Indian Journal of Pharmacology 1996; 28: 32-34 SHORT COMMUNICATION

COMPARATIVE BIOAVAILABILITY OF TWO COMMERCIAL CENTCHROMAN

TABLETS IN HEALTHY FEMALE SUBJECTS+

J. LAL, S. NITYANAND, O.P. ASTHANA*, R.C. GUPTA

Pharmacokinetics and Metabolism Division and

Clinical and Experimental Medicine Division,
Central Drug Research Institute,
Chattar Manzil,
Lucknow - 226 001.

Accepted for publication: December 04, 1995.

Summary Centchroman serum levels were determined in six healthy female subjects after oral ad-
ministration of single 30 mg tablets of Saheli (Hindustan Latex Ltd.) and Centrol (Torrent
Pharmaceuticals Ltd.) in a double blind cross-over study. The mean peak serum centchroman
concentrations of 67.55 no/ml was observed between 4-8 h from Saheli and was similar to
that from Centron. The pharmacokinetic parameters of centchroman from both the tablets
were comparable without significant variation. The mean relative biovailability of Centron
to Saheli was 101.97%.

Key words Contraceptive non-steroidal centchroman bioequivalence saheli centron

Centchroman, a biphenyl chroman derivative with In this study, the bioequivalence of two pharmaceuti-
weak estrogenic and potent anti-estrogenic activity, cally equivalent brands of centchroman tablets (30
is the only non-steroidal oral contraceptive¹,². Also mg) viz. Saheli (Hindustan Latex Ltd) and Centron
it is under phase III clinical trials for the treatment (Torrent Pharmaceuticals Ltd) was studied. The
of advanced breast cancer. The weak inherent tablets were administered in a crossover fashion to
estrogenic property of this drug led its use in the six subjects. On each occasion, the subjects
treatment of bone loss³. The therapeutic dose of received one tablet with 250 ml of water after an
centchroman for contraceptive efficacy is 30 mg overnight fast at an intervening period of eight
twice a week for first twelve weeks followed by 30 weeks. Food and fluids were allowed 2 h after the
mg weekIf. The product is marketed in the brand dose. Blood samples were collected via an in-
names Saheli (Hindustan Latex Ltd) and Centon dwelling canula placed in the anterior cubital vein
(Torrent Pharmaceuticals Ltd). of forearm at 0 (predose), 1, 2, 4, 6, 8, 10 and 12
h followed by venipuncture at 24, 48, 72, 96, 120,
Since, marketed products of the same drug may
144, 168, 192, 216, 240, 312, 384, 456, 528, 600
differ with respect to bioavailability, the objective of
and 672 h after drug ingestion. Blood samples were
this study was to study the comparative
allowed to clot, serum was separated by centrifuga-
bioavailability (bioequivalence) of Saheli and Cen- tion and stored at -6O°C pending analysis.
tron.
Centchroman was measured in serum by the HPLC
assay method of Lal et a/5. Briefly, standards were
MATERIALS AND METHODS
prepared by adding known amounts of centchroman
Following approval of the protocol from the ethics to drug-free human serum to obtain final concentra-
committee which was in accordance with the regula- tions in the range l-250 ng/ml. Serum samples (0.5
tions of drugs controller of India, six healthy female ml) after basifying with 25 µI of 1 M potassium
subjects of age between 23 and 31 years with body hydroxide solution were extracted with 2 x 3 ml
weight from 35 to 68 kg were recruited. The nature diethyl ether. The ether was evaporated to dryness
and purpose of the study were fully explained to using Savant speed vac concentrator and the
them and an informed written consent was obtained residue reconstituted in 0.1 ml of mobile phase (60%
from each of the subjects before study. They had acetonitrile in 20 mM phosphate buffer, pH 3.0) by
not been exposed to any other medication for at vortexing. The aliquots were subjected to HPLC
least two weeks before and during the study. analysis after centrifugation. The HPLC system

