to respond to anti-tuberculosis drugs, such as
slow responders and predisposed patients with drug
interactions, as well as for early detection of therapeutic failure.5,6 Low anti-tuberculosis drug concentrations are common, and are associated with relapse,
treatment failure and resistance, resulting in poor
clinical outcomes.7 The measurement of plasma concentrations of anti-tuberculosis drugs and the establishment of a correlation between drug concentrations
and likely contributing factors are therefore essential,8,9 although it should be kept in mind that drug
concentrations are only one of many factors affecting
anti-tuberculosis treatment.5 Anti-tuberculosis drug
plasma concentrations have been observed to be related to factors such as age, sex, albumin, HIV infection, smoking status and alcohol consumption.10–12
The aim of the present study was to determine
plasma concentrations of the first-line anti-tuberculosis
drugs isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) simultaneously in pulmonary TB patients. The analytical method was developed using a
Correspondence to: Fanak Fahimi, Clinical Pharmacy Department, School of Pharmacy, Shahid Beheshti University of
Medical Sciences, Niayesh and Vali e Asr Intercept, Tehran, Iran. Tel: (+98) 21 8820 0081. Fax: (+98) 21 8887 3704. e-mail:
[email protected]; Payam Tabarsi, Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Masih
Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Tel: (+98) 21 2712 2036. e-mail:
[email protected]
Article submitted 11 January 2013. Final version accepted 2 August 2013.
TDM of anti-tuberculosis drugs
high performance liquid chromatography (HPLC)
system equipped with an ultraviolet (UV) detector. As
ethambutol (EMB) does not have a chromophore
group, it is not detectable by a UV detector; EMB
concentrations were therefore not determined in our
study.13 Moreover, EMB has less therapeutic value
than other first-line anti-tuberculosis drugs and is
rarely responsible for serious adverse effects, such as
hepatotoxicity, frequently associated with the other
anti-tuberculosis drugs.14 Few data are available on
plasma concentrations of anti-tuberculosis drugs in
patients in Iran or other countries in the region.
STUDY POPULATION AND METHODS
Study population and definitions
The present observational study was performed at
the Masih Daneshvari Hospital, National Research
Institute of Tuberculosis and Lung Diseases, Tehran,
Iran, from May 2009 to June 2011 following approval by the hospital’s Ethics Committee. Patients
aged >14 years admitted to the hospital with a diagnosis of pulmonary TB were enrolled in the study after providing written informed consent.
Study subjects were administered the conventional
daily 2-month intensive phase of the four-drug antituberculosis regimen, consisting of 250–300 mg INH
(Darou Pakhsh Pharmaceutical Co, Tehran, Iran), 450–
600 mg RMP (Alhavi Pharmaceutical Co, Tehran,
Iran), 1000 mg PZA (Laboratoires Sterop, Brussels,
Belgium) and 400 mg EMB (Iran Darou Co, Tehran,
Iran). All drugs were approved by the Iran Ministry
of Health and their bioequivalence was confirmed by
the manufacturer. All drugs were taken on an empty
stomach. Blood samples were drawn once patients
had been on treatment for 7 days. Hospital staff observed daily ingestion of anti-tuberculosis drugs.
Patients with any of the following conditions were
excluded from the study: HIV infection, heavy smoking (more than one pack per day), chronic alcohol
consumption, pregnancy, known drug resistance, diabetes mellitus, end stage renal or hepatic disease and
cystic fibrosis, and patients receiving drugs known to
interact with INH, RMP and PZA, such as antifungal
azoles, macrolids that may increase the concentration
of RMP, antacids, and corticosteroids, which can reduce INH values.
