Tazarotene (AGN 190168) is a new acetylenic retinoid which is effective for the topical treatment of patients with stable plaque psoriasis and mild to moderate acne vulgaris. Topical gel application provides direct delivery of tazarotene into the skin. At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis. Tazarotene is rapidly hydrolysed by esterases to its active metabolite, tazarotenic acid. Tazarotenic acid does not accumulate in adipose tissue, but undergoes further metabolism to its sulfoxide and to other polar metabolites and is rapidly eliminated via both urinary and faecal pathways with a terminal half-life of about 18 hours. Percutaneous absorption is similar between healthy individuals and patients with facial acne, leading to plasma concentrations below 1 microg/L. The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin. In patients with psoriasis under typical conditions of use, systemic bioavailability increased during the initial 2 weeks of treatment from 1% (single dose) to 5% or less (steady state). The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene. Steady-state concentrations of tazarotenic acid are achieved within 2 weeks of topical treatment in both healthy and psoriatic skin types. The large variability in plasma concentrations observed in patients with psoriasis is probably because of the large differences in lesional skin condition, the amount of drug applied and the surface area of application. There was no significant drug accumulation in the body with long term treatment of patients with psoriasis. Topical administration of tazarotene requires dosages much smaller than those usually required for oral retinoids, such as isotretinoin, acitretin and etretinate, and it delivers the drug directly into the target skin tissues. The low systemic absorption and rapid systemic elimination of tazarotene and tazarotenic acid results in limited systemic exposure. Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis.

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LGD-4665, a new generation small molecule oral thrombopoietin (TPO) mimetic, increases platelet counts in a dose proportional manner, and is associated with a high safety margin in healthy subjects after single and multiple daily, or weekly doses. Phase I characterization of LGD-4665 has demonstrated comparable platelet profiles following daily or weekly dosing, minimal effects of food on absorption, and no drug interaction with CYP 3A4 substrates. These attributes have led to the design of Phase II studies with flexible dose regimens for immune thrombocytopenic purpura (ITP), Hepatitis C and myelodysplastic syndrome (MDS). Weekly dosing regimen for a supportive therapy such as LGD-4665 in thrombocytopenic patients is desirable for patient convenience, compliance and overlap with concomitant therapies including peg-interferon in hepatitis C and certain chemotherapeutic agents in cancer patients. LGD-4665’s long elimination half-life of 90 hrs and sustained increases in platelet counts in the Phase I single or multiple daily dose trials suggested a weekly dosing regimen should be evaluated. A Phase-I study was designed to assess once weekly, oral dosing for safety, pharmacodynamics (PD; platelet response) and pharmacokinetics (PK). This was conducted in 23 healthy volunteers randomized to receive 30 mg, 45 mg or 60 mg capsules of LGD-4665 for up to 6 weeks. All three LGD-4665 doses demonstrated a sustained increase in platelet counts that was dose proportional following weekly administration. The mean maximum percentage increase in platelet counts were 36%, 71% and 81% at 30 mg, 45 mg and 60 mg, respectively. The platelet increase of 71% after a weekly dose of 45 mg was comparable to a 79% increase following daily dosing of 7.5 mg with a loading dose. Platelets responded more quickly following the higher weekly doses (45 mg and 60 mg), with counts approaching 50% above baseline values within two weeks, and reaching a plateau at 4 to 5 weeks. Platelet counts gradually returned to baseline within three weeks post-treatment. Food effects were tested in 16 normal subjects and showed only a minimal decrease (23%) in absorption in a cross-over study, and should have no significant clinical impact. In another Phase I study in 25 healthy subjects, there was no pharmacokinetic drug-drug interaction between LGD-4665 and simvastatin, a sensitive substrate for CYP 3A4. In Phase I studies, LGD-4665 was safe and well tolerated. Only a few adverse events (AEs), with majority being mild in severity, were reported with single doses up to 120 mg, multiple daily doses (14 days) of up to 10 mg/day without a loading dose, up to 7.5 mg/ day with a 6-fold loading dose and following weekly administration of up to 60 mg for 6 weeks. The most common AEs in LGD-4665-treated subjects were: upper respiratory tract infection (7%), nausea (6%), headache (5%), rash (4%), pharyngolaryngeal pain (4%), and constipation (3%). Overall, the frequencies of these events did not appear to be dose-related. Furthermore, there were no clinically significant changes in vital sign measurements, no notable laboratory abnormalities and no early withdrawals related to LGD-4665. In summary, results from several Phase I trials have permitted flexible dose regimens of LGD-4665 due to its long elimination half-life, a faster 3–5 day onset of platelet increases following a loading dose, favorable sustained platelet increases, and a high safety margin across a wide dose range. Interim platelet and safety data from an ongoing Phase-II study of 24 patients with ITP who are treated with 7.5 mg LGD-4665 daily, will be available for comparison with Phase I results. Additional Phase II studies involving weekly dosing are planned in subjects with hepatitis C and MDS.

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