INT J TUBERC LUNG DIS 17(11):1442–1447

© 2013 The Union

http://dx.doi.org/10.5588/ijtld.12.0771

Pharmacokinetics and serum concentrations

of antimycobacterial drugs in adult Turkish patients

A. Babalık,* I. H. Ulus,† N. Bakirci,‡ T. Kuyucu,* H. Arpag,* L. Dagyildiz,* E. Çarpaner§

* Süreyyapaşa Chest Disease and Thoracic Surgery Training and Research Hospital, Istanbul, † Department of
Pharmacology, Acibadem University Medical School, Istanbul, ‡ Department of Public Health, Acibadem University
Medical School, Istanbul, § Kaan Medical Research Laboratory, Istanbul, Turkey

SUMMARY

O B J E C T I V E : To document the pharmacokinetics and R E S U LT S : Wide variations in pharmacokinetic param-

serum concentrations of first-line anti-tuberculosis eters were observed among patients. In respectively 8
drugs in adult Turkish patients with pulmonary tuber- (38%), 17 (81%), 3 (14%) and 1 (5%) patients, the max-
culosis (PTB). imum INH, RMP, PZA and EMB serum concentrations
D E S I G N : Consenting 21 adult patients (aged 38 ± 4 were below the accepted therapeutic concentrations.
years, 10 female and 11 male) with newly diagnosed ac- C O N C L U S I O N : Our data show that the serum concen-
tive PTB participated in the study. Blood samples were trations of anti-tuberculosis drugs varied considerably
collected 1, 2, 4, 6 and 24 h after simultaneous isoniazid in the study patients. Therapeutic drug monitoring is
(INH), rifampicin (RMP), pyrazinamide (PZA) and eth- necessary to identify patients with subtherapeutic INH
ambutol (EMB) ingestion. Serum concentration-time and RMP serum concentrations.
profiles, maximum serum concentrations, time to achieve K E Y W O R D S : isoniazid; rifampicin; pyrazinamide; eth-
maximum serum concentrations, the half-life and the ambutol; subtherapeutic levels
areas under the serum concentration-time curve for each
of the four drugs were determined.

TUBERCULOSIS (TB) is one of the oldest known in- bioavailability, pharmacokinetics and serum con-
fectious diseases. Despite the existence of effective drug centrations of orally administered anti-tuberculosis
treatment and recent progress in global control efforts, drugs are influenced by patient age, sex and ethnic-
it remains an important health problem, with around ity, gastrointestinal disorders, drug formulations
8.8 million new cases and 1.1 million deaths world- and drug interactions.7–18 Some studies have sug-
wide in 2010.1 Treatment for TB requires good pa- gested that reduced anti-mycobacterial drug absorp-
tient adherence to combination chemotherapy for an tion and bioavailability can delay or reduce the cure
extended period. In most countries, including Turkey, rate for TB,19–21 and enhance the emergence of drug
patients with newly diagnosed active TB receive stan- resistance.16–18 Published data further show that low
dardised treatment comprising a 6-month regimen of serum levels of anti-tuberculosis drugs are associ-
isoniazid (INH), rifampicin (RMP), pyrazinamide ated with slow response to treatment and increased
(PZA) and ethambutol (EMB) for 2 months, followed risk of relapse and acquired drug resistance.21–27 Ad-
by INH and RMP for 4 months.2–5 Most countries, verse outcomes may thus be related to subtherapeu-
including Turkey, have also adopted the World Health tic serum levels of anti-tuberculosis drugs in some
Organization-recommended DOTS strategy as a means patients.
of increasing patient adherence and reducing treat- Given the impact of serum concentration of anti-
ment failure, relapse and the emergence of acquired tuberculosis drugs on chemotherapy outcomes, the
drug resistance.2–5 present study was designed to determine the serum
By applying the DOTS strategy, Turkey has suc- concentrations of INH, RMP, PZA and EMB in Turk-
cessfully increased its TB cure and completion rates;6 ish patients with active pulmonary TB. No data are
however, overall rates for cure, relapse and emer- currently available on the serum concentrations of
gence of drug resistance are far from optimal.6 The these drugs after oral administration in Turkish pa-
exact mechanisms for treatment failure, relapse and tients. The study demonstrated that INH and RMP
acquired drug resistance in the DOTS setting is cur- serum levels obtained were below standard effective
rently not known. It is known, however, that the levels in approximately half the patients studied.