The demographic data of eligible patients were extracted from the patient charts (Table). Variables studied included age, sex, weight, smoking status, daily
dose of each drug studied, drug-induced hepatitis,
baseline liver function tests and 2 and 6 h post-dose
drug concentrations. Reference ranges for INH, RMP
and PZA were respectively 3–5, 8–24 and 20–50 μg /
ml.5,15 These ranges represent the expected (average)
concentrations in adults with standard doses of antituberculosis drugs.5
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Table Patients’ demographics and anti-tuberculosis drug
concentrations in the study population (N = 60)
Characteristic
Age, years, mean ± SD
54.2 ± 20.9
Female, n (%)
Weight, kg, mean ± SD
39 (65)
53.6 ± 10.90
HIV-positive, n
Daily drug dose, mg/day, median [IQR]
INH (n = 60)
RMP (n = 58)
PZA (n = 60)
Daily drug dose, mg/kg, median [IQR]
INH (n = 60)
RMP (n = 58)
PZA (n = 60)
Peak plasma concentration 2 h post
dose, μg /ml, median [IQR]
INH (n = 57)
RMP (n = 54)
PZA (n = 57)
Drug concentration 6 h post dose,
μg /ml, median [IQR]
INH (n = 39)
RMP (n = 51)
PZA (n = 51)
Baseline liver enzymes, units/l,
mean ± SD
AST (n = 60)
ALT (n = 60)
ALP (n = 59)
Bilirubin, mg /dl (n = 58)
0
275 [250–300]
600 [450–600]
1000 [1000–1000]
5.10 [4.81–5.53]
9.73 [8.97–11.06]
20.14 [18.52–22.22]
2.5 [1.5– 4.3]
4.0 [2.4–6.4]
43.6 [33.0–53.0]
1.5 [0.8–2.1]
3.9 [2.3–5.3]
34.7 [28.6– 44.6]
27.2 ± 34.6
21.7 ± 23.2
308.4 ± 383.7
0.4 ± 0.3
SD = standard deviation; HIV = human immunodeficiency virus; IQR = interquartile range; INH = isoniazid; RMP = rifampicin; PZA = pyrazinamide;
AST = aspartate aminotransferase; ALT = alanine aminotransferase; ALP =
alkaline phosphatase.
Drug-induced liver injury
Drug-induced liver injury is considered when alanine
aminotransferase levels are three times higher than
the upper limit of normal (ULN) in the presence of
hepatitis symptoms or elevation of up to five times
the ULN in the absence of symptoms.16
Sample preparation and calibration curves
Blood samples were taken 2 and 6 h after drug administration. Separated plasma was centrifuged and
immediately frozen at −70°C. Samples were then
prepared for injection into the HPLC system using
nicotinamide as internal standard (10 μg /ml). Acetonitrile, zinc sulphate and ammonia were used to precipitate the plasma proteins. Samples were vigorously
mixed using a vortex shaker after each addition. The
chromatographic equipment consisted of an Agilent
HPLC 1200 series pump (Agilent Technologies, Santa
Clara, CA, USA); a UV detector adjusted at two set
wavelengths: 254 to detect INH and PZA, and 336 nm
to detect RMP; a C18 reversed-phase column (250.0 ×
4.6 mm, 5 μm); and a micro autosampler. The volume
of injection of the clear supernatant was 100 μl, and
chromatographic separation was performed at room
temperature for 28 min. The mobile phase was a
gradient of water and methanol. The method was
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The International Journal of Tuberculosis and Lung Disease
designed to simultaneously detect first-line antituberculosis drug plasma concentrations (INH, RMP
and PZA) in one HPLC runtime.
Calibration curves were constructed using spiked
plasma samples over the concentration ranges of respectively 0.5–20, 1– 40 and 1.5–60 μg /ml for INH,
RMP and PZA. Finally, concentrations of unknown
samples were calculated by interpolation on the calibration curves.
To confirm the applicability of this method, the
linearity of the calibration curves, precision, accuracy
and limits of quantification and detection were determined for the analysis of INH, RMP and PZA. The
linearity of the calibration plot was in the following
ranges: 0.5–20 μg/ml for INH, 1.5–60 μg/ml for PZA
and 1.0– 40 μg /ml for RMP. Intra-day precision was
2.6– 4% for INH, 5.2–8% for PZA and 2.1–9.3% for
RMP. Inter-day precision was 3.5– 4% for INH, 2.7–
11.5% for PZA and 3.6–8.9% for RMP. The ranges
of accuracy of the method were 92.5–106.5% for
INH, 96–99% for PZA and 92–105% for RMP. The
limits of quantification were respectively 0.5, 1.5 and
1.0 μg /ml for INH, PZA and RMP. The limits of detection were calculated as one third of the limits of
quantification. All calibration standards were prepared
using the procedure mentioned above; the integrated
peak areas were used to draw calibration curves.
