CLINICAL PHARMACOLOGY
Mechanism Of Action
Tinidazole is an antiprotozoal, antibacterial agent. [See Microbiology].
Pharmacokinetics
Absorption
After oral administration, tinidazole is rapidly and completely
absorbed. A bioavailability study of Tindamax tablets was conducted in adult
healthy volunteers. All subjects received a single oral dose of 2 g (four 500
mg tablets) of Tindamax following an overnight fast. Oral administration of
four 500 mg tablets of Tindamax under fasted conditions produced a mean peak
plasma concentration (Cmax ) of 47.7 (±7.5) μg/mL with a mean time to peak
concentration (Tmax) of 1.6 (±0.7) hours, and a mean area under the plasma
concentration-time curve (AUC, 0-∞) of 901.6 (± 126.5) μg/hr/mL at
72 hours. The elimination half-life (T1/2) was 13.2 (±1.4) hours. Mean plasma
levels decreased to 14.3 μg/mL at 24 hours, 3.8 μg/mL at 48 hours and
0.8 μg/mL at 72 hours following administration. Steady-state conditions
are reached in 2½ - 3 days of multi-day dosing.
Administration of Tindamax tablets with food resulted in
a delay in Tmax of approximately 2 hours and a decline in Cmax of approximately
10% compared to fasted conditions. However, administration of Tindamax with
food did not affect AUC or T1/2 in this study.
In healthy volunteers, administration of crushed Tindamax
tablets in artificial cherry syrup, [prepared as described in Dosage and
Administration (2.2)] after an overnight fast had no effect on any pharmacokinetic
parameter as compared to tablets swallowed whole under fasted conditions.
Distribution
Tinidazole is distributed into virtually all tissues and
body fluids and also crosses the blood-brain barrier. The apparent volume of
distribution is about 50 liters. Plasma protein binding of tinidazole is 12%.
Tinidazole crosses the placental barrier and is secreted in breast milk.
Metabolism
Tinidazole is significantly metabolized in humans prior
to excretion. Tinidazole is partly metabolized by oxidation, hydroxylation, and
conjugation. Tinidazole is the major drug-related constituent in plasma after
human treatment, along with a small amount of the 2-hydroxymethyl metabolite.
Tinidazole is biotransformed mainly by CYP3A4. In an in
vitro metabolic drug interaction study, tinidazole concentrations of up to 75
μg/mL did not inhibit the enzyme activities of CYP1A2, CYP2B6, CYP2C9,
CYP2D6, CYP2E1, and CYP3A4.
The potential of tinidazole to induce the metabolism of
other drugs has not been evaluated.
Elimination
The plasma half-life of tinidazole is approximately 12-14
hours. Tinidazole is excreted by the liver and the kidneys. Tinidazole is
excreted in the urine mainly as unchanged drug (approximately 20-25% of the
administered dose). Approximately 12% of the drug is excreted in the feces.
Patients With Impaired Renal Function
The pharmacokinetics of tinidazole in patients with
severe renal impairment (CrCL < 22 mL/min) are not significantly different
from the pharmacokinetics seen in healthy subjects. However, during
hemodialysis, clearance of tinidazole is significantly increased; the half-life
is reduced from 12.0 hours to 4.9 hours. Approximately 43% of the amount
present in the body is eliminated during a 6-hour hemodialysis session [see Use
in Specific Populations]. The pharmacokinetics of tinidazole in patients
undergoing routine continuous peritoneal dialysis have not been investigated.
Patients With Impaired Hepatic Function
There are no data on tinidazole pharmacokinetics in
patients with impaired hepatic function. Reduction of metabolic elimination of
metronidazole, a chemically-related nitroimidazole, in patients with hepatic
dysfunction has been reported in several studies [see Use in Specific
Populations].
Microbiology
Mechanism Of Action
Tinidazole is an antiprotozoal, antibacterial agent. The
nitro- group of tinidazole is reduced by cell extracts of Trichomonas. The
free nitro- radical generated as a result of this reduction may be responsible
for the antiprotozoal activity. Chemically reduced tinidazole was shown to
release nitrites and cause damage to purified bacterial DNA in vitro. Additionally,
the drug caused DNA base changes in bacterial cells and DNA strand breakage in
mammalian cells. The mechanism by which tinidazole exhibits activity against Giardia and Entamoeba species is not known.
