Translated from Indonesian to English - www.onlinedoctranslator.

com

See discussions, stats, and author profiles for this publication at:https://www.researchgate.net/publication/47395016

Relative bioavailability of rifampicin in a three-drug fixed-dose combination

formulation

ArticlesinThe International Journal of Tuberculosis and Lung Disease November 2010

Source: PubMed

CITATIONS READS

30 562

8 authors, including:

Rosa Milan Adriana Domínguez

Universidad Autónoma de San Luis Potosí Metropolitan Autonomous University

38PUBLICATIONS302CITATIONS 64PUBLICATIONS672CITATIONS

SEE PROFILE SEE PROFILE

Helgi Jung Susanna Edith Medellin-Garibay Universidad

Universidad Nacional Autónoma de México Autónoma de San Luis Potosí

91PUBLICATIONS1,080CITATIONS 42PUBLICATIONS440CITATIONS

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

tuberculosisView projects

Clinic pharmacokinetics of casiopeinasView projects

All content following this page was uploaded byAdriana Domínguezon 04 January 2016.

The user has requested enhancement of the downloaded file.

INT J TUBERC LUNG DIS 14(11):1454–1460 ©
2010 The Union

Relative bioavailability of rifampicin in a three-drug

fixed-dose combination formulation

RC Milan-Segovia,*†AM Domínguez-Ramírez,* H. Jung-Cook,‡M. Magaña-Aquino,§

MC Romero-Méndez,†SE Medellín-Garibay,†M. Vigna-Pérez,†S. Romano-Moreno†
* Universidad Autónoma Metropolitana, Unidad Xochimilco, Mexico DF,†Facultad de Ciencias Químicas, Universidad
Autónoma de San Luís Potosí, San Luis Potosí,‡Facultad de Química, Universidad Nacional Autónoma de México, Mexico
City,§Hospital Central 'Dr Ignacio Morones Prieto' Secretaria de Salud, San Luis Potosí, Mexico

SUMMARY

SETTI NG :In
a previous monitoring study of rifampicin
(RMP) in tuberculosis (TB) patients treated with a
generic formulation of a three-drug fixed-dose
combination (3FDC), very low RMP levels were found.
This led us to investigate the bioavailability of the
product.
OBJECTIVE :To investigate the relative bioavailability of
RMP from a generic 3FDC formulation used in the
Mexican health care system, in comparison to the
reference product, in healthy volunteers.
DESI GN :Two-period, two-sequence crossover study.
RESU LT S :The mean pharmacokinetic parameter values
obtained for the test and reference product were
respectively 3.13±2.01μg/ml and 9.95±2.66μg/ml for peak
plasma concentration (Cmax), 15.51±9.77μg/ml and 58.03±
16.1μgh/ml for area under the concentration (AUC) time
curve to the last measurable concentration
(AUC0–12h) and 17.92±10.66 and 68.43±10:39 p.mμgh/ml for
AUC up to time infinity (AUC0–∞). The test/reference ratio
of the means (90%CI) was 25.36% (17.33–37.10) for Cmax,
21.25% (14.61–30.89) forAUC0–12hand 22.08% (15.44–31.56)
for AUC0–∞.These results did not meet the criteria for
bioequivalence.
CON CLUSION ON :The test product displayed delayed
absorption and markedly inferior RMP bioavailability in
comparison to the reference product. RMP-containing
generic formulations should only be used if their
bioavailability has been evaluated to ensure
interchangeability with the reference product and to
avoid the risk of markedly inferior RMP exposure
through the use of such a product.
DS KEY WORKS :relative bioavailability; rifampicin; fixed-
dose combinations

