Isotretinoin

Isotretinoin is used primarily as a treatment for severe acne, but it also helps reduce wrinkles and lighten the skin when applied topically or when taken orally.

Effects


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments

A

Wrinkle treatment

Strong

Ameliorates wrinkles by increasing the concentration of collagen and decreasing the concentration of elastic fibers.

A

Acne treatment

Strong

Impacts sebum production, comedogenesis and suppresses the growth of P. acnes, thereby improving acne.

A

Skin lightening

Moderate

Improves the appearance of pigmented spots and skin colour.

A

Warts treatment

Moderate

Effective in treating genital and flat warts.

A

Smoother skin

Moderate

Significantly improves skin texture.

C

Psoriasis treatment

Moderate

Limited efficacy when used as monotherapy, but highly effective when combined with phototherapy.

D

Less oiliness

Strong

0.5–1.0 mg/kg/day lowers sebum excretion by 90% within 6 weeks.

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Scientific Research


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Table of contents:

1. Sources

Isotretinoin, or 13-cis-retinoic acid, is a synthetic retinoid pharmaceutical.[1] It also appears to occur naturally as a metabolite of tretinoin, probably by in vivo isomerization.[2]

2. Bioavailability

2.1 Oral administration

Isotretinoin is rapidly absorbed following oral administration. It is highly bound to plasma protein, with the maximum blood concentration occurring between 1-4 hours after ingestion.[3][4] Its major blood metabolite is 4-oxo-isotretinoin, which attains maximum concentration at 6-16 hours after isotretinoin dosing.[3][5] Isotretinoin blood concentrations does not appear to increase with higher doses in the fasting state, so single oral doses in excess of 240mg should be used with caution.[6]

As a vitamin A derivative, isotretinoin is not soluble in water.[7] The complexation of isotretinoin with cyclodextrins however increases its aqueous solubility, aiding oral absorption.[7][8]

Food increases the bioavailability of isotretinoin. The relative bioavailability has been found to be approximately 1.5 to 2 times greater when isotretinoin was administered 1 hour before, concomitantly with, or 1 hour after a meal than when it was given during a complete fast.[9] In fact, current practice guidelines recommend administration of oral isotretinoin with high-fat meals, for optimal absorption.[10][11]

Lipid encapsulation technology has also been developed to enhance the absorption of oral isotretinoin in the absence of dietary fat. An open label, single dose randomized crossover study demonstrated pharmacokinetic bioequivalence of this new formulation (Isotretinoin-Lidose, Epuris) to standard isotretinoin formulations during fed states, with significantly greater absorption during fasting.[10][11]

The half-lives of elimination of isotretinoin and 4-oxo-isotretinoin range from 10-20 hours and 24-29 hours, respectively.[3][4][12]

Unabsorbed isotretinoin is excreted mainly in the feces, with 53% to 74% of a 100mg oral dose recovered as intact isotretinoin in one study.[12]

2.2 Topical administration

Less isotretinoin penetrates through to the dermis than for tretinoin. In one experiment, 33.5% of isotretinoin applied to human skin was recovered from the epidermis and another 1.8% from the dermis after 48 hours, compared to 27.8% and 11.4% respectively for tretinoin.[13]

The penetration of topical isotretinoin is vehicle-dependent, with propylene glycol and isopropyl alcohol yielding better results that mineral oil, diisopropyl adipate and PEG 400 in one study on monkey skin.[13] Formulations using isotretinoin loaded into solid lipid nanoparticles, nanocapsules and nanolipid carriers have also been shown to enhance isotretinoin skin penetration and enhance its skin targeting effect.[14][15][16][17][18][19]

One concern about isotretinoin is its poor photostability. Just 4 hours of exposure to incandescent light degrades 20% of 0.05% topical isotretinoin, and only 2 hours of exposure to fluorescent light degrades up to 40% of topical isotretinoin.[20] In sunlight, UVA radiation is the major contributor to photolysis of isotretinoin.[21] Inclusion of isotretinoin in cyclodextrin complexes, liposomes, microemulsions and solid lipid nanoparticles have been demonstrated to improve its photostability.[8][15][22][23]

