Absorica

CLINICAL PHARMACOLOGY

Mechanism of Action

Absorica™ is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day, inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with isotretinoin and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation. The exact mechanism of action of Absorica™ is unknown.

Pharmacodynamics

The pharmacodynamics of Absorica™ are unknown.

Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. Absorica™ is bioequivalent to Accutane® (isotretinoin) capsule when both drugs are taken with a high-fat meal. Absorica™ is more bioavailable than Accutane® (isotretinoin) capsules when both drugs are taken fasted; the AUC0-t of Absorica™ is approximately 83% greater than that of Accutane®. Absorica™ is therefore not interchangeable with generic products of Accutane®.

A single dose two-way crossover pharmacokinetic trial was conducted in 14 healthy adult male subjects comparing Absorica™ 40 mg (1 x 40 mg capsules), dosed under fasted and fed conditions. Under fed conditions after a high-fat meal, it was observed that the mean AUC0-t and Cmax were approximately 50% and 26% higher, than that observed under fasting conditions (Table 2). The observed elimination half-life (T1/2) was slightly lower in the fed state versus fasted. The time to peak concentration (Tmax) increased with food and this may be related to a longer absorption phase.

Table 2: Pharmacokinetic parameters of Absorica™ mean (%CV) following administration of 40 mg strength, N=14

Absorica™
(1 x 40 mg capsules)
AUC0-t (ng x hr/mL) Cmax (ng/mL) Tmax (hr) T½ (hr)
Fed 6095 (26 %) 395 (39 %) 6.4 (47 %) 22 (25 %)
Fasted 4055 (20 %) 314 (26 %) 2.9 (34 %) 24 (28 %)

Published clinical literature has shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Distribution

Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism

Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.

After a single 40 mg oral dose of Absorica™ to 57 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

Elimination

Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%).

After a single 40 mg (2 x 20 mg) oral dose of Absorica™ to 57 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (T1/2) of isotretinoin and 4-oxo-isotretinoin under fed states were 18 hours and 38 hours, respectively.

Special Patient Populations

The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years) who received isotretinoin for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo tretinoin were also observed. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.

Animal Toxicology

In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

Clinical Studies

A double-blind, randomized, parallel group trial (Study 1) was conducted in patients with severe recalcitrant nodular acne to evaluate the efficacy and safety of Absorica™ compared to a generic product of Accutane® under fed conditions. Enrolled patients had a weight of 40 to 110 kg with at least 10 nodular lesions on the face and/or trunk. A total of 925 patients were randomized 1:1 to receive Absorica™ or a generic product of Accutane® (isotretinoin). Study patients ranged from 12 to 54 years of age, were approximately 60% male, 40% female, and were 87% White, 4% Black, 6% Asian, and 3% Other. Patients were treated an initial dose of 0.5 mg/kg/day in two divided doses for the first 4 weeks followed by 1 mg/kg/day in two divided doses for the following 16 weeks.

Change from Baseline to Week 20 in total nodular lesion count and proportion of patients with at least a 90% reduction in total nodular lesion count from Baseline to Week 20 are presented in Table 3. Total nodular lesion counts by visit are presented in Figure 1.

Table 3: Efficacy Results at Week 20 (Study 1)

  Absorica™
N=464
Isotretinoin*
N=461
Nodular Lesions
Mean Baseline Count 18.4 17.7
Mean Reduction -15.68 -15.62
Patients Achieving 90% Reduction 324 (70%) 344 (75%)
*A generic product of Accutane®

Figure 1 : Total Nodular (Facial and Truncal) Lesion Count by Visit in Study 1

Total Nodular (Facial and Truncal) Lesion Count - Illustration

Last reviewed on RxList: 6/6/2012
This monograph has been modified to include the generic and brand name in many instances.

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