Statistical analysis
To explore the associations between the drug concentrations and the study variables, data analyses
were performed using the following statistical tests:
Spearman’s rank correlation and Kendall’s rank correlation for ratio variables with a non-normal distribution of residuals; Student’s t-test for normally
distributed variables; the Mann-Whitney U-test for
non-normally distributed variables; the χ2 test for
categorical parameters; and the multivariate ridge regression for final model building of variables correlated to anti-tuberculosis drug concentrations. P <
0.05 was considered significant. PASW Statistics version 18.0 (SPSS Inc, Chicago, IL, USA) was used for
data analysis.
A three-stage data analysis was developed in which
any relationship between the study variables and the
anti-tuberculosis drug concentrations was assessed using univariate analyses. In the second stage, significant
interactions between the variables (obtained from the
first-stage analyses) that were associated with plasma
levels of anti-tuberculosis drugs with P < 0.05, were
evaluated. At the third stage of the data analysis, a
multivariate ridge regression analysis was performed
instead of the ordinary multivariate regression analysis, as statistically significant interactions were observed
between the study variables in the second stage. These
variables were highly likely correlated with the plasma
concentrations of the anti-tuberculosis drugs.
RESULTS
A total of 60 TB patients (mean [± standard deviation] age 54.2 [±20.9] years; 39 females; mean
weight 53.6 [±10.9] kg) who met the study criteria
were enrolled in the study (Table). All samples were
taken at least 7 days after starting treatment. One
hundred and sixty samples collected from another
group of 80 patients were discarded due to inappropriate storage at −20°C and sample collection was
repeated and frozen at −70°C.
Three patients suffered from drug-induced hepatitis. In two of these, the plasma concentrations of the
three study drugs were higher than the mean plasma
concentrations overall. The highest value of the 2-h
and 6-h concentrations is considered the peak plasma
concentration (Cmax), which was similar to 2-h values
in our study. The median Cmax of INH, RMP and
PZA was respectively 2.5, 4.0 and 43.6 μg /ml.
The assessment of the plasma concentrations of
anti-tuberculosis drugs generated the following results: 81% of the patients had drug plasma concentrations lower than the target ranges for at least one
administered drug. Concentrations were lower than
expected for at least two drugs in 48% of the patients. In 12% of the study population, the plasma
concentrations of all three administered drugs were
lower than target ranges.
The following low drug concentrations were observed: INH (28/57, 49.1%); RMP (50/54, 92.5%)
and PZA (5/57, 8.7%); 34% of the patients had low
concentrations of both INH and RMP. There was no
significant relationship between plasma concentrations and the factors studied, apart from an apparent
difference in 2-h INH plasma concentration between
female and male patients, as well as a trend towards
a lower 6-h INH plasma concentration in males than
in females. The median 2-h INH plasma concentrations were respectively 3.2 (interquartile range [IQR]
1.9–5.0) and 1.9 (IQR 1.2–2.5) μg /ml in females and
males (P = 0.003). The median 6-h INH plasma
concentrations were respectively 1.6 (IQR 1.1–2.3)
and 1.0 (IQR 0.6–1.6) μg /ml in females and males
(P = 0.06).
DISCUSSION
In the present study, we observed low concentrations
of anti-tuberculosis drugs in a significant number of
patients (respectively 49%, 92% and 8% for INH,
RMP and PZA). RMP induces its own metabolism
over the first few weeks of treatment,17 and our results
would include this auto-induction effect. By delaying
TDM after the completion of auto-induction, more
patients with low drug concentrations would be expected.17 In one study, patients who were identified
as slow responders had low RMP and INH concentrations.15 TDM, followed by the correction of lower
TDM of anti-tuberculosis drugs
than expected ranges, could therefore aid in avoiding
drug resistance as well as unnecessary costs. In the
case of PZA, the majority of our patients had concentrations within the target range, which is perhaps due
to the wide reference range for PZA (20–50 μg /ml).
