title: Single dose sublingual testosterone and oral sildenafil vs. a dual route/dual release fixed dose combination tablet: a pharmacokinetic comparison.
abstract: The aim was to compare the pharmacokinetic profiles of two formulations of a combination drug product containing 0.5 mg testosterone and 50 mg sildenafil for female sexual interest/arousal disorder. The prototype (formulation 1) consists of a testosterone solution for sublingual administration and a sildenafil tablet that is administered 2.5 h later. The dual route/dual release fixed dose combination tablet (formulation 2) employs a sublingual and an oral route for systemic uptake. This tablet has an inner core of sildenafil with a polymeric time delay coating and an outer polymeric coating containing testosterone. It was designed to increase dosing practicality and decrease potential temporal non-adherence through circumventing the relatively complex temporal dosing scheme.
  
  
  
  Twelve healthy premenopausal subjects received both formulations randomly on separate days. Blood was sampled frequently to determine the pharmacokinetics of free testosterone, total testosterone, dihydrotestosterone, sildenafil and N-desmethyl-sildenafil.
  
  
  
  Formulation 2 had a higher maximum concentration (Cmax ) for testosterone, 8.06 ng ml(-1) (95% confidence interval [CI] 6.84, 9.28) and higher area under the plasma concentration-time curve (AUC), 7.69 ng ml(-1)  h (95% CI 6.22, 9.16) than formulation 1, 5.66 ng ml(-1) (95% CI 4.63, 6.69) and 5.12 ng ml(-1)  h (95% CI 4.51, 5.73), respectively. Formulation 2 had a lower Cmax for sildenafil, 173 ng ml(-1) (95% CI 126, 220) and a lower AUC, 476 ng ml(-1)  h (95% CI 401, 551) than formulation 1, 268 ng ml(-1) (95% CI 188, 348) and 577 ng ml(-1)  h (95% CI 462, 692), respectively. Formulation 2 released sildenafil after 2.75 h (95% CI 2.40, 3.10).
  
  
  
  The dual route/dual release fixed dose combination tablet fulfilled its design criteria and is considered suitable for further clinical testing.
  
  
  
  Female sexual interest/arousal disorder (FSIAD) is a significant problem impacting psychological well-being, but the pharmacotherapeutic options for this problem are lacking. The combined, on-demand, sublingual administration of low dose sublingual testosterone and oral administration of sildenafil is a novel pharmacotherapeutic option under development for FSIAD. In proof-of-concept trials, these compounds were successfully administered via different dosage forms (sublingual and oral) at different time points (separated by 2.5 h) because of their markedly different pharmacokinetic-pharmacodynamic profiles. For future larger scale studies and the clinical practice, this raises obvious adherence issues.
  
  
  
  A newly developed dual route/dual release fixed dose combination tablet containing testosterone and sildenafil mimics the pharmacokinetic profile of these components when they are administered as different dosage forms, 2.5 h apart. This combination tablet is a suitable final pharmaceutical drug product that will be used in future studies.
authors.affiliation: Emotional Brain B.V., Almere.|Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht.
authors.forename: Jos
authors.initials: J
authors.lastname: Bloemers
authors.affiliation: Emotional Brain B.V., Almere.|Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht.
authors.forename: Kim
authors.initials: K
authors.lastname: van Rooij
authors.affiliation: Exelion Bio-Pharmaceutical Consultancy B.V., Waddinxveen.
authors.forename: Leo
authors.initials: L
authors.lastname: de Leede
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Henderik W
authors.initials: HW
authors.lastname: Frijlink
authors.affiliation: Emotional Brain B.V., Almere.
authors.forename: Hans P F
authors.initials: HP
authors.lastname: Koppeschaar
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht.|Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.affiliation: Emotional Brain B.V., Almere.|Department of Psychopharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Adriaan
authors.initials: A
authors.lastname: Tuiten
mesh_terms: D000284:Administration, Oral; D000286:Administration, Sublingual; D000293:Adolescent; D000328:Adult; D013196:Dihydrotestosterone / Q000097:blood; D004338:Drug Combinations; D005260:Female; D006801:Humans; D000068677:Sildenafil Citrate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D013739:Testosterone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D013196:Dihydrotestosterone; D013739:Testosterone; D000068677:Sildenafil Citrate
keywords: Lybrido; combination-tablet; pharmacokinetics; sildenafil; testosterone