title: A randomized study of the safety, absorption and efficacy of pimecrolimus cream 1% applied twice or four times daily in patients with atopic dermatitis.
abstract: BACKGROUND
  Pimecrolimus cream 1% (Elidel), a non-steroid inhibitor of inflammatory cytokines, is effective in the treatment of atopic dermatitis, without corticosteroid-related side effects such as skin atrophy. It is indicated for twice-daily application. More frequent applications might be expected either to enhance efficacy or increase toxicity. This study compared the safety, efficacy and systemic absorption of pimecrolimus administered twice daily (recommended dose) and four times daily early in the treatment of patients with moderate to severe atopic dermatitis.
  
  
  METHODS
  Adolescent and adult patients with moderate to severe atopic dermatitis were randomly assigned to a twice daily (BID) treatment group (n = 24) or a four times daily (QID) group (n = 25). During days 1-7, patients in the QID group applied pimecrolimus four times daily, and patients in the BID group applied pimecrolimus twice daily plus vehicle equivalent twice daily. During days 8-21, all patients were required to use pimecrolimus twice daily and had the option to use up to two further daily treatments (pimecrolimus in the QID group and vehicle equivalent in the BID group). Blood sampling occurred 2, 4, and 6 hours after the first morning application on days 1 and 5 and then prior to the first morning application on days 8 and 15, and any time on day 22.
  
  
  RESULTS
  Only 3 (12%) QID patients and 4 (17%) BID patients reported adverse events (primarily mild, transient application-site burning) with no significant difference between treatment groups in the frequency, type, or severity of adverse events. The median daily number of applications in the QID group during days 8-21 when two additional doses were optional remained at four. Pimecrolimus blood levels from a subgroup of 22 patients showed no difference in systemic exposure between the two dosing regimens. All but three (one in the QID group, two in the BID group) patients had blood levels below the limit of quantification; the highest single blood level of pimecrolimus measured in any patient was 1.37 ng/ml (QID group). Both the QID and BID regimens improved the signs and symptoms of atopic dermatitis similarly as measured by improvements in pruritus severity score, Investigator's Global Assessment, Eczema Area and Severity Index, percentage of body surface area affected, and patient's self-assessment of disease control.
  
  
  CONCLUSIONS
  The data suggest that increasing pimecrolimus application from twice daily to four times daily to treat moderate to severe atopic dermatitis for up to 3 weeks does not alter the safety profile nor does it increase the efficacy of treatment. Systemic absorption of pimecrolimus applied BID and QID is minimal and is not different between dosing regimens. Patients and physicians familiar with the potential hazards of overuse of topical corticosteroids should be reassured that if pimecrolimus is applied at twice the recommended BID dose for short periods of time, there is no effect on safety, tolerability, or systemic absorption.
authors.affiliation: MedaPhase Inc., Newman, GA 30263, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Ling
authors.forename: Alice
authors.initials: A
authors.lastname: Gottlieb
authors.forename: David
authors.initials: D
authors.lastname: Pariser
authors.forename: Ivan
authors.initials: I
authors.lastname: Caro
authors.forename: Daniel
authors.initials: D
authors.lastname: Stewart
authors.forename: Graham
authors.initials: G
authors.lastname: Scott
authors.forename: Ken
authors.initials: K
authors.lastname: Abrams
mesh_terms: D000287:Administration, Topical; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D003876:Dermatitis, Atopic / Q000188:drug therapy*; D003879:Dermatologic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D009824:Ointments; D011446:Prospective Studies; D012449:Safety; D018709:Statistics, Nonparametric; D016559:Tacrolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014481:United States
chemical_list: D003879:Dermatologic Agents; D009824:Ointments; C117268:pimecrolimus; D016559:Tacrolimus