IN MEXICO, there were more than 17000 new cases of
tuberculosis (TB), 488 cases of multidrug-resistant
tuberculosis (MDR-TB) and nearly 2000 deaths due to
TB during 2009, indicating an important health
problem.1The DOTS course for the treatment of TB
consists of isoniazid (INH), rifampicin (RMP),
pyrazinamide (PZA) and ethambutol (EMB),
administered in fixed-dose combinations (FDC) to
prevent the emergence of resistant strains.2
A target range for peak concentrations of 8– 24 μg/
ml is proposed for patients receiving daily doses of
600 mg RMP.3However, wide variations in plasma
concentrations have been reported for this drug.4,5
Studies identifying high inter- and intrasubject variability
of RMP pharmacokinetics5,6have been reported. The
bioavailability of RMP also shows great variability,7–9and
is altered by idiosyncratic and physiological factors, such
as pH at the absorption site, p-glycoprotein mediated
efflux and gastrointestinal metabolism, as well as
physicochemical and formula-
tion characteristics.8,10,11RMP belongs to Class II (low
solubility–high permeability) of the Biopharmaceutical
Classification System (BCS).11Variations in
bioavailability have been attributed to RMP adsorption
onto excipients and to the chemical instability of RMP
in the presence of INH at the gastric level.7,12,13
Marked differences have been identified in RMP
bioavailability between formulations containing RMP
alone and in FDC products.8,14INH, PZA and EMB do
not present bioavailability problems attributed to
differences in formulations, as these drugs belong to
Class III or borderline Class III/I of the BCS.15
In a previous RMP monitoring study carried out on
Mexican TB patients administered with different
generic brands of 3FDC (RMP/INH/PZA) containing
600 mg RMP, 84% of the plasma concentrations found
at 2 h and 6 h post-dose were lower than 4μg/ml. In
contrast, RMP plasma levels were between 8 and 12.7
µg/ml in patients treated with the reference 3FDC
product. These results led us to question

Correspondence to: Rosa del Carmen Milán-Segovia, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí,
Av Manuel Nava 6, Zona Universitaria, 78210 San Luis Potosí, Mexico. Tel: (+52) 444 826 2440. Fax: (+52) 444 826 2372. e-mail:
milanros@uaslp.mx
Article submitted 5 December 2009. Final version accepted 23 April 2010.

the absorption characteristics of the generic product
being administered.
The aim of the present study was to determine the
relative bioavailability of RMP in a 3FDC formulation
used in the Mexican health care system in comparison
to a reference product.
MATERIALS AND METHODS
3FDC formulations
Both the reference formulation (sugar-coated Rifater®
, Sanofi Aventis, Mexico City, Mexico) and the test
formulation (generic brand supplied by the Mexican
health system) were tablets containing 150 mg RMP,
75 mg INH and 400 mg PZA.
In vitro evaluation
The drug content and dissolution profiles of both
formulations were determined in accordance with the
United States Pharmacopeia 29 (USP).16The
dissolution study was conducted using a USP
apparatus 1 (Varian VK 7025, Varian Inc, Palo Alto, CA,
USA) operating at 100 rpm and 37°C and using 900 ml
of gastric fluid, pH 1.2, without pepsin. Dissolved RMP
was assayed at 475 nm using a Beckman Coulter
DU650 UV/VIS spectrophotometer (Beckman Coulter,
Danvers, MA, USA).
Relative bioavailability study
Experimental design
The study was performed according to a protocol
approved by the local Hospital Ethics Committee.
Eighteen healthy subjects underwent a randomized
two-treatment, two-period crossover double-blind
study. The washout period between treatments was 7
days. The volunteers were selected based on physical
examinations, medical history, liver function tests and
routine blood and urine analysis. The subjects' mean
age was 23±2 years, the mean average weight was
68.73±9.5 kg and the mean body mass index (BMI)
was 24.45±1.8. Each volunteer signed an informed
consent form before starting the study. Pregnant or
lactating women and individuals with a history of
adverse drug reactions, drug or alcohol abuse,
smokers or subjects taking medications were
excluded. All subjects were under continuous medical
supervision throughout the study. Finally, the
consumption of alcoholic beverages or beverages
containing caffeine/xanthine, intense physical activity
and smoking were not allowed during the study.
Dosing schedule
At each experimental session and after overnight
fasting, each subject received four 3FDC tablets of
either the reference or the test product (containing a
single dose of 600 mg RMP) with 250 ml of water.
Volunteers received a light breakfast and lunch at 3 h
and 7 h post-dose. The administration sequence was
Relative bioavailability of RMP 1455
randomized to reduce the effect of sequence and
period.
Blood samples (3 ml) were collected in heparinized
tubes at 0, 20, 40 and 60 min post-dose, and at 1.5, 2,
2.5, 3, 4, 6, 9 and 12 h post-dose. Plasma was
separated and stored at −80°C with protection from
light exposure until analysis.
Assay method
HPLC apparatus and conditions
A Waters High Performance Liquid Chromatography
Systems apparatus (Waters Corp, Milford, MA, USA)
equipped with a model 1525 multi-solvent delivery
system, a model 717 Plus, loop injector, a model 2487
ultraviolet/visible (UV/VIS) detector and version 3.2 of the
Breeze software (Waters) was used.
The determination of RMP plasma concentration
was performed as follows:17100 μl of plasma sample
was deproteinized with 100 μl of acetonitrile. The
mixture was vortexed for 20 s and centrifuged for 20
min at 20817×g; 20 μl of the supernatant was injected
into the chromatographic system. Analysis was
performed using an X-terra RP18columns (30× 150
mm, with a particle size of 3.5 mm) and a Guard Pak X-
terra RP18(10×30 mm) column (Waters). The mobile
phase was a mixture of phosphate buffer (0.01 M, pH
4.5):acetonitrile:methanol (60:37:3 v/v/v). A flow rate
of 0.4 ml/min was employed, and the detection of
RMP was carried out at 334 nm.
Method validation was conducted according to
published guidelines.18Selectivity was assessed in the
presence of INH, PZA and EMB. No interference was
found with endogenous plasma compounds. The
assay was linear over the range of 0.1–20 µg/ml (r2=
0.9999), with a mean absolute recovery of 99.7%.
Coefficients of variation (CV) for intra- and interday
precision were less than 5%, with an accuracy of±5%.
The limits of quantification and detection of RMP were
0.1 µg/ml and 0.03 µg/ml respectively. RMP remained
stable at −80ºC over a period of 31 days.
Pharmacokinetics and statistical analyses
Pharmacokinetic parameters for RMP were obtained
by noncompartmental analysis. The elimination rate
constant (λ) was estimated by log-linear regression
analysis of data from the terminal log-linear phase,
and the elimination half-life t1/2(λ)was calculated as
0.693/λ. Peak plasma concentration (Cmax) and time to
reach Cmax(Tmax) were directly obtained from individual
plasma concentration-time profiles. The area under
the concentration-time curve to the last measurable
concentration (AUC0–12h) and the area under the curve
from zero to Tmax, or early exposure (EE), were
calculated by the linear trapezoidal method. AUC up to
time infinity (AUC0–∞) was computed as AUC0–∞= AUC0–o
+Clast/λ,where Clastis the last measurable
concentration. Moreover, the CmaxThe /AUC ratio was
calculated as an effective metric of absorption rate.19
1456 The International Journal of Tuberculosis and Lung Disease