Correspondence to: Aylin Babalik, Department of Chest Disease, Süreyyapaşa Education and Research Hospital, Ministry
of Health, Maltepe, Istanbul 3544, Turkey. Tel: (+90) 505 311 9345. Fax: (+90) 441 4150. e-mail: [email protected]
Article submitted 5 October 2012. Final version accepted 2 July 2013.
 Pharmacokinetics of anti-tuberculosis drugs 1443

STUDY POPULATION AND METHODS ration of INH, RMP and PZA. The 5 μm C18 reverse-
phase column was used to separate EMB. The gra-
Subjects and general procedures
dient elution method was employed for elution of
A total of 21 adult patients (aged 38 ± 4 years, 10 fe- INH, RMP and PZA from the column using mobile
male and 11 male) with newly diagnosed active pul- phases of monopotassium phosphate (10 mM) and
monary TB participated in the study. Written informed acetonitrile, while EMB was eluted isocratically using
consent was obtained from all patients before the study. methanol as a mobile phase. The UV wavelength was
The study protocol and the contents of the written adjusted to 261 nm for the determination of INH,
consent form were approved by the Acibadem Univer- RMP and PZA plasma concentrations and 200 nm
sity Ethical Committee, Maltepe, Istanbul, Turkey. for EMB.
The study was conducted at the Süreyyapaşa Chest Quality control samples and drug standards were
Disease and Thoracic Surgery Training and Research prepared in drug-free plasma samples and processed
Hospital. Patients aged >18 years with a clinical, in parallel to the patient samples. The average recov-
bacteriological (smear- or culture-positive), radiolog- ery of INH, RMP, PZA and EMB from samples was
ical or histological diagnosis of TB were included. Pa- respectively 94%, 102%, 99% and 103%. The de-
tients with comorbid disorders, those using concomi- tection limit was respectively 0.40, 0.39, 0.33 and
tant medications and those with abnormal serum 0.36 μg/ml for INH, RMP, PZA and EMB. The av-
laboratory test results suggestive of renal and/or he- erage within-run and between-run coefficients of
patic dysfunction were excluded. variation were respectively 7% and 8%, 5% and 8%,
5% and 6% and 4% and 7% for INH, RMP, PZA
Treatment and blood collection and EMB.
All patients were administered identical anti-
tuberculosis drugs provided by the Turkish Ministry Analysis of pharmacokinetic parameters
of Health from a national drug manufacturer (Kocak Maximum serum concentrations (Cmax) and the times
Farma, Tekirdag, Istanbul, Turkey). The drugs were when these were attained (Tmax) were determined di-
manufactured under strict government control and rectly from the time vs. plasma concentration data
according to current good manufacturing practices, from individual patients. The plasma half-life (t1/2)
with regular quality control and bioavailability stud- was calculated using the decline in plasma drug con-
ies. All four drugs were formulated in separate tablets centrations between 4 h and 6 h, as described previ-
or capsules. ously.30,31 The area under the curve (AUC) for AUC0–24
After overnight fasting (⩾8 h), patients received was determined per the trapezoidal rule using Med-
300 mg (4.3–6.5 mg/kg) of INH (INH®, Kocak Calc® Software (Broekstraat 52, B-9030, Mariakerke,
Farma), 600 mg (8.6–13.1 mg/kg) of RMP (RIF Belgium).
Cap®, Kocak Farma), 1500 mg (21.4–32.6 mg/kg) of
PZA (Pirazinid®, Kocak Farma) and 1500 mg (21.4– Data and statistics
32.6 mg/kg) of EMB (Miambutol®, Kocak Farma) Data were analysed using Sigmaplot® 11.2 (Systat
orally with a glass of water. Blood samples (approxi- Soft Ware Inc, San Jose, CA, USA), and are shown as
mately 4 ml) were collected immediately before and mean ± standard error of mean, median and 1st and
1, 2, 4, 6 and 24 h after the ingestion of the drugs. Pa- 3rd quartiles. The Pearson moment correlation pro-
tients were released from hospital after receiving their cedure and regression analyses were used to deter-
second-day drugs and were continued on treatment mine correlations between age, body weight, height,
in the DOTS setting at local dispensaries. On days 14 body mass index (BMI) and drug doses (mg/kg), and
and 30 after the initiation of treatment, the patients drug serum concentrations.
were invited to the hospital and blood samples were
collected 2 h after simultaneous drug ingestion.
Serum was separated by centrifugation at 2000× g RESULTS
for 10 min at +4ºC within 15 min after collection. The demographic, laboratory and clinical character-
Serum was aliquoted and frozen for about 6 weeks istics of patients are given in Table 1. The Figure
until analysis, per published recommendations.28 shows the time-course of changes in drug serum lev-
els over 24 h after the oral administration of drugs.
Measurement of plasma drug concentrations Wide variations in serum drug concentrations of pa-
Serum levels of INH, RMP, PZA and EMB were de- tients at each sampling time were observed (Figure).
termined using a high-performance liquid chroma- The pharmacokinetic measurements (Cmax, Tmax,
tography system28,29 (LC-20AT Model; Shimadzu, t1/2 and AUC0–24) for INH, RMP, PZA and EMB in
Kyoto, Japan) equipped with an ultraviolet (UV) de- pulmonary TB patients are summarised in Table 2.
tector and an autosampler. A Nova-Pak 4 μm C18 The pharmacokinetic parameters were similar in
reverse-phase column (HPLC System; Waters, Mil- male and female patients (data not shown). Correla-
ford, MA, USA) was used for chromatographic sepa- tion and regression analyses revealed that Cmax and
1444 The International Journal of Tuberculosis and Lung Disease