Antibacterial
Culture and sensitivity testing of bacteria are not
routinely performed to establish the diagnosis of bacterial vaginosis [see INDICATIONS
AND USAGE]; standard methodology for the susceptibility testing of
potential bacterial pathogens, Gardnerella vaginalis, Mobiluncus spp. or
Mycoplasma hominis, has not been defined. The following in vitro data
are available, but their clinical significance is unknown. Tinidazole is active
in vitro against most strains of the following organisms that have been
reported to be associated with bacterial vaginosis:
Bacteroides spp.
Gardnerella vaginalis
Prevotella spp.
Tinidazole does not appear to have activity against most
strains of vaginal lactobacilli.
Antiprotozoal
Tinidazole demonstrates activity both in vitro and in
clinical infections against the following protozoa: Trichomonas vaginalis;
Giardia duodenalis (also termed G. lamblia); and Entamoeba histolytica.
For protozoal parasites, standardized susceptibility
tests do not exist for use in clinical microbiology laboratories.
Drug Resistance
The development of resistance to tinidazole by G.
duodenalis, E. histolytica, or bacteria associated with bacterial vaginosis
has not been examined.
Cross-resistance
Approximately 38% of T. vaginalis isolates
exhibiting reduced susceptibility to metronidazole also show reduced
susceptibility to tinidazole in vitro. The clinical significance of such an
effect is not known.
Animal Toxicology And/Or Pharmacology
In acute studies with mice and rats, the LD50 for mice
was generally > 3,600 mg/kg for oral administration and was > 2,300 mg/kg
for intraperitoneal administration. In rats, the LD50 was > 2,000 mg/kg for
both oral and intraperitoneal administration.
A repeated-dose toxicology study has been performed in
beagle dogs using oral dosing of tinidazole at 100 mg/kg/day, 300 mg/kg/day,
and 1000 mg/kg/day for 28-days. On Day 18 of the study, the highest dose was
lowered to 600 mg/kg/day due to severe clinical symptoms. The two
compound-related effects observed in the dogs treated with tinidazole were
increased atrophy of the thymus in both sexes at the middle and high doses, and
atrophy of the prostate at all doses in the males. A no-adverse-effect level
(NOAEL) of 100 mg/kg/day for females was determined. There was no NOAEL
identified for males because of minimal atrophy of the prostate at 100
mg/kg/day (approximately 0.9-fold the highest human dose based upon plasma AUC
comparisons).
Clinical Studies
Trichomoniasis
Tinidazole (2 g single oral dose) use in trichomoniasis
has been well documented in 34 published reports from the world literature
involving over 2,800 patients treated with tinidazole. In four published,
blinded, randomized, comparative studies of the 2 g tinidazole single oral dose
where efficacy was assessed by culture at time points post-treatment ranging
from one week to one month, reported cure rates ranged from 92% (37/40) to 100%
(65/65) (n=172 total subjects). In four published, blinded, randomized,
comparative studies where efficacy was assessed by wet mount between 7-14 days post-treatment,
reported cure rates ranged from 80% (8/10) to 100% (16/16) (n=116 total
subjects). In these studies, tinidazole was superior to placebo and comparable
to other anti-trichomonal drugs. The single oral 2 g tinidazole dose was also
assessed in four open-label trials in men (one comparative to metronidazole and
3 single-arm studies). Parasitological evaluation of the urine was performed
both pre- and post-treatment and reported cure rates ranged from 83% (25/30) to
100% (80/80) (n=142 total subjects).
Giardiasis
Tinidazole (2 g single dose) use in giardiasis has been
documented in 19 published reports from the world literature involving over
1,600 patients (adults and pediatric patients). In eight controlled studies involving
a total of 619 subjects of whom 299 were given the 2 g à 1 day (50 mg/kg à 1
day in pediatric patients) oral dose of tinidazole, reported cure rates ranged
from 80% (40/50) to 100% (15/15). In three of these trials where the comparator
was 2 to 3 days of various doses of metronidazole, reported cure rates for
metronidazole were 76% (19/25) to 93% (14/15). Data comparing a single 2 g dose
of tinidazole to usually recommended 5-7 days of metronidazole are limited.