Figure 1Dissolution profiles of RMP from 3FDC in gastric

fluid pH 1.2 without pepsin at 100 rpm in USP apparatus 1.
Dissolution profiles are represented as the mean of six
tablets± SD. RMP = rifampicin; 3FDC = three-drug fixed-dose
combination; USP = United States Pharmacopeia; SD =
standard deviation.
Figure 2 Mean concentration-time profiles of RMP after
administration of FDC formulations in 18 healthy volunteers. Y-
error bars indicate SD. RMP = rifampicin; FDC = fixed-dose
combinations; SD = standard deviation.

Mean test/reference ratios for the logarithmic
transformed data for Cmax, AUC0–12hand AUC0–∞
parameters were evaluated by analysis of variance
(ANOVA) using WinNonlin version 4.1 (Pharsight, St
Louis, MO, USA). ANOVA was applied to evaluate
significant sequence and/or period effects (P<0.05).
Bioavailability equivalence was accepted if the 90%
confidence intervals (90%CI) calculated for the test/
reference formulation mean ratios of the indicated
parameters were within the 80–125% range.
RESULTS
In vitro evaluation
Both pharmaceutical products meet the requirements
of the assay and dissolution test. The dissolution
profiles appear in Figure 1. The percentage of RMP
dissolved after 30 min for the reference and test
formulations was aboveQ=80% (90.25%±1.39 and
85.1%±0.46, respectively). Both formulations can
be considered to be fast-dissolution products (Q⩾
85% in 15min).
Relative bioavailability study
Figure 2 shows mean RMP concentration-time profiles
for each product. Plasma concentrations of the
reference formulation were 4-fold higher throughout
the full sampling time interval than those obtained
with the test product. Table 1 shows the mean
pharmacokinetic parameters and the statistical
comparison of the formulations. We found substantial
intersubject variability. The mean half-life was 2.94±
1.24 h for the generic formulation and 3.67±1.32 h for
the reference product, a statistically significant
difference (P=0.0299). The half-life value of the
reference product was within the interval reported by
other authors.4,20
The Tmaxdiffered significantly between formulations
(P=0.0024). The reference product had a mean value
of 2.07±1.11 h, which represents a faster

Table 1 Mean pharmacokinetic parameters of RMP from 3FDC products (n=18)