Table 1 Patient characteristics before the start of treatment

All subjects Males Females

(n = 21) (n = 11) (n = 10)
mean ± SEM mean ± SEM mean ± SEM
Patient characteristic (median, min–max) (median, min–max) (median, min–max)
Age, years 38 ± 4 (33, 18–77) 46 ± 6 (51, 18–77) 29 ± 3 (28, 18– 45)
Body weight, kg 58 ± 2 (58, 46–70) 60 ± 3 (63, 47–70) 56 ± 3 (53, 46–70)
Height, cm 165 ± 2 (168, 150–175) 168 ± 2 (170, 155–175) 162 ± 2 (163, 150–172)
BMI, kg/m2* 21.2 ± 0.6 (21.6, 17.4–30.3) 21.3 ± 0.6 (21.8, 17.4–24.2) 21.1 ± 1.2 (20.8, 17.6–30.2)
Drug dose, mg/kg of body weight
Isoniazid 5.3 ± 0.2 (5.2, 4.2–6.5) 5.1 ± 0.2 (4.8, 4.3–6.4) 5.5 ± 0.2 (5.7, 4.3–6.5)
Rifampicin 10.6 ± 0.3 (10.3, 8.6–13.0) 0.1 ± 0.5 (9.5, 8.6–12.8) 11.0 ± 0.5 (11.3, 8.6–13.0)
Pyrazinamide 26.4 ± 0.9 (25.9, 21.4–32.6) 25.3 ± 1.1 (23.8, 21.4–31.9) 27.5 ± 1.2 (28.3, 21.4–32.6)
Ethambutol 26.4 ± 0.9 (25.9, 21.4–32.6) 25.3 ± 1.1 (23.8, 21.4–31.9) 27.5 ± 1.2 (28.3, 21.4–32.6)
Laboratory findings
AST, IU/l 19 ± 2 (18, 9– 43) 21 ± 3 (21, 9– 43) 17 ± 1 (16, 13–21)
ALT, IU/l 18 ± 2 (16, 7–52) 18 ± 4 (15, 7–52) 17 ± 2 (17, 10–27)
BUN, mg/dl 12 ± 1 (11, 7–22) 14 ± 1 (13, 9–22) 10 ± 1 (10, 7–13)
Creatinine, mg/dl 0.68 ± 0.02 (0.65, 0.60–0.91) 0.73 ± 0.03 (0.71, 0.60–0.91) 0.63 ± 0.01 (0.63, 0.60–0.67)
Total protein, g/l 7.3 ± 0.1 (7.4, 5.9–8.1) 7.2 ± 0.2 (7.3, 5.9–8.1) 7.5 ± 0.1 (7.45, 6.9–8.1)
Albumin, g/l 3.7 ± 0.1 (3.7, 2.4– 4.9) 3.7 ± 0.3 (3.7, 2.4– 49) 3.8 ± 0.1 (3.9, 3.2– 4.2)
Haemoglobin, g/l 13.2 ± 0.4 (13.4, 9.9–15.5) 13.7 ± 0.5 (14.4, 10.0–15.5) 12.6 ± 0.6 (12.4, 9.9–14.9)
Haematocrit, % 39 ± 1 (41, 31– 44) 41 ± 1 (43, 32– 44) 37 ± 1 (36, 31– 42)
Sputum smear, +/− 11/10 3/8 8/2
Culture, +/− 16/5 9/2 6/5
Radiological lung lesions
Unilateral, number 15 8 7
Bilateral, number 6 3 3