Intestinal Amebiasis
Tinidazole use in intestinal amebiasis has been
documented in 26 published reports from the world literature involving over
1,400 patients. Most reports utilized tinidazole 2 g/day à 3 days. In four published,
randomized, controlled studies (1 investigator single-blind, 3 open-label) of
the 2 g/day à 3 days oral dose of tinidazole, reported cure rates after 3 days
of therapy among a total of 220 subjects ranged from 86% (25/29) to 93%
(25/27).
Amebic Liver Abscess
Tinidazole use in amebic liver abscess has been
documented in 18 published reports from the world literature involving over 470
patients. Most reports utilized tinidazole 2 g/day à 2-5 days. In seven published,
randomized, controlled studies (1 double-blind, 1 single-blind, 5 open-label)
of the 2 g/day à 2-5 days oral dose of tinidazole accompanied by aspiration of
the liver abscess when clinically necessary, reported cure rates among 133
subjects ranged from 81% (17/21) to 100% (16/16). Four of these studies
utilized at least 3 days of tinidazole.
Bacterial Vaginosis
A randomized, double-blind, placebo-controlled clinical
trial in 235 non-pregnant women was conducted to evaluate the efficacy of
tinidazole for the treatment of bacterial vaginosis. A clinical diagnosis of
bacterial vaginosis was based on Amsel's criteria and defined by the presence
of an abnormal homogeneous vaginal discharge that (a) has a pH of greater than
4.5, (b) emits a “fishy” amine odor when mixed with a 10% KOH
solution, and (c) contains ≥ 20% clue cells on microscopic examination.
Clinical cure required a return to normal vaginal discharge and resolution of
all Amsel's criteria. A microbiologic diagnosis of bacterial vaginosis was
based on Gram stain of the vaginal smear demonstrating (a) markedly reduced or
absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype,
and (c) absent or few white blood cells, with quantification of these bacterial
morphotypes to determine the Nugent score, where a score ≥ 4 was required
for study inclusion and a score of 0-3 considered a microbiologic cure.
Therapeutic cure was a composite endpoint, consisting of both a clinical cure
and microbiologic cure. In patients with all four Amsel's criteria and with a baseline
Nugent score ≥ 4, tinidazole oral tablets given as either 2 g once daily
for 2 days or 1 g once daily for 5 days demonstrated superior efficacy over
placebo tablets as measured by therapeutic cure, clinical cure, and a
microbiologic cure.
Table 2: Efficacy of Tindamax in the Treatment of Bacterial
Vaginos is in a Randomized, Double-Blind, Double-Dummy, Placebo-Controlled
Trial: Modified Intent-to-Treat Population1 (n=227)
Outcome |
Tindamax 1 g x 5 days
(n=76) |
Tindamax 2 g x 2 days
(n=73) |
Placebo
(n=78) |
% Cure |
% Cure |
% Cure |
Therapeutic Cure |
36.8 |
27.4 |
5.1 |
Difference2
97.5% CI3 |
31.7
(16.8, 46.6) |
22.3
(8.0, 36.6) |
|
Clinical Cure |
51.3 |
35.6 |
11.5 |
Difference2
97.5% CI3 |
39.8
(23.3, 56.3) |
24.1
(7.8, 40.3) |
|
Nugent Score Cure Difference2
97.5% CI3 |
38.2 33.1
(18.1, 48.0) |
27.4 22.3
(8.0, 36.6) |
5.1 |
1Modified Intent-to-Treat defined as all
patients randomized with a baseline Nugent score of at least 4
2Difference in cure rates (Tindamax-placebo)
3CI: confidence interval
p-values for both Tindamax regimens vs. placebo for therapeutic, clinical and Nugent
score cure rates for both 2 and 5 days < 0.001 |
The therapeutic cure rates reported in this clinical
study conducted with Tindamax were based on resolution of 4 out of 4 Amsel's
criteria and a Nugent score of < 4. The cure rates for previous clinical studies
with other products approved for bacterial vaginosis were based on resolution
of either 2 or 3 out of 4 Amsel's criteria. At the time of approval for other
products for bacterial vaginosis, there was no requirement for a Nugent score
on Gram stain, resulting in higher reported rates of cure for bacterial vaginosis
for those products than for those reported here for tinidazole.