Reference formulation Test formulation

Pharmacokinetic parameters Means±SD CV, % Range Means±SD CV, % Range Pvalue

λ, h−1 0.21±0.07 36.31 0.09–0.42 0.27±0.09 35.26 0.10–0.48 0.0444
t1/2(λ), h 3.67±1.32 36.08 1.63–7.42 2.94±1.24 42.21 1.42–6.52 0.0289
Qmax, h 2.07±1.11 53.60 0.66–4.00 3.08±1.45 47.28 1.00–6.00 0.0024
Cmax, μg/ml 9.95±2.66 26.79 5.41–14.75 3.13±2.01 64.38 0.55–7.04 <0.0001
Early exposure, μg.h/ml 10.09* 1.88–24.47 3.25* 0.98–12.13 0.0020
AUC0–12h, μg. h/ml AUC0 –∞, 58.03±16.1 27.75 36.44–82.31 15.51±9.77 63.04 2.42–32.19 <0.0001
μg. h/ml 68.43±10:39 p.m 32.72 41.61–109.4 17.92±10.66 59.48 4.04–35.97 <0.0001
Cmax/AUC0 –∞, μg/ml/μg.h/ml 0.15±0.04 26.52 0.09–0.22 0.17±0.04 25.18 0.09–0.24 0.0456

* Median.
RMP = rifampicin. 3FDC = three-drug fixed-dose combination; SD = standard deviation; CV = coefficient of variation; λ = elimination rate constant of RMP; t1/2(λ)= half-life of
RMP; Cmax= highest concentration after administration of 3FDC formulation; Qmax= time to Cmax; AUC0–12h= area under the plasma concentration-time profile up to 12 h;
early exposure = AUC up to Tmax; AUC0 –∞= area under the curve of plasma concentration-time profile up to infinite time.

