CLINICAL PHARMACOLOGY
Microbiology
Doxycycline is a broad-spectrum semisynthetic tetracycline.1 Doxycycline
is bacteriostatic, inhibiting bacterial protein synthesis due to disruption
of transfer RNA and messenger RNA at ribosomal sites.1 In vitro testing
has shown that Porphyromonas gingivalis, Prevotella intermedia, Campylobacter
rectus, and Fusobacterium nucleatum, which are associated with periodontal
disease, are susceptible to doxycycline at concentrations ≤ 6.0 μg/mL.2
A single-center, single-blind, randomized, clinical study in 45 subjects with
periodontal disease demonstrated that a single treatment with ATRIDOX (doxycycline hyclate) ® resulted
in the reduction in the numbers of P. gingivalis, P. intermedia, C. rectus,
F. nucleatum, Bacteroides forsythus, and E. corrodens in subgingival
plaque samples. Levels of aerobic and anaerobic bacteria were also reduced after
treatment with ATRIDOX (doxycycline hyclate) ®. The clinical significance of these findings, however,
is not known. During these studies, no overgrowth of opportunistic organisms
such as Gram-negative bacilli and yeast were observed. However, as with other
antibiotic preparations, ATRIDOX (doxycycline hyclate) ® therapy may result in the overgrowth of
nonsusceptible organisms including fungi. (See PRECAUTIONS)
Pharmacokinetics
In a clinical pharmacokinetic study, subjects were randomized to receive either
ATRIDOX (doxycycline hyclate) ® covered with Coe-Pak™ periodontal dressing (n=13), ATRIDOX (doxycycline hyclate) ®
covered with Octyldent™ periodontal adhesive (n=13), or oral doxycycline
(n=5) (according to package dosing instructions). The doxycycline release characteristics
in gingival crevicular fluid (GCF), saliva, and serum were evaluated.
Doxycycline levels in GCF peaked (~1,500 μg/mL and ~2000 μg/mL for Coe-Pak™
and Octyldent™ groups, respectively) 2 hours following treatment with
ATRIDOX (doxycycline hyclate) ®. These levels remained above 1000 μg/mL through 18 hours, at
which time the levels began to decline gradually. However, local levels of doxycycline
remained well above the minimum inhibitory concentration (MIC90) for periodontal
pathogens ( ≤ 6.0 μg/mL)2 through Day 7. In contrast, subjects
receiving oral doxycycline had peak GCF levels of ~2.5 μg/mL at 12 hours
following the initial oral dosing with levels declining to ~0.2 μg/mL by
Day 7. High variability was observed for doxycycline levels in GCF for both
oral and ATRIDOX (doxycycline hyclate) ® treatment groups.
The ATRIDOX (doxycycline hyclate) ® doxycycline release profile in GCF is illustrated in the figure
below.
The maximum concentration of doxycycline in saliva was achieved at 2 hours
after both treatments with ATRIDOX (doxycycline hyclate) ®, with means of 4.05 μg/mL and 8.78
μg/mL and decreased to 0.36 μg/mL and 0.23 μg/mL at Day 7 for the Coe-Pak™
group and the Octyldent™ group, respectively.
The concentration of doxycycline in serum following treatment of ATRIDOX (doxycycline hyclate) ®
never exceeded 0.1 μg/mL.
Clinical Studies
In two well-controlled, multicenter, parallel-design, nine-month clinical trials,
831 patients (Study 1=411; Study 2=420) with chronic adult periodontitis characterized
by a mean probing depth of 5.9 to 6.0 mm were enrolled. Subjects received one
of four treatments: 1) ATRIDOX (doxycycline hyclate) ®, 2) Scaling and Root Planing, 3) Vehicle
Control, or 4) Oral Hygiene. Treatment was administered to sites with probing
depths 5 mm or greater that bled on probing. Subjects with detectable subgingival
calculus on greater than 80% of all tooth surfaces were excluded from enrollment.
All subjects received a second administration of the initially randomized treatment
four months after their Baseline treatment. Changes in the efficacy parameters,
attachment level, pocket depth, and bleeding on probing, between Baseline and
Month 9 showed that: 1) ATRIDOX (doxycycline hyclate) ® was superior to Vehicle Control and Oral
Hygiene, and 2) ATRIDOX (doxycycline hyclate) ® met the decision rule of being at least 75% as
good as Scaling and Root Planing (SRP) (the standard of at least 75% as good
as SRP is required for any product approved as a stand alone therapy for periodontitis).
Clinicians should note that the studies were of nine months duration. Additional
research would be necessary to establish long term comparability to SRP. The
results of Studies #1 and 2 for efficacy parameters of attachment level gain
and probing depth reduction are included in the following graphs.
 |
 |
* denotes statistically significant superiority of ATRIDOX (doxycycline hyclate) ® and Sc/RP vs.
Vehicle and Oral Hygiene
† denotes statistically significant superiority of ATRIDOX (doxycycline hyclate) ® vs. Vehicle
and Oral Hygiene
Data were not collected at months 3 and 7
* denotes statistically significant superiority of ATRIDOX (doxycycline hyclate) ® and Sc/RP vs.
Vehicle and Oral Hygiene
† denotes statistically significant superiority of ATRIDOX (doxycycline hyclate) ® vs. Vehicle
and Oral Hygiene
Data were not collected at months 3 and 7
A third clinical trial was conducted to determine whether the product can be
left in the pocket to bioabsorb or be expelled naturally and achieve comparable
clinical results. In this study the product was retained with Octyldent™
dental adhesive rather than Coe-Pak™ periodontal dressing as in the previously
mentioned studies. This was a 3-arm, randomized, controlled, parallel group,
single blind trial that enrolled 605 subjects. The patient population studied
and study design were comparable to that in Studies 1 and 2. Subjects received
one of three treatments: 1) ATRIDOX (doxycycline hyclate) ® with Coe-Pak™ removed after 7
days as in the pivotal trials, 2) ATRIDOX (doxycycline hyclate) ® retained with Octyldent™
and left to bioabsorb or be expelled naturally or 3) Vehicle Control with Octyldent™
left to bioabsorb or be expelled naturally. Changes in the efficacy parameters,
attachment level, pocket depth and bleeding on probing were equivalent to those
observed in Studies 1 and 2. The results of the third study support the use
of ATRIDOX (doxycycline hyclate) ® retained with Octyldent™ and left to bioabsorb or be expelled
naturally.
REFERENCES
1. Stratton CW, Lorian V. Mechanisms of action for antimicrobial
agents: general principles and mechanisms for selected classes of antibiotics.
Antibiotics in Laboratory Medicine, 4th edition, Williams and Wilkins, Baltimore,
MD, 1996.
2. Slots J, Rams TE. Antibiotics in periodontal therapy: advantages
and disadvantages. J Clin Periodontol 1990; 17:479-493.