The prevalence of low drug plasma concentration
is common and has been studied previously.10,18,19 In
Tappero et al., 30% of patients had low serum concentrations of INH and 26% had low concentrations
of both INH and RMP.18 Low values for both INH
and RMP, the two most effective anti-tuberculosis
drugs, were also identified in 34% of our patients. Although the prevalence of low drug plasma concentrations may show wide variations for a particular drug
in TB patients,7,10 other studies have reported that low
drug concentrations were associated with factors such
as patient age, sex, drug dosage, malabsorption, low
albumin and patient acetylator profile.4,7 In most cases,
low drug concentrations can be corrected by dose adjustment;20 however, the relation between low plasma
concentrations and clinical outcome is not well defined
and requires extensive pharmacokinetic studies.7
According to previous studies, low concentrations
of INH range from 2% to 48% and plasma concentrations are related to factors such as age, sex, history
of TB, HIV infection and fixed-drug combination
formulations.20 In a previous clinical study on INH
blood concentrations, we observed low concentrations
of the drug in 14.6% of patients and reported a significant correlation between INH plasma concentrations
and duration of INH administration (P < 0.001),
i.e., INH concentration increased with each day of
treatment.21 In the present study, low INH concentrations were found in almost half of our patients. Furthermore, the median INH serum concentration was
higher in female patients than in males at 2 and 6 h
post dose. This may indicate the need for lower doses
of INH in female patients. Female sex could be a risk
factor for hepatotoxicity, and this may be an explanation for the higher plasma concentrations in women
than men at similar INH doses. INH hepatotoxicity
may also be unrelated to drug plasma concentrations,
being an idiosyncratic mechanism.22,23
The distribution of acetylator status in the Iranian
population shows a higher prevalence of slow acetylators over rapid acetylators; slow acetylation is a risk
factor for hepatotoxicity induced by anti-tuberculosis
treatment.24 However, as we did not determine genotyping, and patients with HIV infection or diabetes
mellitus, which are well known determinants of low
serum concentrations of anti-tuberculosis drugs, were
excluded, it is possible that the most common factors
related to exposure to TB drugs were omitted in our
study. Furthermore, the fact that we could not determine EMB concentrations is a limitation of our study.
RMP concentrations were not significantly associated with any of the factors studied, and RMP
plasma concentrations were outside the therapeutic
1605
range in the majority of our patients. According to
one study, peak serum concentrations of RMP were
more likely to be low in patients with diabetes mellitus (P = 0.03),15 probably explaining the slower response in these patients. Although patients with diabetes were excluded from our study, RMP plasma
values were lower than the target range in almost all
patients (92%). In another study, RMP concentrations were substantially outside the target range (low
in 47% and high in 2% of patients).19 Plasma concentrations outside the target ranges should therefore
be adjusted accordingly and patients’ underlying conditions need to be taken into account.
Although TDM is a recognised tool in the treatment of TB, it is currently under-utilised, and is reserved for patients with more serious illness or nonresponders due to its relatively high cost.11,25 TDM
performed earlier in the course of treatment may positively affect treatment outcomes such as treatment
duration, particularly in slow responders.15
In this study, we measured 2-h concentrations of
anti-tuberculosis drugs to obtain peak serum concentrations, and 6-h concentrations to confirm the rate
and completeness of drug absorption. We did not assess EMB concentrations in our patient population as
it is not detectable by a UV detector, which is a limitation of the study. Although EMB is less effective
than other first-line drugs, it also has fewer serious
adverse effects.14 According to previous studies, the
patient’s acetylator status affects INH serum concentrations, and slow acetylation profile is a risk factor
for drug-related hepatotoxicity;12,26 it may therefore
be necessary to monitor the patient’s acetyl-INH:
INH ratio at 2 and 6 h post dose.
Improper administration of anti-tuberculosis drugs
and poor patient adherence are other reasons for low
drug concentrations; however, these factors are less
of a concern in a hospital setting, where directly observed therapy is routinely performed. Periodic liver
function tests were not performed for many patients,
another study limitation. The degradation of antituberculosis drugs in plasma samples (particularly
RMP) is another limiting factor in TDM studies.27 In
the current study, 160 drug samples collected from
80 patients were degraded due to inappropriate storage at −20°C. It has been shown that adding ascorbic
acid to RMP samples can effectively prevent drug degradation, prolonging RMP stability.28 Plasma samples
should thus be supplemented with ascorbic acid, frozen at −70°C and analysed as soon as possible.
CONCLUSIONS
As low anti-tuberculosis drug concentrations are
closely related to drug resistance and therapeutic failure, determinants of drug plasma concentrations
should be identified and dose adjustments performed
accordingly before starting treatment. Subsequent
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The International Journal of Tuberculosis and Lung Disease
studies should focus on developing a comprehensive
procedure for TDM of anti-tuberculosis drugs and
the recruitment of a larger study population to examine the correlation between factors affecting drug
plasma concentrations and drug-induced hepatitis.
