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Brief Report
de Estudios Cientficos y Clnicos Pharma, S.A. de C.V., Mexico City, Mexico; and 2Fundacin
Liomont A.C., Mexico City, Mexico
ABSTRACT
Background: Acyclovir is an important antiviral
drug, used extensively for treatment of herpes simplex
and varicella zoster. Six oral generic formulations of
acyclovir are available in Mexico; however, a literature search failed to identify data information concerning the bioavailability of these formulations in the
Mexican population.
Objective: The aim of these 2 studies was to compare the bioavailability of 4 oral formulations of acyclovir 400 mg2 tablet formulations and 2 suspension
formulationswith their corresponding listed drug
references in Mexico (a list issued by Mexican Health
Authorities).
Methods: Two separate, single-dose, open-label, randomized, 2-period crossover studies were conducted
at the Centro de Estudios Cientficos y Clnicos
Pharma, S.A. de C.V. (clinical unit), Mexico City,
Mexico. For each study, a different set of eligible subjects were selected. They included healthy Mexican
volunteers of either sex. For each study, subjects were
randomly assigned to receive 1 test formulation of
acyclovir 400 mg followed by the reference formulation, or vice versa, with a 1-week washout period between doses. After a 12-hour (overnight) fast, subjects
received a single 400-mg dose (tablet or 10-mL suspension) of the corresponding formulation. For the
analysis of pharmacokinetic properties, including
Cmax, AUC from time 0 (baseline) to time t (AUC0t ),
and AUC from baseline to infinity (AUC0 ), blood
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INTRODUCTION
Study Design
Acyclovir (9-[2-hydroxyethoxy]-methylguanine) is a
nucleoside analog with antiviral activity for the treatment of herpes simplex viruses, varicella zoster virus,
Epstein-Barr virus, cytomegalovirus, and human herpes virus 6 (HHV-6).1,2 Acyclovir exerts its antiviral activity by acting as a substrate that inhibits viral DNA
polymerase.14 Because of the efficacy and tolerability
of this drug, it is widely used in Mexico.
The bioavailability of oral acyclovir is from 10% to
30% and decreases with increasing administration
frequency. The Tmax and t1/2 for a single, 400-mg oral
dose of acyclovir are 2.4 hours and 1.5 to 2 hours,
respectively.2
Although several oral generic formulations of acyclovir are available in Mexico, a MEDLINE search
(19912006; key terms: bioequivalence, bioavailability, Mexico, and acyclovir) failed to identify data concerning the bioavailability of each formulation in the
Mexican population. Thus, the aim of these studies
was to compare the bioavailability of 4 oral formulations of acyclovir 400 mg (2 tablet formulations and
2 suspension formulations) with their corresponding
listed drug references in Mexico. In each study, 2 formulations were compared to determine bioavailability: Cicloferon tablet (Laboratorios Liomont S.A. de
C.V., Mexico City, Mexico; test formulation) versus
The 2 protocols were approved by the ethics and research committees of the Centro de Estudios Cientficos
y Clnicos Pharma, S.A. de C.V. The studies were carried out in accordance with the principles of the
Declaration of Helsinki and its amendments5 and the
International Conference on Harmonisation Guideline
for Good Clinical Practice.6 A 2 2 crossover, openlabel, randomized design was used in both studies.
The subjects for each study arrived at the clinical
unit the day before the beginning of the study and
were randomized in a 1:1 ratio using a table of random numbers to receive Cicloferon followed by
Zovirax, or vice versa, with a 1-week washout period
between doses. After subjects were fasted for 12 hours
overnight, blood was drawn for baseline plasma measurements in the following manner: a 20-G catheter
(Jelco Plus, Medex Medical Ltd., Ascot, United
Kingdom) was placed in a suitable forearm vein and a
6-mL blood sample was drawn into a heparinized vacuum tube (Vacutainer , Becton, Dickinson and
Company, Franklin Lakes, New Jersey). Subjects received a single 400-mg tablet or 10 mL of suspension
(whichever was applicable in the corresponding study)
of the study medication, given with 250 mL of water
(either tablet or suspension formulation), and additional blood samples were drawn at 0.25, 0.5, 0.75, 1.0,
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Clinical Therapeutics
1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, and 24 hours after
study drug administration. Plasma was obtained by
centrifugation (2000g for 10 minutes at room temperature) and stored frozen at 70C until analyzed using
high-performance liquid chromatography (HPLC). After
the washout period, subjects returned to the clinical
unit where the alternative formulation was administered and samples were drawn and analyzed as before.
Tolerability
Tolerability was assessed by monitoring vital signs
(blood pressure, heart rate, body temperature) at
baseline, 3.5, 11.5, and 23.5 hours, and at the end of
each period, laboratory analysis results, and subject
interviews regarding the potential presence of adverse
events (AEs) during the study.
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RESULTS
A total of 26 subjects were enrolled in the study for the
suspension dosage form. One subject was withdrawn
because he or she did not comply with the dietary requirements established in the corresponding protocol,
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Pharmacokinetic Parameters
For the suspension study, mean and SD values of
Cmax, Tmax, t1/2, AUC0t, and AUC0 for each formulation are shown in Table I. No period or sequence
effects were observed for the pharmacokinetic properties in the ANOVA.