Table 2Test/reference ratios and 90%CI derived from
pharmacokinetic parameters of RMP for the assessment
of bioequivalence
Pharmacokinetics Ratio
parameter % 90% CI
Cmax 25.36 17.33–37.10*
AUC0–12h 21.25 14.61–30.89*
AUC0–∞ 22.08 15.44–31.56*
* Outside the limits of bioequivalence; bioequivalence criteria 80–125%. CI
= confidence interval; RMP = rifampicin; Cmax= highest concentration after
administration of 3FDC formulation; AUC0–12h= area under the plasma
concentration-time profile up to 12 h; AUC0–∞=area under curve of plasma
concentration-time profile up to infinite time.
absorption than for the test formulation, for which
the Tmaxwas 3.08±1.45 h.
The parameters Cmax, AUC0–12hand AUC0–∞for the
reference formulation were significantly higher (P<
0.0001) than for the test product. For the reference
product, Cmaxranged from 5.41 to 14.75 µg/ml, and
60% of the subjects showed RMP levels > 8 µg/ml. In
contrast, the Cmaxthe values of the test product
ranged from 0.55 to 7.04 μg/ml, and none of the
volunteers reached the minimum target level.
The EE parameter showed the highest intersubject
variability in both dosage forms, as this parameter is a
measure of AUC up to Tmax. Another secondary metric
used for testing bioavailability was the Cmax/AUC0–∞
ratio, which also showed a statistically significant
difference between formulations (P=0.045).
No period or sequence effects were observed for
any pharmacokinetic parameter (P>0.05) on ANOVA
analysis, but a significant formulation effect on t1/2(λ), C
max, AUC0–oand AUC0–∞was found (P< 0.05). The relative
bioavailability of the RMP from the generic brand was
21.25% and 22.08%, respectively, compared to the
reference brand, when the mean test/reference ratios
of AUC0–12hand AUC0–∞
were calculated (Table 2). The 90%CI for Cmaxand
the AUC ratios was clearly outside the 80–125%
range, indicating bioequivalence of the test
formulation compared to the reference product.
DISCUSSION
The treatment of TB, which remains a major public
health problem in Mexico, requires high-quality drug
products. In bioequivalence studies, the use of one
FDC formulation as a reference product to evaluate
the quality of other FDC formulations has been
approved when it is backed up by its own safety,
efficacy and quality.21,22As Rifater has been
established as the reference 3FDC product by the
Mexican Health Ministry,23it was used as the reference
product in this study.
USP dissolution conditions applied in vitro were not able
to distinguish any differences in RMP release characteristics,
and both products satisfied the pharmacopeial dissolution
requirements. The test product
Relative bioavailability of RMP 1457
showed a faster release of RMP than the reference
formulation during the first 10 min (P<0.05), but after
this time both products are dissolved at the same
rate. The recommended dissolution conditions, such
as 0.1 N HCl (hydrochloric acid) or simulated gastric
fluid at 100 rpm, are likely to mask batch-to-batch
variations during the manufacturing process. This is
due to very high RMP solubility in these media.11.24
For this reason, performing dissolution studies at two
or three pH levels (0.01 N HCl and phosphate buffer at
pH levels of 6.8 and 4.5) has been proposed for the
purpose of ensuring consistency and predicting, a
priori, the quality of FDC products containing
RMP.24,25
Although dissolution testing is considered to be an
important tool in assessing the quality of pharmaceutical
formulations of many drugs, the relationship between
RMP dissolution properties and bioavailability is poor.25It
has been shown that even when RMP formulations meet
dissolution requirements the drug is not always well
absorbed, and vice versa.26Hence, the low bioavailability
of RMP-containing products, including those with
adequate dissolution profiles, should not only be
restricted to FDCs, but should also be applied to single-
drug formulations as well.27
The World Health Organization (WHO) has
recommended a sampling protocol limited to 8 h with
22 subjects for performing a bioequivalence study for
RMP.21,28In this study, the choice of 18 subjects was
based on previous studies6,29that have reported a 16%
intraindividual variation for AUC. In addition, in one of
these studies, the authors reduced the number of
volunteers to 12 subjects and employed a sampling
period of 24 h without affecting the precision and
estimation of bioequivalence. For this reason, we
chose 18 subjects and a sampling time of 12 h. This
period covered four half-lives of elimination of the
drug and allowed the characterization of over 80% of
the AUC0–∞.18It was thus possible to demonstrate
bioinequivalence.
RMP levels were below the target range and high
variability was observed with the test formulation.
Statistical differences between the mean values of
pharmacokinetic parameters of both products were
found, but no sequence or period effect was observed
(P>0.05). Significant half-life differences between
products might be attributed to saturable metabolism
when the RMP reference product with better
bioavailability was used. It has been reported that
RMP shows nonlinear saturable elimination kinetics.30
Saturation of first pass effects at high doses results in the
Cmaxattaining an increase higher than the proportional
dose. The elimination half-life therefore markedly
increases with dose size due to the saturation of the p-
glycoprotein in the intestinal region.31
The shorter half-life observed for the generic product
could therefore be related to the lower fraction of the
absorbed dose.
1458 The International Journal of Tuberculosis and Lung Disease
The rate and extent of RMP absorption estimated
by Cmax, EE and AUC were significantly lower for the
generic 3FDC formulation (P<0.0001), demonstrating a
lack of bioequivalence with the reference product
remaining outside the 90%CI of 80–125%.21It is
feasible that the RMP plasma levels <4 µg/ml
observed during the monitoring study in TB patients