Acknowledgements
The authors thank the nursing personnel of tuberculosis wards
and laboratory personnel, especially N Fakhari, S Khobeiri, E
Abdi, M A Khan Mohammadzade, A Sigaroudi and S Mahmoudian
for their collaboration in this study. They also thank S Baniasadi
for her assistance in responding to the reviewers. The study was
performed as part of a Pharmacy thesis. This research was supported financially by a grant received from the National Research
Institute of Tuberculosis and Lung Diseases.
Conflict of interest: none declared.
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TDM of anti-tuberculosis drugs
i
RÉSUMÉ
Les faibles concentrations de médicaments
antituberculeux sont en relation avec la résistance aux
médicaments et les échecs du traitement.
O B J E C T I F : Déterminer la prévalence des concentrations
plasmatiques faibles des médicaments antituberculeux.
M É T H O D E S : Cette étude a été menée chez 60 patients
hospitalisés pour tuberculose pulmonaire dans un hôpital
affilié à une université de soins tertiaires de Téhéran,
Iran. On a prélevé les échantillons de médicaments 2 et
6 heures après la dose d’isoniazide (INH), de rifampicine
(RMP) et de pyrazinamide (PZA) et les concentrations
correspondantes ont été déterminées par chromatographie liquide à haute performance. Les concentrations
plasmatiques des médicaments, la durée du traitement,
l’âge, le sexe, le niveau d’enzymes hépatiques, la dose
administrée et le statut tabagique ont été évalués et
enregistrés.
CONTEXTE :
R É S U LTAT S : Sur les 60 patients recrutés, 39 étaient des
femmes. L’âge moyen (± déviation standard) était de
54,2 (± 20,9) ans. Le pic médian de concentration plasmatique (Cmax) a été de 2,5 μg /ml pour INH, de 4,0 pour
RMP et de 43,6 pour PZA. Au total, les concentrations
plasmatiques des médicaments étaient inférieures aux
limites-cible pour au moins un médicament administré
chez 81% des patients. Des concentrations basses d’INH
ont été présentes chez 49,1% des patients, celles de RMP
chez 92,5% et celles de PZA chez 8,7%.
C O N C L U S I O N : Les résultats de l’étude en cours indiquent que les concentrations de RMP sont inférieures à
la limite de référence chez la plupart des patients, alors
qu’avec la dose couramment administrée, la concentration de PZA se situe à l’intérieur des valeurs-cible.
RESUMEN
D E R E F E R E N C I A : La baja concentración
plasmática de los medicamentos antituberculosos se
asocia con la aparición de resistencia y el fracaso
terapéutico.
O B J E T I V O : Determinar la prevalencia de baja concentración plasmática de los medicamentos antituberculosos.
M É T O D O S : Fue este un estudio realizado en 60 pacientes hospitalizados por tuberculosis (TB) pulmonar en
un hospital universitario de atención terciaria de
Teherán, en Irán. Se tomaron muestras de sangre 2 y 6 h
después de la administración de una dosis de isoniazida
(INH), rifampicina (RMP) y pirazinamida (PZA) y se
midieron las concentraciones plasmáticas respectivas
mediante cromatografía líquida de alta eficiencia. Se
evaluaron y se registraron las concentraciones plasmáticas, la duración del tratamiento, la edad, el sexo, la concentración de las enzimas hepáticas y el tabaquismo.
MARCO
De los 60 pacientes que participaron,
39 fueron mujeres. La media de la edad fue 54,2 años
(desviación estándar: 20,9). La mediana de las concentraciones plasmáticas máximas fue como sigue: INH
2,5 μg/ml, RMP 4,0 μg/ml y PZA 43,6 μg/ml. En general, el 81% de los pacientes presentó concentraciones
plasmáticas inferiores a los límites esperados por lo
menos con uno de medicamentos administrados. Se observaron bajas concentraciones de INH en 49,1% de los
pacientes, de RMP en 92,5% y de PZA en 8,7%.
C O N C L U S I Ó N : Los resultados del presente estudio indican que en la mayoría de los pacientes, con las dosis
corrientes de RMP se alcanzan concentraciones que son
inferiores a los márgenes de referencia pero con la PZA
se obtienen concentraciones que están dentro de los
límites esperados.
R E S U LTA D O S :