* Defined (and calculated) as kg/m2. Patients’ weight and height were measured using the hospital type sensitive weight-height meter.
SEM = standard error of the mean; BMI = body mass index; AST = aspartate aminotransferase; ALT = alanine aminotransferase; BUN = blood urea nitrogen;
+ = positive; − = negative.

Figure Serum concentrations of INH, RMP, PZA and EMB at 1, 2, 4, 6 and 24 h after oral ingestion of drugs. The boxes represent
the 25% to 75% percentile ranges; the horizontal bar in the boxes indicate median values; error bars show the ranges of concentra-
tions; and filled circles below and above the boxes show the 5% and 95% percentile values, respectively. INH = isoniazid; RMP = rifam-
picin; PZA = pyrazinamide; EMB = ethambutol.
 Pharmacokinetics of anti-tuberculosis drugs 1445

Table 2 Pharmacokinetic parameters of INH, RMP, PZA and EMB in patients with
pulmonary tuberculosis
Interquartile
range Minimum-
Drug /parameter Mean ± SEM Median (25%–75%) maximum
INH
Cmax, μg/ml 2.1 ± 0.4 3.2 1.6– 4.0 0.5–6.6
Tmax, h 2.2 ± 0.3 2.0 1.0–2.0 1.0–6.0
t1/2, h 1.3 ± 0.1 1.3 1.0–1.5 0.5–2.0
AUC0–24, μg.h/ml 16.5 ± 2.7 12.1 6.0–26.5 1.0–39.0
RMP
Cmax, μg/ml 5.2 ± 0.6 5.1 3.1–7.0 0.7–10.3
Tmax, h 3.2 ± 0.3 2.0 2.0– 4.0 1.0–6.0
t1/2, h 2.4 ± 0.4 2.0 2.0–2.5 1.5–5.0
AUC0–24, μg.h/ml 58.5 ± 5.2 54.6 42.2–76.8 7.7–97.2
PZA
Cmax, μg/ml 25.8 ± 2.2 26.6 21.4–33.3 1.1– 41.8
Tmax, h 1.7 ± 0.1 2.0 1.0–2.0 1.0–3.0
t1/2, h 14.6 ± 0.6 14.5 13.0–16.0 11.0–18.0
AUC0–24, μg.h/ml 354 ± 23 321 304– 420 181– 621
EMB
Cmax, μg/ml 5.5 ± 0.5 4.8 4.1–7.2 1.4–10.7
Tmax, h 3.0 ± 0.3 2.0 2.0– 4.0 1.0–6.0
t1/2, h 2.3 ± 0.4 1.6 1.4–2.2 1.3–8.0
AUC0–24, μg.h/ml 45.9 ± 3.2 46.9 35.4–58.2 18.8–66.4
INH = isoniazid; RMP = rifampicin; PZA = pyrazinamide; EMB = ethambutol; SEM = standard error of the mean;
Cmax = maximum serum concentrations; Tmax = times when maximum serum concentrations occurred; t1/2 = plasma
half-life; AUC0–24 = area under the curve.

AUC0–24 values were not related to age, body weight, its. In six patients (29%), INH and RMP serum con-
height, BMI or drug dose (in mg/kg). centrations were both below the lower limits.
In 8 (38%), 17 (81%), 3 (14%) and 1 (5%) of the To determine whether the chronic administration
21 patients, the Cmax values of serum INH, RMP, PZA of drugs alters drug serum concentrations, we com-
and EMB were lower than the accepted lower limit of pared serum drug levels in blood samples collected 2 h
therapeutic concentration at 2 h, at respectively 3, 8, after the oral ingestion of INH, RMP, PZA and EMB
20 and 2 μg/ml.11 In one patient, the serum concen- on days 1, 14 and 30 of treatment. Drug serum con-
trations of all four drugs were lower than the ac- centrations were similar on days 1, 14 and 30 of
cepted lower limits. In three patients, INH, RMP and treatment (Table 3). Intra-individual variations be-
PZA serum concentrations were below the lower lim- tween the 2-h serum concentrations determined on
three occasions in the same patient were respectively
12.3 ± 1.7%, 9.8 ± 0.9%, 8.7 ± 0.7% and 11.6 ±
Table 3 INH, RMP, PZA and EMB serum concentrations in 1.2% for INH, RMP, PZA and EMB.
pulmonary tuberculosis patients at 2 h after oral administration
of drugs at days 1, 14 and 30 after start of treatment
DISCUSSION
Interquartile Minimum-
Drug / Mean ± SEM Median range maximum These results show that the serum concentrations of
parameter μg/ml μg/ml (25%–75%) μg/ml first-line anti-tuberculosis drugs such as INH, RMP,
INH PZA and EMB vary greatly among pulmonary TB
Day 1 2.5 ± 0.4 2.0 1.0–3.9 0.0–6.6 patients when administered together as part of the
Day 14 2.4 ± 0.5 2.6 1.2–3.9 0.0– 4.5
Day 30 2.6 ± 0.5 2.1 1.2–3.3 0.2–6.2 6-month DOTS-based regimen. Several-fold differ-
RMP ences in AUC0–24 and in serum INH and RMP Cmax
Day 1 3.9 ± 1.0 2.8 1.7–6.0 0.7–10.3 values among patients were observed. The serum
Day 14 4.2 ± 0.9 4.1 3.5–5.5 3.3–5.4 INH and RMP Cmax values were subtherapeutic in re-
Day 30 4.9 ± 0.6 4.7 3.4–5.9 2.6–8.2
spectively 8 (38%) and 17 (81%) patients, and the
PZA
Day 1 24.4 ± 2.3 24.7 19.9–32.5 1.0– 41.8 serum Cmax values of both INH and RMP were sub-
Day 14 25.5 ± 2.3 26.8 22.7–32.5 6.4–37.9 therapeutic in about one third of the patients.
Day 30 26.2 ± 1.4 25.3 22.9–30.0 15.5–35.8 The Tmax and t1/2 values observed for INH, RMP,
EMB PZA and EMB are comparable to values reported in
Day 1 4.0 ± 0.5 4.1 1.8– 4.9 1.0–10.7
Day 14 4.0 ± 0.6 4.1 1.7–5.7 0.3–7.0 previous studies.11,16 However, the wide variation in
Day 30 3.7 ± 0.4 3.9 2.5– 4.9 0.7–5.7 Cmax and AUC0–24 values observed among patients
INH = isoniazid; RMP = rifampicin; PZA = pyrazinamide; EMB = ethambutol;
was unexpected. According to previous studies, the
SEM = standard error of the mean. serum concentrations of anti-tuberculosis drugs are
1446 The International Journal of Tuberculosis and Lung Disease

