title: An innovative phase I population pharmacokinetic approach to investigate the pharmacokinetics of an intranasal fentanyl spray in healthy subjects.
abstract: BACKGROUND
  Intranasal Fentanyl Spray (INFS) was developed for the treatment of breakthrough pain (BTP) in cancer patients using a new route of administration. Dose strengths of 50, 100, and 200 μg INFS (Instanyl®) are currently on the market, however, some adult cancer patients with BTP may require higher doses up to 400 μg INFS.
  
  
  OBJECTIVE
  As pharmacokinetic (PK) samples from cancer patients with BTP are hard to obtain, PK of 400 μg INFS was investigated in healthy volunteers. Using prior knowledge from an available population PK (PopPK) model, a PK trial design was derived which aimed for short study duration and reduced trial costs without jeopardizing trial readout.
  
  
  METHODS
  Different trial designs to investigate the systemic exposure of 400 μg INFS were simulated using the available PopPK model. Parameters with strong influence on Cmax and AUC, i.e., clearance (CL), absorption rate constant (KA), central volume (V2) and bioavailability (F1), were estimated, while other parameters were fixed to previous model estimates. The concentration-time data obtained from the applied trial design was subjected to a PopPK analysis. From the final individual parameter estimates, single-dose concentration-time profiles with wash-out were simulated, and AUC and Cmax values were calculated as for a classical trial design.
  
  
  RESULTS
  The final trial design was a two-sequence, three period, and three-treatment cross-over design with no wash-out intervals between treatments. 20 subjects received three doses of INFS. Four hours after a single dose of 200 μg INFS (Treatment A), subjects received either a single dose of 400 μg INFS (Treatment B) or two single doses (10 minutes apart) of 400 μg INFS (Treatment C). At t = 24 hours subjects received either Treatment B or Treatment C as cross-over. Plasma samples were taken up to 72 hours. The study duration per subject was less than 4 days. PopPK analysis and validation were performed successfully. The estimated primary PK parameters were F1 = 59%, CL=33.5 l/h, V2 = 68.8 l and KA = 12.8 1/h. The ratio analysis of the least square geometric means of dose normalized AUC∞ values resulted in point estimates of 97 - 104%, indicating dose proportionality in the investigated dose range of 200 μg - 2 × 400 μg.
  
  
  CONCLUSIONS
  The implementation of a PopPK approach in the planning and analysis of this trial yielded an innovative, cost- and time-saving trial design that successfully delivered the required information about the PK of the 400 μg dose strength within this small clinical study.
authors.affiliation: Takeda Pharmaceuticals International GmbH, Zürich, Switzerland. nele.kaessner@takeda.com
authors.forename: Nele
authors.initials: N
authors.lastname: Plock
authors.forename: Axel
authors.initials: A
authors.lastname: Facius
authors.forename: Lene
authors.initials: L
authors.lastname: Hartmann
authors.forename: Sybille
authors.initials: S
authors.lastname: Baumann
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Nave
mesh_terms: D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D059390:Breakthrough Pain / Q000188:drug therapy; D003198:Computer Simulation; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D059085:Nasal Sprays; D012107:Research Design; D013997:Time Factors; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D059085:Nasal Sprays; D005283:Fentanyl