Pharmacokinetics, safety, and tolerability of GLPG0259, a mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5) inhibitor, given as single and multiple doses to healthy male subjects.

BACKGROUND AND OBJECTIVES: GLPG0259 is a small-molecule inhibitor of mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5), a kinase enzyme that plays a role in important inflammatory pathways. The main objectives of the phase I clinical studies in early development were to characterize the pharmacokinetics, tolerability, and safety of GLPG0259 in healthy subjects, including the development of a solid dosage form (free-base pellets and fumarate salt capsules) and the potential for interaction of GLPG0259 with methotrexate. SUBJECTS AND METHODS: Four phase I studies were initiated. Study 1 was a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses (1.5-150 mg) and multiple oral doses (20 and 50 mg once daily) of GLPG0259 in healthy male subjects (n = 34). Study 2 was a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of oral multiple ascending doses of GLPG0259 (25-75 mg once daily) given for 14 days to healthy male subjects, and to get preliminary information on the potential pharmacokinetic interaction between GLPG0259 and methotrexate (n = 24). Studies 3 and 4 were open-label, randomized, crossover studies to compare the oral bioavailability of two solid dosage forms of GLPG0259 (a capsule) relative to an oral solution after a 100 mg or 50 mg single dose and to evaluate the effect of food on these formulations (n = 12 for each study). MAIN OUTCOME MEASURES: The non-compartmental pharmacokinetic parameters for plasma concentrations of GLPG0259 were determined, and a population pharmacokinetic model of GLPG0259 was developed to support the planning of the number and timing of the sparse samples to be taken per patient in the phase II study. Safety and tolerability data are also summarized. RESULTS: The absorption of GLPG0259 was slow, with a decrease in the absorption rate with increasing dose, and there was decreased elimination, with an apparent terminal elimination half-life of 26.0 hours. On the basis of statistical analysis of variance, the exposure to GLPG0259 increased in proportion to the dose over a 30-150 mg single-dose range and a 25-75 mg repeated-dose range. Between- and within-subject variability in GLPG0259 pharmacokinetics was low/moderate (coefficient of variation [CV] 16-30%). After once-daily repeated dosing, steady-state plasma concentrations were reached at between 5 and 8 dosing days, which is consistent with the long apparent elimination half-life of GLPG0259. Food increased the bioavailability of GLPG0259 given in a solid dosage form. Co-administration of GLPG0259 with a single dose of methotrexate 7.5 mg did not result in any change in the pharmacokinetic profiles of either GLPG0259 or methotrexate. CONCLUSION: In summary, the investigation of safety/tolerability and pharmacokinetics in the early development phase showed that single and repeated doses of GLPG0259 were safe and well tolerated. The most common adverse event reported was mild gastrointestinal discomfort. The pharmacokinetics characterized in healthy male subjects showed no major obstacles and supports a once-daily oral regimen in patients.

Expression of retinoid-regulated genes in lamellar ichthyosis vs. healthy control epidermis: changes after oral treatment with liarozole.

Lamellar ichthyosis is a keratinization disorder caused by TGM1, Ichthyin and several other gene mutations. A new treatment option is liarozole, which blocks the cytochrome P450 (CYP26)-mediated catabolism of endogenous all-trans retinoic acid. This study focuses on the expression of retinoid-related genes in ichthyotic epidermis before and after treatment with oral liarozole. We first compared the mRNA expression of cellular retinoic acid binding protein II (CRABPII), keratin (KRT) 2 and 4, CYP26A1 and B1, and two markers of inflammation (interleukin-1alpha and tumours necrosis factor (TNF)-alpha) in shave biopsies from 11 genetically defined, untreated patients and 12 age- and sex-matched healthy controls, finding no overt differences between the groups, besides elevated CRABPII expression. We then studied the biomarkers before and after 4 weeks of treatment with liarozole (75 or 150 mg/day), which produced a better therapeutic response in patients with Ichthyin (n=3) than in those with TGM1 (n=6) mutations. A significant decrease in the mRNA expression of KRT2 and TNF-alpha, and trends toward increased expression of KRT4 and CYP26A1 were observed in liarozole-treated patients, consistent with an increased retinoid stimulation of epidermis. However, there were no dose-related responses and the results of the immunostaining did not always parallel the mRNA findings. The results suggest that liarozole exerts a therapeutic effect in lamellar ichthyosis by mildly affecting the expression of retinoid- regulated genes in epidermis.

Ketoconazole gel 2% in the treatment of moderate to severe seborrheic dermatitis.

Seborrheic dermatitis traditionally has been treated with topical steroids. In current practice, however, antifungal agents such as ketoconazole often are used because Malassezia yeasts are thought to play a role in the disease pathogenesis. Ketoconazole gel 2% has been developed for the once-daily treatment of seborrheic dermatitis. This gel is almost invisible after application, unlike ketoconazole cream, and may offer advantages in patient acceptance and adherence to treatment. Three randomized, double-blinded, vehicle-controlled, multicenter, parallel-group phase 3 studies evaluated the efficacy and tolerability of ketoconazole gel 2% compared with a vehicle gel in more than 900 subjects with moderate to severe seborrheic dermatitis who applied treatment for 14 days and were followed for an additional 14 days. Two of these studies also compared a combination gel containing ketoconazole 2% and desonide 0.05%, each active gel individually, and a vehicle control. Subjects were considered effectively treated if the erythema and scaling as well as investigator global assessment (IGA) scores decreased to 0 (or 1 if the baseline score was > or =3) by day 28. Pooled data from these studies showed that the proportion of effectively treated subjects was significantly greater in the ketoconazole gel 2% treatment group compared with the vehicle group (P < .001). The comparison of the combination gel to its individual components revealed that the efficacy of ketoconazole alone was comparable to the combination gel as well as desonide gel alone for up to 2 weeks after the end of treatment. These data suggest that once-daily ketoconazole gel 2% is an effective treatment for seborrheic dermatitis and a viable alternative to the ketoconazole cream 2% formulation.