related to several factors such as age, sex, history of only a few patients (in three patients with PZA and
treatment, human immunodeficiency virus (HIV) one patient with EMB). One participant with a sub-
infection, diabetes, drug formulation, concurrent food, therapeutic EMB level (1.4 μg/ml) also had very low
dosage and the use of laxatives.7–17,27 We included concentrations of all three of the other drugs (Cmax
only newly diagnosed, previously untreated pulmo- values for INH, RMP and PZA respectively 0.5, 0.7
nary TB patients with no known comorbid disease in and 1.2 μg/ml). Similarly, three patients with sub-
our study, and the patients fasted before ingesting the therapeutic serum PZA levels also had very low se-
drugs. No significant differences in serum concentra- rum INH (1.1 μg/ml) and RMP (0.7 μg/ml) levels.
tions of any of the four drugs among female vs. male Although there are no known common risk factors,
patients were found. There was also no significant as- the patients in the current study appear to have had
sociation of drug serum concentrations with age or impaired absorption of most or all of the four anti-
body weight. tuberculosis drugs.19,21
It has recently been reported that the absorption The data obtained in the present study have im-
and bioavailability of INH and RMP decrease signifi- portant clinical implications. The observed high prev-
cantly in TB patients due to decreases in the intestinal alence of subtherapeutic serum levels of INH and
area of absorption for these drugs.21,32 It is also RMP is reason for concern. Although we failed to de-
known that the quality and pharmaceutical formu- termine the effect of identified deficiencies on the fi-
lations of anti-tuberculosis drugs affect their in- nal outcome of treatment in our patients, previous
testinal absorption and oral bioavailability.12,13 The studies have clearly shown that low concentrations
wide variations in drug serum concentrations ob- of INH and RMP are associated with slow response
served may thus have resulted from variations in to treatment,20 treatment failure,20–27 increased risk
the bioavailability of the drugs due to differences of relapse23 and acquired drug resistance.24 Adjust-
in intestinal absorption among the patients,12,13 and/ ments of INH and RMP doses may result in improve-
or unsuitable (inferior, non-standardised) pharma- ments in clinical outcomes.20,22 To avoid inadequate
ceutical formulations of the drugs.12,13,16 It is well clinical response and treatment failure after the stan-
known that the rate of acetylation by arylamine N- dard 6-month regimen, it may be necessary to moni-
acetyltransferase type 2 (NAT2) significantly alters tor the serum concentrations of drugs and to opti-
the serum concentrations of INH and its half-life in mise drug dosages at the beginning of treatment, as
the circulation.33 We did not determine the NAT2 suggested by others.11,22,27,35 As drug serum levels
genotype of our patients. Ozbek et al. reported the were not different on days 1, 14 and 30 at 2 h, one or
prevalence of slow, intermediate and fast acetylators two measurements may be sufficient to determine the
in a Turkish population to be respectively 47%, 44% drug serum concentrations attained with the inges-
and 9%.34 The wide variation observed in INH se- tion of a specific drug dosage.
rum concentrations could also have resulted from
differences in acetylation rate, affecting the INH
CONCLUSION
elimination rates in our patients. This possibility is
supported by the observation that the two lowest The serum concentrations of the anti-tuberculosis
values for Cmax and AUC for INH were observed in drugs varied considerably among 21 Turkish TB pa-
the two patients with the shortest half-lives (t1/2 = tients when treated with the standard four-drug
0.5 h and t1/2 = 0.8 h) for INH. DOTS-based regimen under direct observation. The
The wide variations observed in serum concentra- achieved maximal serum concentrations of INH and
tions were associated with a high prevalence of sub- RMP were below the accepted lower therapeutic
therapeutic concentrations of RMP and INH. We ob- limit in about 80% and 40% of patients, respectively.
served that 81% of the serum RMP and 38% of the About one third of the patients had subtherapeutic
serum INH concentrations were below the lower limit serum concentrations for both INH and RMP. Thera-
of the suggested therapeutic concentrations. Accord- peutic drug monitoring should be considered as early
ing to previous studies, the prevalence of low concen- as possible after initiating the standard regimen to
trations of INH and RMP varies widely among TB pa- identify patients with low serum concentrations of
tients, between 2% and 68% for INH,14,16,22,25,28,35 drug(s), to make the necessary dose-adjustments for
and 5% and 78% for RMP.14–16,20,22,28,35 Such large the successful treatment of pulmonary TB and for im-
differences in the reported frequency of low serum proved outcomes.
INH and RMP concentrations could be explained by
the use of different drug formulations, dosages, race/ Acknowledgements
ethnicity or the use of different methods in determin- The authors are grateful to the Kaan Medical Toxicology Labora-
ing serum drug concentrations. tory, Istanbul, Turkey, for their analysis of the serum concentra-
tions of the drugs.
The majority of our patients achieved serum PZA
This study was supported by the research fund of the Turkish
and EMB levels within the suggested therapeutic Thoracic Society, Ankara, and the Turkish Academy of Science,
range.11,27 Contrary to RMP and INH, subtherapeu- Ankara, Turkey.
tic serum levels of PZA and EMB were observed in Conflict of interest: none declared.
 Pharmacokinetics of anti-tuberculosis drugs 1447

