title: Safety and pharmacokinetics of efinaconazole 10% solution in healthy volunteers and patients with severe onychomycosis.
abstract: OBJECTIVE
  To characterize the systemic exposure and pharmacokinetics of efinaconazole 10% solution and assess the potential for drug-drug interaction (DDI) in human volunteers and onychomycosis patients following topical administration.
  
  
  METHODS
  Two single-center, open-label studies in healthy volunteers and severe onychomycosis patients. Efinaconazole 10% solution was applied topically to all 10 toenails (0.42 mL total daily dose volume); administered as single and then 7 daily doses to 10 healthy volunteers, and once daily for 28 days to 19 severe onychomycosis patients. Plasma concentrations of efinaconazole and its major metabolite H3 were determined by LC-MS-MS at multiple timepoints. Safety evaluations were carried out throughout both studies.
  
  
  RESULTS
  The mean peak plasma concentrations (Cmax) of efinaconazole and H3 were 0.54 and 1.63 ng/mL, respectively, in healthy volunteers; and 0.67 and 2.36 ng/mL, respectively, in patients. Both parent drug and metabolite accumulated following repeat dosing, and reached steady state in plasma by 14 days. Efinaconazole was well tolerated in both studies; no drug-related adverse events were reported.
  
  
  CONCLUSIONS
  Efinaconazole 10% solution resulted in very low systemic exposures to efinaconazole and H3 when applied topically at maximum use conditions to healthy volunteer and onychomycosis patients' toenails. Efinaconazole is a CYP inhibitor like other azole antifungals, and its lowest ki is 91 ng/mL for CYP2C9, a >130-fold higher concentration than the mean steady state Cmax observed in patients. The Cmax/ki ratio was 0.007, well below the threshold for clinical DDI evaluation as recommended in regulatory guidances, thereby suggesting efinaconazole 10% solution has remote potential for drug-drug interactions.
authors.forename: Michael
authors.initials: M
authors.lastname: Jarratt
authors.forename: William Jo
authors.initials: WJ
authors.lastname: Siu
authors.forename: Eiko
authors.initials: E
authors.lastname: Yamakawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kodera
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Pillai
authors.forename: Kathleen
authors.initials: K
authors.lastname: Smith
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005006:Ethnicity; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009262:Nails / Q000473:pathology; D014009:Onychomycosis / Q000188:drug therapy*; D019999:Pharmaceutical Solutions; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D019999:Pharmaceutical Solutions; D014230:Triazoles; C431707:efinaconazole