Topically applied isotretinoin does not reach the systemic circulation. In one study, 0.05% isotretinoin gel (Isotrex) was applied to 12 male patients on large swaths of skin on the face, back and chest for 30 days. Collected blood samples did not have measurable plasma concentrations of isotretinoin, tretinoin or 4-oxo-tretinoin even after multiple applications of the gel at doses approximately 12 times greater than normal daily use, indicating negligible systemic availability.[24] Likewise, another study where a cream containing 0.1% isotretinoin and chemical sunscreens was applied for 4 weeks, found no statistically or clinically significant increases in plasma retinoid levels post-treatment.[25]

3. Effects on the skin

3.1 Anti-wrinkle effect

Topical and possibly oral isotretinoin is able to improve the appearance of wrinkles and fine lines.

Results from clinical studies involving low-dose oral isotretinoin on wrinkling are mixed. A number of uncontrolled studies previously found that treatment with 10-20mg of isotretinoin thrice weekly for 2-3 months, alone or combined with different procedures of facial rejuvenation improved frontal wrinkling, glabellar lines, crow's feet, circumoral lines, neck lines and smoothed rhytids.[26][27] However, the first controlled trial discovered that oral isotretinoin produced slight improvements in fine wrinkles and skin smoothness, but without significant difference from the control group.[28]

Unlike for oral isotretinoin, there have been several controlled clinical trials evaluating the effects of topical isotretinoin. The results of these studies agree that treatment with 0.05% or 0.1% isotretinoin cream led to superior improvements over vehicle for wrinkles based on patients' and physicians' assessment, clinical panel assessment and computerized image analysis.[29][30][31]

In a separate 6-month, multicentre, randomized, double-blind, parallel-group, vehicle-controlled study of 346 subjects, a cream formulation containing 0.05% isotretinoin and sunscreens was also found to improve the appearance of fine wrinkles associated with photoaged skin. The subjects in this study applied the test cream (Isotrexol) to the entire face and hands, including the wrists, once-daily in the morning after washing and drying. An emollient cleanser (Neutrogena liquid soap) and a sunscreen (L'Oreal Ombrelle) were also allowed to be applied after washing, but not shortly before or after application of Isotrexol. Profilometry measurements indicated that the treatment had a distinct effect on skin topography, reflecting a smoothing of the skin surface. Subjective clinical scoring of wrinkling and fine lines also found a statistically significant difference between groups in favour of the treatment with isotretinoin and sunscreens.[32]

The improvement in wrinkling has been hypothesized to be a consequence of increased accumulation of collagen and fibrillin in the dermis, as isotretinoin is isomerized to tretinoin.[32][33] Isotretinoin therapy has been shown to increase the concentration of collagen and decrease the concentration of elastic fibers.[27]

3.2 Lightening effect

There is modest evidence that oral isotretinoin improves skin colour and pigmentation. One study showed that patients who had undergone surgical procedures for facial rejuvenation and who had also been treated with 10-20mg of oral isotretinoin thrice weekly for 2 months, had lighter skin and a reduction in pigmented lesions and mottled hyperpigmentation than patients who had undergone the same surgical procedures without oral isotretinoin treatment.[26] Digital photographs with UV filters also indicated that patients who received 20mg of oral isotretinoin 3 times a week for 3 months had decreased pigmentation after treatment, in a separate study.[27] A third study also concluded that low-dose oral isotretinoin was as effective as 0.05% topical tretinoin in reducing lentigines.[34] All of these studies were not controlled, but their findings are supported by those of a controlled trial, which found a slight but significant improvement in solar melanosis.[28] Interestingly, a case report also noted that treatment with oral isotretinoin for acne vulgaris resolved minocycline-induced, blue-black pigmentation in a 23-year-old Hispanic man.[35]

Topical isotretinoin also has beneficial effects on skin colour and pigmentation. Clinical assessments have indicated that 0.05% and 0.1% isotretinoin cream improves the appearance of discrete pigmentation, hyperpigmented macules and sallowness (skin yellowing) in patients.[29][30][31]

3.3 Acne vulgaris treatment

Isotretinoin is commonly prescribed to treat severe forms of acne vulgaris, such as cystic and conglobate acne. Oral isotretinoin was first approved as treatment for severe acne by the US Food and Drug Administration (FDA) in 1982, and still remains the most clinically effective therapy for severe acne as well as many cases of more moderate disease that are unresponsive to other treatment modalities.[36]

