Isotretinoin is a retinoid, which when administeredin 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.
Clinical improvement in nodular acne patients occursin association with a reduction in sebum secretion. The decrease insebum secretion is temporary and is related to the dose and durationof treatment with Accutane, and reflects a reduction in sebaceousgland size and an inhibition of sebaceous gland differentiation.[ 1 ]
Due to its high lipophilicity, oral absorption ofisotretinoin is enhanced when given with a high-fat meal. In a crossoverstudy, 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 (Cmax) and the total exposure(AUC) of isotretinoin were more than doubled following a standardizedhigh-fat meal when compared with Accutane given under fasted conditions(see Table 2). The observed elimination half-life was unchanged. Thislack of change in half-life suggests that food increases the bioavailabilityof isotretinoin without altering its disposition. The time to peakconcentration (Tmax) was also increased with food and maybe related to a longer absorption phase. Therefore, Accutane capsulesshould always be taken with food (see DOSAGE AND ADMINISTRATION). Clinicalstudies have shown that there is no difference in the pharmacokineticsof isotretinoin between patients with nodular acne and healthy subjectswith normal skin.
Table 2 Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74
2 — 40 mg Capsules
|FedEating a standardized high-fatmeal ||10,004 (22%) ||862 (22%) ||5.3 (77%) ||21 (39%) |
|Fasted ||3,703 (46%) ||301 (63%) ||3.2 (56%) ||21 (30%) |
Isotretinoin is more than 99.9% bound to plasma proteins,primarily albumin.
Following oral administration of isotretinoin, atleast 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 isomersand show reversible interconversion. The administration of one isomerwill give rise to the other. Isotretinoin is also irreversibly oxidizedto 4- oxo -isotretinoin, whichforms its geometric isomer 4- oxo -tretinoin.
After a single 80 mg oral doseof Accutane to 74 healthy adult subjects, concurrent administrationof food increased the extent of formation of all metabolites in plasmawhen compared to the extent of formation under fasted conditions.
All of these metabolites possess retinoid activity thatis in some in vitro models more than that of the parent isotretinoin.However, the clinical significance of these models is unknown. Aftermultiple oral dose administration of isotretinoin to adult cysticacne patients (≥18 years), the exposure of patients to 4- oxo -isotretinoin at steady-state underfasted and fed conditions was approximately 3.4 times higher thanthat of isotretinoin.
In vitro studies indicatethat the primary P450 isoforms involved in isotretinoin metabolismare 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are furthermetabolized into conjugates, which are then excreted in urine andfeces.
Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activityin blood declined with a half-life of 90 hours. The metabolites ofisotretinoin and any conjugates are ultimately excreted in the fecesand urine in relatively equal amounts (total of 65% to 83%). Aftera single 80 mg oral dose of Accutane to 74 healthy adult subjectsunder fed conditions, the mean ± SD elimination half-lives (t1/2) 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 accumulationratios of isotretinoin ranged from 0.90 to 5.43 in patients with cysticacne.
Special Patient Populations
The pharmacokinetics of isotretinoin were evaluatedafter single and multiple doses in 38 pediatric patients (12 to 15years) and 19 adult patients (≥18 years) who received Accutanefor the treatment of severe recalcitrant nodular acne. In both agegroups, 4- oxo -isotretinoinwas the major metabolite; tretinoin and 4- oxo -tretinoin were also observed. The dose-normalized pharmacokineticparameters for isotretinoin following single and multiple doses aresummarized in Table3 for pediatric patients. There were no statisticallysignificant differences in the pharmacokinetics of isotretinoin betweenpediatric and adult patients.
Table 3 Pharmacokinetic Parameters of Isotretinoin FollowingSingle and Multiple Dose Administration in Pediatric Patients, 12to 15 Years of Age Mean (± SD), N=38The single andmultiple dose data in this table were obtained following a non-standardizedmeal that is not comparable to the high-fat meal that was used inthe study in Table2.
|Parameter ||Isotretinoin |
|Cmax (ng/mL) ||573.25 (278.79) ||731.98 (361.86) |
|AUC(0-12) (ngâˆ™hr/mL) ||3033.37 (1394.17) ||5082.00 (2184.23) |
|AUC(0-24) (ngâˆ™hr/mL) ||6003.81 (2885.67) ||â€“ |
|Tmax (hr)Median (range) ||6.00 (1.00-24.60) ||4.00 (0-12.00) |
|Cssmin (ng/mL) ||â€“ ||352.32 (184.44) |
|T1/2 (hr) ||â€“ ||15.69 (5.12) |
|CL/F (L/hr) ||â€“ ||17.96 (6.27) |
In pediatric patients (12 to 15 years), the mean± SD elimination half-lives (t1/2) of isotretinoinand 4- oxo -isotretinoin were15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. Theaccumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatricpatients.