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Arestin (Minocycline Hydrochloride) - Description and Clinical Pharmacology

 
 



ARESTIN®
(minocycline hydrochloride) Microspheres, 1 mg

DESCRIPTION

ARESTIN® (minocycline hydrochloride) Microspheres is a subgingival sustained-release product containing the antibiotic minocycline hydrochloride incorporated into a bioresorbable polymer, Poly (glycolide-co-dl-lactide) or PGLA, for professional subgingival administration into periodontal pockets. Each unit-dose cartridge delivers minocycline hydrochloride equivalent to 1 mg of minocycline free base.

The molecular formula of minocycline hydrochloride is C23H27N3O7. HCl, and the molecular weight is 493.94. The structural formula of minocycline hydrochloride is:

CLINICAL PHARMACOLOGY

Microbiology

Minocycline, a member of the tetracycline class of antibiotics, has a broad spectrum of activity.1 It is bacteriostatic and exerts its antimicrobial activity by inhibiting protein synthesis.1 In vitro susceptibility testing has shown that the organisms Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, Eikenella corrodens, and Actinobacillus actinomycetemcomitans, which are associated with periodontal disease, are susceptible to minocycline at concentrations of ≤8 μg/mL2; qualitative and quantitative changes in plaque microorganisms have not been demonstrated in patients with periodontitis, using this product.

The emergence of minocycline-resistant bacteria in single-site plaque samples was studied in subjects before and after treatment with ARESTIN at 2 centers. There was a slight increase in the numbers of minocycline-resistant bacteria at the end of the 9-month study period, however, the number of subjects studied was small and the clinical significance of these findings is unknown.

The emergence of minocycline-resistant bacteria and changes in the presence of Candida albicans and Staphylococcus aureus in the gastrointestinal tract were studied in subjects treated with ARESTIN in one phase 3 study. No changes in the presence of minocycline-resistant bacteria or C albicans or S aureus were seen at the end of the 56-day study period.

Pharmacokinetics

In a pharmacokinetic study, 18 patients (10 men and 8 women) with moderate to advanced chronic periodontitis were treated with a mean dose of 46.2 mg (25 to 112 unit doses) of ARESTIN. After fasting for at least 10 hours, patients received subgingival application of ARESTIN (1 mg per treatment site) following scaling and root planing at a minimum of 30 sites on at least 8 teeth. Investigational drug was administered to all eligible sites ≥5 mm in probing depth. Mean dose normalized saliva AUC and Cmax were found to be approximately 125 and 1000 times higher than those of serum parameters, respectively.

Clinical Studies

In 2 well-controlled, multicenter, investigator-blind, vehicle-controlled, parallel-design studies (3 arms), 748 patients (study OPI-103A = 368, study OPI-103B = 380) with generalized moderate to advanced adult periodontitis characterized by a mean probing depth of 5.90 and 5.81 mm, respectively, were enrolled. Subjects received 1 of 3 treatments: (1) scaling and root planing, (2) scaling and root planing + vehicle (bioresorbable polymer, PGLA), and (3) scaling and root planing + ARESTIN. To qualify for the study, patients were required to have 4 teeth with periodontal pockets of 6 to 9 mm that bled on probing. However, treatment was administered to all sites with mean probing depths of 5 mm or greater. Patients studied were in good general health. Patients with poor glycemic control or active infectious diseases were excluded from the studies. Retreatment occurred at 3 and 6 months after initial treatment, and any new site with pocket depth ≥5 mm also received treatment. Patients treated with ARESTIN were found to have statistically significantly reduced probing pocket depth compared with those treated with SRP alone or SRP + vehicle at 9 months after initial treatment, as shown in Table 1.

Table 1: Probing Pocket Depth at Baseline and Change in Pocket Depth at 9 Months From 2 Multicenter US Clinical Trials
Study OPI-103AStudy OPI-103B
TimeN=368N=380

SE = standard error; SRP = scaling and root planing; PD = pocket depth.

Significantly different from SRP *(P ≤0.05); **(P ≤0.001).

Significantly different from SRP + vehicle †(P ≤0.05); ††(P ≤0.001).