were associated with the low bioavailability of the
generic product.
In both single-drug and FDC presentations, both
good quality products with adequate RMP
bioavailability9,27,31and products with low and variable
bioavailability11.20have been previously documented.
Products with low and variable bioavailability have
captured the attention of health authorities around
the world, in efforts to provide pharmaceutical
formulations of good quality.
It is therefore troubling that products of
questionable biopharmaceutical quality for TB
treatment, such as the one in the present study, are
distributed on the market.32Any reduction in
bioavailability could have serious implications for both
the individual patient and for TB control programs
due to potential treatment failure and the selection of
drugresistant mutants.14,32,33Since the introduction of
FDC products for the treatment of TB, the WHO and
the International Union Against Tuberculosis and
Lung Disease (The Union) have recommended that
only drug products subjected to quality assurance
procedures and with approved bioavailability should
be used.21.34Because the WHO has not defined a
bioequivalence waiver for RMP, our results support
the need to continue conducting bioequivalence
assessment studies.15
In Mexico, the requirement for bioequivalence was
updated in 2008 to ensure the interchangeability of
generic RMP products.35However, no previous studies
have been conducted to compare the bioavailability
and bioequivalence of anti-tuberculosis products
made in this country. The results shown here
emphasize the need for a rigorous evaluation of these
products before their distribution within the Mexican
health system to prevent prescriptions of
bioinequivalent formulations.
CONCLUSIONS
The relative bioavailability of the RMP in a Mexican 3FDC
product showed significant differences when compared
to the reference product, despite similarities in their
dissolution performance. The poor bioavailability of RMP
documented here for the generic product under study
represents a serious problem for the success of
treatment programs for TB which must be addressed by
the Mexican health authorities.
Acknowledgments
The authors thank CONACYT (Consejo Nacional de Ciencia y
Tecnología) of Mexico for financial assistance for this study (Fondo
Mixto Gobierno del Estado de San Luis Potosí—CONACYT
FMSLP-2002-5585), and Fondo de Apoyo a la Investigación (C07-
FAI-11-24.60 Ref: 16/2007) de la Universidad Autónoma de San
Luis Potosí, México.
References
1 Secretaría de Salud, Centro Nacional de Vigilancia Epidemioló-
gica y Control de Enfermedades. Programas Preventivos. Alianza
comunitaria SOLUCIÓN TB. Mexico City, Mexico: CENAVE, Boletín
informivo 2010; 12, Februaryro. http://www.cenave. gob.mx/
tuberculosis/WEB/descargas-1/2010/BTB_Feb.pdf Accessed July
2010. [Spanish]
2 Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for
recommending fixed-dose combination tablets for the treatment of
tuberculosis. Bull World Health Organization 2001; 79:61–68.
3 Peloquin C. Therapeutic drug monitoring in the treatment of
tuberculosis. Drugs 2002; 62:2169–2183.
4 van Crevel R, Alisjahbana B, de Lange WC, et al. Low plasma
concentrations of rifampicin in tuberculosis patients in
Indonesia. Int J Tuberc Lung Dis 2002; 6: 497–502.
5 McIlleron H, Wash P, Burger A, Norman J, Folb PI, Smith P.
Determinants of rifampin, isoniazid, pyrazinamide, and
ethambutol pharmacokinetics in a cohort of tuberculosis patients.
Antimicrobial Agents Chemother 2006; 50:1170–1177.
6 Agrawal S, Kaur KJ, Singh I, Bhade S, Kaul CL, Panchagnula
R. Minimum sample size and sampling time requirements for
assessment of rifampicin bioequivalence from FDC formulations.
Int J Tuberc Lung Dis 2005; 9: 1273–1280.
7 Singh S, Mariappan TT, Sanka R, Sarda N, Singh B. A critical
review of the probable reasons for the poor/variable
bioavailability of rifampicin from anti-tubercular fixed-dose
combination (FCD) products, and the possible solutions to the
problem. Int J Pharm 2001; 228:5–17.
8 Panchagnula R, Agrawal S. Biopharmaceutic and pharmaco-
kinetic aspects of variable bioavailability of rifampicin. Int J
Pharm 2004; 271:1–4.
9 Panchagnula R, Parmar J, Kaur K, Singh I, Bade SR, Ashokraj
Y. Statistical evaluation of physiological variability of rifampicin in
fixed dose combinations. Int J Pharm 2006; 313:5–13. 10 Agrawal
S, Panchagnula R. Implications of biopharmaceutics
and pharmacokinetics of rifampicin in variable bioavailability
from solid oral dosage forms. Biopharm Drug Dispos 2005;
26:321–334.
11 Becker C, Dressman JB, Junginger HE, et al. Biowaiver mono-
graphs for immediate release solid oral dosage forms: rifampicin.
J Pharm Sci 2009; 98:2252–2267.
12 Shishoo CJ, Shah SA, Rathod IS, Savale SS, Kotecha JS, Shah
P B. Stability of rifampicin in dissolution medium in the presence
of isoniazid. Int J Pharm 1999; 190:109–123.
13 Immanuel C, Gurumurthy P, Ramachandran G, Venkatesan P,
Chandrasekaran V, Prabhakar R. Bioavailability of rifampicin
following concomitant administration of ethambutol or
isoniazid or pyrazinamide or a combination of the three
drugs. Indian J Med Res 2003; 118:109–114.
14 Pillai G, Fourie PB, Padayatchi N, et al. Recent bioequivalence
studies on fixed-dose combination anti-tuberculosis drug
formulations available on the global market. Int J Tuberc
Lung Dis 1999; 3 (Suppl 3): S309–S316.
15 World Health Organization. Annex 8: proposal to waive in
vivo bioequivalence requirements for WHO Model List of Essential
Medicines immediate-release, solid oral dosage forms. WHO
Technical Report Series No 937. Geneva, Switzerland: WHO, 2006.
http://apps.who.int/prequal/info_general/documents/TRS937/
WHO_TRS_937__annex8_eng.pdf Accessed July 2010. 16
Farmacopea de los Estados Unidos de América. Manual edition
en Español. USP 29/NF 24. Rockville, MD, USA: United States
Pharmacopeial Convention, 2006: pp 2100–2101. [Spanish] 17 Le
Guellec Ch, Gaudet ML, Lamanetre S, Breteau M. Stability

