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Sotret

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Sotret

Sotret

CLINICAL PHARMACOLOGY

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is unknown.

Nodular Acne

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 Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) , and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1

Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin were more than doubled following a standardized high-fat meal when compared with isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Sotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin between patients with nodular acne and healthy subjects with normal skin.

Table 2: Pharmacokinetic Parameters of Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin Mean (%CV), N=74

Isotretinoin Capsules 2 x 40 mg Capsules AUC0-∞
(ng•hr/mL)
Cmax
(ng/mL)
Tmax
(hr)
t1/2(hr)
Fed* 10,004 (22%) 862 (22%) 5.3 (77%) 21 (39%)
Fasted 3,703 (46%) 301 (63%) 3.2 (56%) 21 (30%)
*Eating a standardized high-fat meal
Distribution

Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism

Following oral administration of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, at least three metabolites have been identified in human plasma: 4-oxo-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, 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. Isotret (isotret (isotretinoin capsules) inoin capsules) inoin is also irreversibly oxidized to 4-oxo-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin, which forms its geometric isomer 4-oxo-tretinoin.

After a single 80 mg oral dose of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules to 74 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 isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin to adult cystic acne patients ( ≥ 18 years), the exposure of patients to 4-ojco-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin.

In vitro studies indicate that the primary P450 isoforms involved in isotret (isotretinoin capsules) inoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin 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-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin to 74 healthy adult subjects under fed conditions, the mean + SD elimination half-lives (t1/2) of isotretinoin and 4-ojco-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin were 21.0 + 8.2 hours and 24.0 + 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin ranged from 0.90 to 5.43 in patients with cystic acne.

Special Patient Populations

Pediatric Patients

The pharmacokinetics of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients ( ≥ 18 years) who received isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin capsules for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin between pediatric and adult patients.

Table 3. Pharmacokinetic Parameters of Isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N = 38*

Parameter Isotretinoin (Single Dose) Isotretinoin (Steady-State)
Cmax (ng/mL) 573.25 (278.79) 731.98(361.86)
AUC(0-12) (ng•hr/mL) 3033.37(1394.17) 5082 (2184.23)
AUC(0-24) (ng•hr/mL) 6003.81 (2885.67) -
Tmax (hr) 6.00 (1.00 to 24.60) 4.00 (0 to 12)
Cssmin (ng/mL) - 352.32 (184.44)
T1/2 (hr) - 15.69 (5.12)
CL/F (L/hr) - 17.96 (6.27)
* The single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in Table 2.
Median (range)

In pediatric patients (12 to 15 years), the mean + SD elimination half-lives (ti/i) of isotretinoin and 4- oxo-isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin were 15.7 + 5.1 hours and 23.1 + 5.7 hours, respectively. The accumulation ratios of isotret (isotret (isotret (isotretinoin capsules) inoin capsules) inoin capsules) inoin ranged from 0.46 to 3.65 for pediatric patients.

REFERENCES

1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979.

Last reviewed on RxList: 9/27/2010
This monograph has been modified to include the generic and brand name in many instances.

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