Accutane (Isotretinoin) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1.0 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin 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 Accutane, 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 isotretinoin 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 × 40 mg capsules) of Accutane under fasted and fed conditions. Both peak plasma concentration (C_max) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with Accutane 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 isotretinoin without altering its disposition. The time to peak concentration (T_max) was also increased with food and may be related to a longer absorption phase. Therefore, Accutane capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Table 2 Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74

Accutane 2 × 40 mg Capsules	AUC0-∞ (ng∙hr/mL)	Cmax (ng/mL)	Tmax (hr)	t1/2 (hr)
FedEating a standardized high-fat meal	10,004 (22%)	862 (22%)	5.3 (77%)	21 (39%)
Fasted	3,703 (46%)	301 (63%)	3.2 (56%)	21 (30%)

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

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 80 mg oral dose of Accutane to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t_1/2) of isotretinoin and 4- oxo -isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.

Special Patient Populations

Pediatric Patients

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 Accutane 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. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.

Table 3 Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N=38The 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.

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)	5082.00 (2184.23)
AUC(0-24) (ng∙hr/mL)	6003.81 (2885.67)	–
Tmax (hr)Median (range)	6.00 (1.00-24.60)	4.00 (0-12.00)
Cssmin (ng/mL)	–	352.32 (184.44)
T1/2 (hr)	–	15.69 (5.12)
CL/F (L/hr)	–	17.96 (6.27)

In pediatric patients (12 to 15 years), the mean± SD elimination half-lives (t_1/2) of isotretinoin and 4- oxo -isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.