SRPSRP +SRP +SRPSRP +SRP +
AloneVehicleARESTINAloneVehicleARESTIN
n=124n=123n=121n=126n=126n=128
PD (mm)
at Baseline,5.88±5.91±5.88±5.79±5.82±5.81±
Mean ± SE0.040.040.040.030.040.04
PD (mm) Change
From Baseline-1.04-0.90-1.20*††-1.32-1.30-1.63**††
at 9 Months,±0.07±0.54±0.07±0.07±0.07±0.07
Mean ± SE

In these 2 studies, an average of 29.5 (5-114), 31.7 (4-137), and 31 (5-108) sites were treated at baseline in the SRP alone, SRP + vehicle, and SRP + ARESTIN groups, respectively. When these studies are combined, the mean pocket depth change at 9 months was -1.18 mm, -1.10 mm, and -1.42 mm for SRP alone, SRP + vehicle, and SRP + ARESTIN, respectively.

Table 2: Numbers (percentage) of Pockets Showing a Change of Pocket Depth ≥2 mm at 9 Months From 2 Multicenter US Clinical Trials
Study OPI-103AStudy OPI-103B
SRPSRP +SRP +SRPSRP +SRP +
AloneVehicleARESTINAloneVehicleARESTIN
Pockets
≥2 mm
(% of total)
1046
(31.1%)
927
(25.7%)
1326
(36.5%)
1692
(42.2%)
1710
(40.0%)
2082
(51.0%)
Pockets
≥3 mm
(% of total)
417
(12.4%)
315
(8.7%)
548
(15.1%)
553
(13.8%)
524
(12.3%)
704
(17.3%)

SRP + ARESTIN resulted in a greater percentage of pockets showing a change of PD ≥2 mm and ≥3 mm compared to SRP alone at 9 months, as shown in Table 2.

Table 3: Mean Pocket Depth Changes (SE) in Subpopulations, Studies 103A and 103B Combined

SRP = scaling and root planing; YOA = years of age; CV = cardiovascular.

*SRP vs SRP + ARESTIN P ≤0.05; **SRP vs SRP + ARESTIN P ≤0.001.

SRPSRP +SRP +
AloneVehicleARESTIN
Smokersn = 91
-0.96±
0.09 mm
n = 90
-0.98±
0.07 mm
n = 90
-1.24±
0.09 mm**
Nonsmokersn = 159
-1.31±
0.06 mm
n = 159
-1.17±
0.07 mm
n = 159
-1.53±
0.06 mm**
Patients >50 YOAn = 21
-1.07±
0.09 mm
n = 81
-0.92±
0.08 mm
n = 107
-1.42±
0.08 mm**
Patients ≤50 YOAn = 167
-1.24±
0.06 mm
n = 168
-1.19±
0.06 mm
n = 142
-1.43±
0.07 mm*
Patients With CV Diseasen = 36
-0.99±
0.13 mm
n = 29
-1.06±
0.14 mm
n = 36
-1.56±
0.14 mm**
Patients W/O CV Diseasen = 214
-1.22±
0.06 mm
n = 220
-1.11±
0.05 mm
n = 213
-1.40±
0.06 mm**

In both studies, the following patient subgroups were prospectively analyzed: smokers, patients over and under 50 years of age, and patients with a previous history of cardiovascular disease. The results of the combined studies are presented in Table 3. In smokers, the mean reduction in pocket depth at 9 months was less in all treatment groups than in nonsmokers, but the reduction in mean pocket depth at 9 months with SRP + ARESTIN® was significantly greater than with SRP + vehicle or SRP alone.

Table 4: Mean Pocket Depth Change in Patients With Mean Baseline PD ≥5 mm, ≥6 mm, and ≥7 mm at 9 Months From 2 Multicenter US Clinical Trials

*Statistically significant comparison between SRP + ARESTIN and SRP alone.

Study OPI-103AStudy OPI-103B
Mean Baseline
Pocket Depth
SRP
Alone
SRP +
Vehicle
SRP +
ARESTIN
SRP
Alone
SRP +
Vehicle
SRP +
ARESTIN
≥5 mm (n)-1.04 mm
(124)
-0.90 mm
(123)
-1.20 mm*
(121)
-1.32 mm
(126)
-1.30 mm
(126)
-1.63 mm*
(128)
≥6 mm (n)-0.91 mm
(34)
-0.77 mm
(46)
-1.40 mm*
(45)
-1.33 mm
(37)
-1.46 mm
(40)
-1.69 mm*
(25)
≥7 mm (n)-1.10 mm
(4)
-0.46 mm
(5)
-1.91 mm
(3)
-1.72 mm
(3)
-1.11 mm
(3)
-2.84 mm
(2)

The combined data from these 2 studies also show that for pockets 5 mm to 7 mm at baseline, greater reductions in pocket depth occurred in pockets that were deeper at baseline.

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