Correspondence: Dr. R.C. Gupta

+CDRl Communication No.5405
 BIOEQUIVALENCE OF CENTCHROMAN TABLETS 33

Table 1. Pharmacokinetic parameters of centchroman from comprised of an isocratic pump (Pye Unicam,
Saheli and Centrom tablets in six healthy female
subjects.
Cambridge, UK), a 7125 syringe loading injector
(Rheodyne, Berkely, USA) fitted with a fixed 50 µl
Pharmacokinetic Formulation loop, a Pierce nitrile column (100 x 4.6 mm)
parameter F-value preceded by a precolumn (30 x 4.6 mm), and a
Saheli Centron fluorescence detector (Shimadzu, Japan) set at ex-
citation 285 nm and emission 310 nm. The solvent
C, (ng/ ml) 67.55 69.44 0.15
± 6.64 ± 9.36
was pumped at 1.5 ml/min and eluting peaks were
recorded. by Chromatopac recorder (Shimadzu,
La, (h) 5.33 4.33 3.75 Japan). Within and between assay coefficients of
± 0.64 ± 0.67
variation were less than 10%. The lower limit of
KB (h-‘) 0.51 0.70 0.77 quantitation was 1 ng/ml.
± 0.11 ± 0.13
Peak concentrations (Cm& and time to attain Cm,
a (h-l) 0.16 0.20 1.45
± 0.04 ± 0.05 (tm& are the observed values obtained by visual
inspection of the data. The individual phar-
B (h-l) 0.0054 0.0055 0.14 macokinetic parameters were computed with a non-
± 0.0009 ± 0.0009
linear, least-squares, weighted PCNONLIN (version
t,, (h) 1 .01 1.35 0.56 4.2)6 program. Total observed concentrations (Cd
±0.61 ±µ0.36 as a function of time (t) were fitted to a tri-exponential
t, R (h) 145.00 141.33 0.76 equation7:
± 20.06 ± 20.40
C, = A.e-a(t-dag) + B,e-p(t-tkXJ) - (A+ B),e-~(t-tb)
Cl/ F (I/ h) 5.60 6.06 0.14
± 0.96 ± 1.24 in which A and B are intercepts, a and 8 are the
1114.24 1109.62 0.00
first-order rate constants for the distribution and
Vd/ F (I)
± 129.96 ± 126.36 elimination phases, respectively; K, is absorption
rate constant, and trag is the lag time. The total area
AUC,., (ng.h/ ml) 5745.17 5657.43 0.06
± 756.12 ± 996.27 under the curve value (AU&,) was calculated by
trapezoidal method with extrapolation to infinity by
Relative 101.97± 6.49 addition of the last observed concentration divided
(Centron/ Saheli)
bioavailability (%)
by the terminal elimination rate constants. the
elimination half-life (tlk) was calculated from the
Values are mean ± SEM; see MATERIALS AND METHODS ratio of 0.693/8. The clearance (Cl/F) and the volume
section for an explanation of the abbreviations. of distribution (Vd/F) were claculated from CL/F =
Dose/ AUCo., and Vd/F = Cl / 8, in which F is the
fraction of dose absorbed. Assessment of the per-
Figure 1. Serum centchroman concentration-time plot in six
healthy female subjects following single 30 mg oral cent bioequivalence was made by AUCCentron x 100
administration of Saheli and Centron tablets. / AUCSaheli
Analysis of variance (ANOVA) and two sample t-test
-o- SAHELI -.- CENTRON at 90% confidence interval were used to measure
the statistical differences between the phar-
macokinetic parameters and P < 0.05 was consid-
ered significant,

RESULTS
The single 30 mg dose of centchroman was well
tolerated and no changes occurred in ECG, blood
pressure or heart rate, lipid profile HDL cholesterol
and platelet function of any subject during or after
the dose. No evidence of nausea, vomiting, dizzi-
1 ness or breakthrough bleeding were reported.
800
nme (h) The serum centchroman concentration-time profile
(mean± SEM) from the two tablets are presented
 J. LAL et al.

in Figure 1. The estimate of bioequivalence and different to those of the values reported earlier by
pharmacokinetic parameters (mean+ SEM) of the Lal et al g after single 30 mg eroral dose of
drug from Saheli and Centron tablets are sum- centchroman. Like the earlier study B, there was con-
marized in Table 1. The peak serum centchroman siderable intersubject variation in the phar-
concentrations from 45.94 to 90.46 ng/ml and 43.03 macokinetic parameters of centchroman, but no
to 104.90 ng/ml reached between 4 and 8 h from statistically significant differences were observed.
Saheli and Centron tablets, respectively. Peak con- The elimination half-life, systemic clearance and the
centrations declined in a bi-exponential fashion with apparent volume of distribution from the two
the elimination tl12 ranging between 85 and 202 h products were similar to those reported earlie&‘O.
from either product. The AUCc_, varied between
Insignificant differences in the pharmacokinetic
2948.40 - 7677.30 ng.h/ml and 2539.60 - 9764.51
parameters such as C,,,, t,,,, AUCc_, and rate
ng.h/ml from Saheli and Centron tablets, respec-
of elimination of centchroman from the two products
tively. The mean relative bioavailability of
after peroral dose support the bioequivalence of the
centchroman from Saheli was found to be 101.97%.
two products. The study results also meet the re-
The pharmacokinetic parameters of centchroman
quirements of Drug Control Authority of India (DCI)
from the two tablets were not statistically different
as the ratio of AUCO_, and C,, from Saheli and
(P > 0.05).
Centron tablets are within 80 to 125%¹¹. Thus, the
present study adequately demonstrates that both
DISCUSSION the products are bioequivalent.
The concentration-time profile of centchroman from
Saheli and Centron were superimposable (Figure ACKNOWLEDGEMENT
1). The C,,,,x of these products were close to each
other. However, the C,,, from Centron tablets The encouragements by Dr. V.P. Kamboj, Director,
showed more intersubject variation than those ob- Central Drug Research Institute, Lucknow is grate-
t a i n e d f r o m Saheli. T h e C,,, a n d t,, o f fully acknowledged,
centchroman from either product were insignificantly

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