Minimization of CYP2D6 Polymorphic Differences and Improved Bioavailability via Transdermal Administration: Latrepirdine Example

Pharm Res. 2016 Aug;33(8):1873-80. doi: 10.1007/s11095-016-1922-4. Epub 2016 Apr 12.


Purpose: Transdermal delivery has the potential to offer improved bioavailability by circumventing first-pass gut and hepatic metabolism. This study evaluated the pharmacokinetics of oral immediate release and transdermal latrepirdine in extensive and poor CYP2D6 metabolizers (EM/PM).

Methods: Latrepirdine transdermal solution was prepared extemporaneously. The solution was applied with occlusive dressing to upper or middle back for 24 h. Each subject received a single dose of 8.14 mg oral, 5 mg transdermal, and 10 mg transdermal (EMs only) latrepirdine free base in a fixed sequence.

Results: Twelve EMs and 7 PMs (50-79 years) enrolled and completed the study. Latrepirdine was well tolerated following both routes of administration. Dose-normalized latrepirdine total exposures were approximately 11-fold and 1.5-fold higher in EMs and PMs, respectively following administration of transdermal relative to oral. Differences between EM and PM latrepirdine exposures were decreased, with PMs having 1.9- and 2.7-fold higher peak and total exposures, respectively, following transdermal administration compared to 11- and 20-fold higher exposures, respectively, following oral administration.

Conclusion: Transdermal delivery can potentially mitigate the large intersubject differences observed with compounds metabolized primarily by CYP2D6. Transdermal delivery was readily accomplished in the clinic using an extemporaneously prepared solution [NCT00990613].

Keywords: CYP2D6; bioavailability; latrepirdine; pharmacokinetics; transdermal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Aged
  • Biological Availability
  • Cross-Over Studies
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Female
  • Humans
  • Indoles / administration & dosage*
  • Indoles / pharmacokinetics*
  • Male
  • Middle Aged
  • Pilot Projects


  • Indoles
  • Cytochrome P-450 CYP2D6
  • latrepirdine

Associated data