of rifampin in plasma: consequences for therapeutic monitoring
and pharmacokinetic studies. Therapeutic Drug Monit 1997;
19:669–674.
18 Diario Oficial de la Federación. Norma Oficial Mexicana NOM-
177-SSA1-1998. Mexico City, Mexico: Secretaría de Salud,
1999. [Spanish]
19 Tothfalusi L, Endrenyi L. Without extrapolation, Cmax/AUC is
an effective metric in investigations of bioequivalence. Pharm Res
1995; 12:937–942.
20 Padgaonkar KA, Revankar SN, Bhatt AD, et al. comparative
bioequivalence study of rifampicin and isoniazid combinations in
healthy volunteers. Int J Tuberc Lung Dis 1999; 3: 627–631. 21
Fourie B, Pillai G, McIlleron H, Panchagnula R, Ellard G. Es-
tablishing the bioequivalence of rifampicin in fixed dose
formulations containing isoniazid with or without pyrazinamide
and/or ethambutol compared to the single drug reference
preparations administered in loose combinations. protocol
models. Geneva, Switzerland: World Health Organization
Communicable Diseases Cluster, 1999. http://whqlibdoc.who.int/
hq/1999/WHO_CDS_TB_99.274.pdf Accessed July 2010.
22 Ashokraj Y, Singh I, Kaur KJ, et al. Establishment of a refer-
ence formulation for bioequivalence assessment of rifampicin
containing FDCs: an essential step towards improving
tuberculosis treatment. Int J Tuberc Lung Dis 2005; 9:791–796. 23
Federal Commission para la Protección contra Riesgos Sanitarios.
Comisión de Autorización Sanitaria. Relación de medicamentos
de referencia. Mexico City, Mexico: Comisión de Autorización
Sanitaria, 2009. http://201.147.97.103/work/sites/cfp/resources/
LocalContent/1466/6/RelMedRefDic09.pdf Accessed July 2010.
[Spanish]
24 Agrawal S, Panchagnula R. Dissolution test as a surrogate for
quality evaluation of rifampicin containing fixed dose
combination formulations. Int J Pharm 2004; 287:97–112.
25 Ashokraj Y, Agrawal S, Varma MV, et al. quality control of
anti-tuberculosis fixed-dose combination formulations in the
global market: an in vitro study. Int J Tuberc Lung Dis 2004; 8:
1081–1088.
26 Ellard GA, Fourie P B. Rifampicin bioavailability: a review
CONTEXT :Des taux très faibles de la rifampicine (RMP) ont
été observés dans une étude antérieure de suivi de la
rifampicine (RMP) chez les patients tuberculeux traités
par un produit générique de combinaison à dosee de
trois medicaments (3FDC). Ceci nous a poussés à
investiguer la biodisponibilité du product.
OB JECTIVE :Investiguer chez des volontaires sci la
biodisponibilité relative de la RMP provenant d'une
formulation générique de 3FDC utilisée dans le système
de soins de santé au Mexique par comparaison avec le
product de référence.
SCH EMA :Etude transversalal sur deux périodes et deux
sequences.
R É SU LTAT S :Les
valeurs moyennes des paramètres
pharmacocinétiques obtenues pour le produit-test et
le produit-référence ont été respectivement de 3,13±
2.01μg/ml et 9.95±2.66μg/ml pour la concentration
maximum (Cmax), de 15.51±9.77μgh/ml et 58.03±
Relative bioavailability of RMP 1459
of its pharmacology and the chemotherapeutic necessity for
ensuring optimal absorption. Int J Tuberc Lung Dis 1999; 3
(Suppl 3): S301–S308.
27 Agrawal S, Kaur KJ, Singh I, Bhade SR, Kaul CL, Panchag-
nula R. Assessment of bioequivalence of rifampicin, isoniazid and
pyrazinamide in a four drug fixed dose combination with
separate formulations at the same dose levels. Int J Pharm 2002;
233:169–177.
28 McIlleron H, Gabriels G, Smith PJ, Fourie PB, Ellard G A. The
development of a standardized screening protocol for the in vivo
assessment of rifampicin bioavailability. Int J Tuberc Lung Dis
1999; 3 (Suppl 3): S329–S335.
29 Agrawal S, Kaur KJ, Singh I, Bhade SR, Kaul CL, Panchag-
nula R. Determination of rifampicin bioequivalence in a three-
drug FDC by WHO and Indian protocols: effect of sampling