Test formulation
Reference formulation
800
700
600
500
400
300
200
100
0
0
10
12
Figure 1. Mean (SD) plasma concentrations of 2 oral formulations of acyclovir 400-mg suspension (Cicloferon,
Laboratorios Liomont, S.A. de C.V., Mexico City, Mexico, test formulation; Zovirax, GlaxoSmithKline
Mexico, S.A. de C.V., Mexico City, Mexico, reference formulation) over 12 hours in healthy adult Mexican
subjects (N = 25).
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Test formulation
Reference formulation
1000
900
800
700
600
500
400
300
200
100
0
0
10
12
Cicloferon
Zovirax
670.5 (165.1)
1.2 (0.2)
3.8 (1.7)
2649.4 (609.4)
3171.4 (734.0)
599.2 (123.7)
1.4 (0.5)
3.9 (1.2)
2508.4 (609.5)
3015.7 (662.3)
AUC0t = AUC from time 0 (baseline) to time t; AUC0 = AUC from baseline to infinity.
*No significant between-treatment differences were found.
Trademark of Laboratorios Liomont, S.A. de C.V., Mexico City, Mexico (test formulation).
Trademark of GlaxoSmithKline Mexico, S.A. de C.V., Mexico City, Mexico (reference formulation).
Tolerability
In these single-dose studies, no AEs were reported
and lab abnormalities were not found.
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DISCUSSION
Estimated Cmax values for the 2 formulations of the
tablet dosage form were 779 ng/mL (test formulation)
and 800 ng/mL (reference formulation). This was
consistent with respect to those reported by Vergin
et al14 in their crossover study in which they also
compared 2 acyclovir 400-mg tablet formulations in
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Cicloferon
Zovirax
681.1 (281.7)
1.6 (0.8)
2.7 (0.7)
2515.1 (994.7)
2893.2 (1012.6)
704.4 (238.3)
1.4 (0.7)
2.6 (0.6)
2503.3 (978.0)
2874.2 (971.5)
AUC0t = AUC from time 0 (baseline) to time t; AUC0 = AUC from baseline to infinity.
*No significant between-treatment differences were found.
Trademark of Laboratorios Liomont, S.A. de C.V., Mexico City, Mexico (test formulation).
Trademark of GlaxoSmithKline, Research Triangle Park, North Carolina (reference formulation).
Table III. Comparison of 90% CIs of natural log (ln)-transformed Cmax, ln AUC0t, and
ln AUC0, the probability of exceeding the limits of acceptance, and power test
in acyclovir 400 mg (suspension).
Parameter
In Cmax % ratio
In AUC0t % ratio
In AUC0 % ratio
Probability of Exceeding
Limits of Acceptance
Ratio,
% Reference
90% CI
<80%
>125%
Power
111.23
106.01
104.98
106.55116.11
99.29113.19
98.37112.04
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
1.0000
0.9998
0.9998
AUC0t = AUC from time 0 (baseline) to time t; AUC0 = AUC from baseline to infinity.
Table IV. Comparison of 90% CIs of natural log (ln)-transformed Cmax, ln AUC0t, and ln
AUC0, the probability of exceeding the limits of acceptance, and power test in
acyclovir 400 mg (tablets).
Parameter
In Cmax % ratio
In AUC0t % ratio
In AUC0 % ratio
Probability of Exceeding
Limits of Acceptance
Ratio,
% Reference
90% CI
<80%
>125%
Power
93.01
97.82
98.25
83.46103.64
86.16111.05
87.77109.99
0.013
<0.001
<0.001
<0.001
0.002
<0.001
0.9590
0.8972
0.9463
AUC0t = AUC from time 0 (baseline) to time t; AUC0 = AUC from baseline to infinity.
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Clinical Therapeutics
The results of these 2 studies, obtained from 2 samples of healthy Mexican volunteers, might serve as a
reference for future controlled studies of acyclovir in
the Hispanic population.
6.
CONCLUSIONS
In these 2 studies in healthy Mexican subjects, a single,
400-mg dose of the test formulation of acyclovir
(Cicloferon), administered either in tablet or suspension
form, appeared to be bioequivalent to the reference formulation (Zovirax) based on the rate and extent of absorption in accordance with the definition found in the
US Food and Drug Administrations in vivo bioequivalence guidances. All formulations were well tolerated.
7.
8.
9.
ACKNOWLEDGMENTS
These 2 studies were supported in their entirety by
Laboratorios Liomont, S.A. de C.V., Mexico City,
Mexico. The authors would like to thank Patricia
Andrew (Universidad Nacional Autonoma de
Mexico, FES Acatlan, Mexico) for her help with the
English style and grammar of the manuscript.
10.
11.
REFERENCES
1. Wagstaff AJ, Faulds D, Goa KL. Acyclovir. A reappraisal
of its antiviral activity, pharmacokinetic properties and
therapeutic efficacy. Drugs. 1994;47:153205.
2. Laskin OL. Clinical pharmacokinetics of acyclovir. Clin
Pharmacokinet. 1983;8:187201.
3. OBrien JJ, Campoli-Richards DM. Acyclovir. An updated
review of its antiviral activity, pharmacokinetic properties
and therapeutic efficacy. Drugs. 1989;37:233309.
4. Reardon JE, Spector T. Acyclovir: Mechanism of antiviral
action and potentiation of ribonucleotide reductase inhibitors. Adv Pharmacol. 1991;22:127.
5. World Medical Association Declaration of Helsinki:
Recommendations Guiding Medical Doctors in Biomedi-
12.
13.
14.
Address correspondence to: Salvador Namur, MS, Privada Jess del Monte
No. 77, Col. Cuajimalpa, 05000 Mexico City, Mexico. E-mail: snamur@
liomont.com.mx
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