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 Pharmacokinetics of anti-tuberculosis drugs i

RÉSUMÉ

O B J E C T I F : Documenter la pharmacocinétique et les concentration sérique ont été déterminés pour chacun
concentrations sériques des médicaments de première des quatre médicaments.
ligne chez des patients turcs adultes atteints de tubercu- R É S U LTAT S : On a observé parmi les patients de larges
lose pulmonaire (TBP). variations des paramètres pharmacocinétiques. Chez re-
S C H É M A : Ont participé à l’étude 321 adultes consen- spectivement 8 (38%), 17 (81%), 3 (14%) et 1 (5%)
tants (âge moyen 38 ± 4 ans) (10 femmes et 11 hommes) patients, les concentrations sériques maximales pour
atteints d’une TBP active récemment diagnostiquée. On l’INH, la RMP, le PZA et l’EMB se situaient en dessous
a recueilli des échantillons de sang 1, 2, 4, 6 et 24 h des concentrations thérapeutiques admises.
après ingestion simultanée d’isoniazide (INH), de rifam- C O N C L U S I O N : Nos données montrent les variations con-
picine (RMP), de pyrazinamide (PZA) et d’éthambutol sidérables des concentrations sériques des médicaments
(EMB). Les profils de concentrations sériques dans le antituberculeux chez les patients que nous avons étudiés.
temps, les concentrations sériques maximales, la durée Un suivi thérapeutique des médicaments est nécessaire
avant d’atteindre les concentrations sériques maximales, pour identifier les patients où les concentrations sériques
la demi-vie ainsi que les zones sous la courbe temps/ d’INH et de RMP sont sous-thérapeutiques.

RESUMEN

O B J E T I V O : Documentar la farmacocinética y las con- R E S U LTA D O S : Se observaron amplias variaciones de los

centraciones séricas de los medicamentos antituberculo- criterios farmacocinéticos en los pacientes. Se observa-
sos de primera línea en los pacientes adultos con tuber- ron concentraciones séricas máximas que eran inferiores
culosis pulmonar (TBP) en Turquía. a las concentraciones terapéuticas aceptadas de INH en
M É T O D O : Veintiún adultos con diagnóstico reciente de 8 pacientes (38%), de RMP en 17 casos (81%), de PZA
TBP activa aceptaron participar en el estudio (38 ± 4 años en 3 pacientes (14%) y de EMB en 1 caso (5%).
de edad, 10 mujeres y 11 hombres). Se recogieron mue- C O N C L U S I Ó N : Estos resultados ponen de manifiesto
stras sanguíneas 1, 2, 4, 6 y 24 h después de la admini- una considerable variabilidad en las concentraciones
stración simultánea de isoniazida (INH), rifampicina séricas de los medicamentos antituberculosos en los
(RMP), pirazinamida (PZA) y etambutol (EMB). Con pacientes del estudio. Es necesario vigilar las concentra-
cada uno de los medicamentos se determinó la curva de ciones de los medicamentos, con el fin de detectar a los
concentración y tiempo, las concentraciones séricas pacientes que presentan concentraciones séricas infrate-
máximas, el lapso hasta lograr las concentraciones máxi- rapéuticas de INH y RMP.
mas, la vida media y las áreas bajo la curva de la con-
centración sérica y el tiempo.