schedule and size. Int J Tuberc Lung Dis 2005; 9:75–80.
30 Pargal A, Rani S. Non-linear pharmacokinetics of rifampicin in
healthy Asian Indian volunteers. Int J Tuberc Lung Dis 2001;
5: 70–79.
31 Agrawal S, Singh I, Kaur KJ, Bhade S, Kaul CL, Panchagnula
R. Bioequivalence trials of rifampicin containing formulations:
extrinsic and intrinsic factors in the absorption of rifampicin.
Pharmacol Res 2004; 50:317–327.
32 McIlleron H, Wash P, Burger A, Folb P, Smith P. Widespread
distribution of a single drug rifampicin formulation of inferior
bioavailability in South Africa. Int J Tuberc Lung Dis 2002; 6: 356–
361.
33 Laserson KF, Kenyon AS, Kenyon TA, Layloff T, Binkin N J.
Substandard tuberculosis drugs on the global market and their
simple detection. Int J Tuberc Lung Dis 2001; 5:448–454. 34
Blomberg B, Fourie B. Fixed-dose combination drugs for tu-
tuberculosis. Drugs 2003; 63:535–553.
35 Consejo de Salubridad General. Acuerdo por el que se ari-
ciona y modifica la relación de specialidades pharmacéuticas
susceptibles de incorporarse al Catálogo de Medicamentos
Genéricos. Diario Oficial de la Federación, 21 febrero 2008. http://
cdivirtual.salud.gob.mx/interiores/diario_oficial/diario_2008/
pdfs/febrero/a210208.pdf Accessed July 2010. [Spanish]
R É SUM É
16,1μgh/ml pour aire sous la courbe (AUC) de 0 à 12 h
(AUC0–12h) et finalement de 17.92±10.66 et 68.43±
22,39μg/ml pour AUC0–∞.Le ratio des moyennes tests
sur moyennes référence avec IC90% a été de 25.36%
(17.33–37.10) pour Cmax, 21.25% (IC90% 14.61–30.89)
pour AUC0–12het 22.08% (IC90% 15.44–31.56) pour AUC0–
∞.Ces résultats ne répondent pas aux critères de
bioéquivalence.
CON CLUSION ON :Le produit testé démontre un retard
d'absorption et une biodisponibilité nettement inférieure
de la RMP par comparison avec le produit de référence.
Des formulations génériques content de la RMP ne
devraient être utilisées que lorsque leur biodisponibilité
a été évaluée afin d'assurer l'interchangeabilité avec les
products de référence et afin d'éviter le risque d'une
exposition nettement inférieure à la RMP lors de leur util
isation .
 1460 The International Journal of Tuberculosis and Lung Disease
MA R CO DEREFERENCIA :En un estudio previo de
monitorización de rifampicina (RMP) administrada
mediante un medicamento genérico de doses
combinadas conteniendo tres pharmacos (3FDC) a
pacientes con tuberculosis (TB), contraron bajos
niveles plasmáticos. Estos resultados nos condujeron
a evaluar la biodisponibilidad de este producto.
OB JETI VO :Investigar la biodisponibilidad relativa de RMP
en sujetos sanos, a partir de un medicamento genérico
3FDC del sector salud mexicano en comparación con el
medicamento de referencia.
ME T ODO :Estudio cruzado sobre dos periodos en dos
secuencias.
RESU LTADO S :Los valores promedio de los pharmacocinéticos
del producto de prueba y del producto de referencia fueron,
respectivamente, 3,13±2.01μg/ml y 9.95±2.66μg/ml para la
concentration máxima
View publication stats
RESUMEN
(Cmax), 15.51±9.77μg/ml y 58.03±16,1μg/ml for AUC0–
12h, 17.92±10.66 y 68.43±22,39μg/ml for AUC0–∞. El
cociente prueba/referencia de los valores
promedio (IC90%) fue 21.25% (14.61–30.89) para C
max, 25.36% (17.33–37.10) of the AUC0–12hy 22.08%
(15.44–31.56) the AUC0–∞.Estos resultados no
cumplieron con el criterion de bioequivalencia.
CON CLUSION ÓN :El producto de prueba presentó retardo
en la absorption y una biodisponibilidad menor de RMP
en comparación con el producto de referencia. Los
medicamentos genéricos de RMP en presentaciones de
dosage combinations, sólo deben emplearse si su
biodisponibilidad ha sido evaluada, a fin de asegurar su
intercambiabilidad con el medicamento de referencia, y
evitar el riesgo de una menor exposición del fármaco a
través del empleo de dichos products .