RESUMEN
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. CONCLUSION: 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.