Percutaneous absorption of pimecrolimus is not increased in patients with moderate to severe atopic dermatitis when pimecrolimus cream 1% is applied under occlusion.

AIM: To evaluate the systemic exposure of pimecrolimus cream 1% applied under occlusion in atopic dermatitis (AD) patients. METHODS: A noncomparative, open-label study conducted in 3 groups of moderate to severe AD patients: A (adults, n = 9), B (adolescents, n = 4) and C (children, n = 6). Pimecrolimus cream 1% was applied twice daily for 8.5 days with overnight occlusion in patients with investigator's global assessment scores of ≥3 and AD involving at least 30% of their body surface area. Pimecrolimus blood concentrations were analyzed. RESULTS: The highest pimecrolimus blood concentrations observed in adults, adolescents and children were 1.84, 0.55 and 1.29 ng/ml, respectively. Pimecrolimus blood concentrations and affected body surface area showed no apparent correlation. CONCLUSION: No measurable differences were found in pimecrolimus blood concentrations, efficacy and safety profile when pimecrolimus cream 1% was applied under occlusion versus application without occlusion. These findings reflect the high lipophilic properties of pimecrolimus.

Pharmacokinetics of terbinafine in young children treated for tinea capitis.

BACKGROUND: Dermatophytes are the most common cause of human fungal infections. Response rates to existing therapy are lower than optimal, but newer agents like terbinafine hold promise for improved management of such infections. This investigation was designed to evaluate the single dose and steady state pharmacokinetics of terbinafine in young children with tinea capitis. METHODS: Twenty-two otherwise healthy children (4-8 years) with tinea capitis were eligible for enrollment. Children were treated with terbinafine once daily according to body weight (<25 kg, 125 mg; 25-35 kg, 187.5 mg), and pharmacokinetic sampling was conducted after the first dose, at the midpoint of treatment and at steady state. Plasma terbinafine concentrations were quantitated, and the pharmacokinetic indices compared with adult data. RESULTS: Absolute estimates of Cmax and area under the concentration curve (AUC)0-24 were comparable between children and adults for the administered dose; however, children demonstrated significantly lower estimates of exposure when dose was corrected for weight (Cmax SS 200 +/- 104 versus 454 +/- 185 ng/mL per mg/kg dose, P < 0.01; AUCSS: 1110 +/- 640 versus 2756 +/- 1775 ng*h/mL per mg/kg dose, P < 0.01). When examined along a continuum, age accounted for approximately 50% of the variability observed in dose-normalized Cmax and AUC (P < 0.01). A slight but significant reduction in apparent oral clearance was observed with increasing age (0.02 L/h/kg per yr) that likely accounts for the lesser degree of accumulation observed in children at steady state (accumulation ratio, 1.5 +/- 0.8 versus 2.3 +/- 0.6, P < 0.01). Adverse events consisted principally of headache (n = 3) and gastrointestinal complaints (altered eating habits n = 3, loss of appetite n = 3, stomachache n = 4, diarrhea n = 2). A reduction in neutrophil count was observed in 5 children and thought to be related to study drug in 2. CONCLUSIONS: Children require significantly larger weight-normalized doses to approximate the exposure estimates observed in adults. The dosing scheme used in this investigation results in absolute exposure estimates at steady state and a safety profile that are not appreciably different from adults.

Development of tridentate iron chelators: from desferrithiocin to ICL670.

Successful treatment of beta-thalassemia requires two key elements: blood transfusion and iron chelation. Regular blood transfusions considerably expand the lifespan of patients, however, without the removal of the consequential accumulation of body iron, few patients live beyond their second decade. In 1963, the introduction of desferrioxamine (DFO), a hexadentate chelator, marked a breakthrough in the treatment of beta-thalassemia. DFO significantly reduces body iron burden and iron-related morbidity and mortality. DFO is still the only drug for general use in the treatment of transfusion dependent iron overload. However, its very short plasma half-life and poor oral activity necessitate special modes of application (subcutaneous or intravenous infusion) which are inconvenient, can cause local reactions and are difficult to be accepted by many patients. Over the past four decades, many different laboratories have invested major efforts in the identification of orally active iron chelators from several hundreds of molecules of synthetic, microbial or plant origin. The discovery of ferrithiocin in 1980, followed by the synthesis of the tridentate chelator desferrithiocin and proof of its oral activity raised a lot of hope. However, the compound proved to be toxic in animals. Over a period of about fifteen years many desferrithiocin derivatives and molecules with broader alterations led to the discovery of numerous new compounds some of which were much better tolerated and were more efficacious than desferrithiocin in animals, however, none was safe enough to proceed to the clinical use. The discovery of a new chemical class of iron chelators: The bis-hydroxyphenyltriazoles re-energized the search for a safe tridentate chelator. The basic structure of this completely new chemical class of iron chelators was discovered by a combination of rational design, intuition and experience. More than forty derivatives of the triazole series were synthesized at Novartis. These compounds were evaluated, together with more than 700 chelators from various chemical classes. Using vigorous selection criteria with a focus on tolerability, the tridentate chelator 4-[(3,5-Bis-(2-hydroxyphenyl)-1,2,4)triazol-1-yl]-benzoic acid (ICL670) emerged as an entity which best combined high oral potency and tolerability in animals. ICL670 is presently being evaluated in the clinic.