Isotretinoin is able to achieve this remarkable efficacy because it impacts all of the major aetiological factors implicated in acne.[36] It influences cell cycle progression and apoptosis in human sebocytes, resulting in a significant reduction in sebum production.[37][38][39] It also reduces comedogenesis by decreasing follicular hyperkeratinization, though the exact mechanism for this is uncertain.[40] By dramatically reducing the sebum excretion rate and the size of the pilosebaceous duct, oral isotretinoin also alters the microenvironment within the duct, making it much less favorable to colonization with P. acnes[36] and resulting in a marked suppression of P. acnes population.[41][42][43]

Because of the numerous and serious side effects associated with oral dosing of isotretinoin, efforts have also been made to investigate the efficacy of topical isotretinoin in treating acne. One such investigation, a multicenter, double-blind, controlled trial, found 0.05% isotretinoin gel to be statistically more effective than vehicle in reducing inflammatory lesions and noninflammatory lesions as well as acne severity grade after 8 weeks.[44] In fact, topical isotretinoin is equally effective as topical tretinoin and topical adapalene in reducing acne lesions, though topical adapalene is significantly better tolerated.[20][45][46]

3.4 Psoriasis treatment

Psoriasis is a chronic inflammatory immune-mediated disease of the skin and joints[47] in which patients develop erythematous scaly papules and plaques.[48]

Though the efficacy of oral isotretinoin as a single agent therapy for psoriasis vulgaris and chronic plaque vulgaris is limited,[49][50] it is reported to have good clinical efficacy towards the pustular forms.[51][52]

Combining oral isotretinoin with phototherapy such as psoralen + UVA (PUVA) also seems to be highly effective in patients with psoriasis vulgaris.[53][54][55][56]

3.5 Treatment of warts

Warts are benign epithelial proliferations of the skin and mucosa caused by infection with the human papillomavirus (HPV).[57] Conventional management is frequently associated with unsatisfactory response rates and high recurrence rates.[58]

A multitude of clinical studies have shown that oral isotretinoin can be helpful for treating genital warts, also known as condylomata accuminata, though some patients may respond only partially or have no response.[58][59] Combining isotretinoin with systemic interferon did not result in statistically significant reductions in remission rates, but led to a significantly shorter duration of treatment.[60][61]

Case reports and clinical studies indicate that low-dose oral isotretinoin is also effective in the treatment of recalcitrant facial plane or flat warts.[57][62] In one double-blind, randomized, placebo-controlled trial, all patients treated with isotretinoin showed complete clearance of all flat warts, whereas none of the patients in the placebo group showed any improvement.[63]

4. Side Effects

4.1 Systemic toxicity

Oral dosing of isotretinoin is associated with many side effects. The main side effects are cheilitis (inflammation of the lips), eczema and tiredness, while rare side effects include headaches, joint pain, bone disorders, leukopenia and anemia.[64][65][66] Controversial adverse events include elevated risk for hypertrophic scars and keloids after dermabrasion,[67][68][69] depression and suicide,[70][71][72][73] and development of inflammatory bowel disease.[74][75]

For adult women, the most important problem when prescribing oral isotretinoin is teratogenicity,[76] which has an estimated risk of 28% regardless of dose and time of pregnancy.[77]

It is important to note, however, that even multiple and excessive topical application of isotretinoin does not lead to systemic availability of retinoids.[24] Clinical studies show that prolonged topical application of isotretinoin in concentrations found in cosmetic products does not significantly increase plasma retinoid levels, indicating that percutaneous absorption of isotretinoin is negligible in humans.[31] This indicates that topical isotretinoin does not result in the systemic toxicity observed with oral dosing of isotretinoin.

4.2 Skin irritation

Topical application of isotretinoin tends to irritate the skin, with irritation occurring more often on the face than on other sites.[30] Adverse events included erythema, scaling, peeling, burning sensation and pruritus, with the majority of the symptoms being mild or moderate.[31][32] Increased use of emollients minimized these adverse events.[30] The irritation was also usually transient, diminishing over time as treatment continued.[31][32] Up to 10% of patients however experienced severe irritation, according to safety and tolerability profiles documented in 2 studies.[30][31]

Scientific References


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