Why was this research needed?

Fentanyl is one of the most powerful painkillers used to treat chronic pain.  However, accidental overdoses, drug abuse, and potentially life-threatening side effects have caused concern over its use.  The development of safe, effective, and tamper-proof formulations of fentanyl is of paramount importance to public health and the chronic pain community.

What was the aim of the clinical trial? 

Lafenta is a novel fentanyl patch applied to the skin for 72 hours.  Lafenta has a rate-control membrane that allows a more gradual release of fentanyl than other commercially available patches.  

Previous clinical trials in Europe have demonstrated the safety and effectiveness of Lafenta.  Japanese law mandates any drug intended for Japanese people must first be tested in native volunteers.  Therefore, Phase I clinical trials in healthy Japanese volunteers were needed to provide data on the safety and effectiveness of Lafenta in the Japanese drug market.

How were the studies done?

Both studies took place at the London-based clinical research facility at Richmond Pharmacology.  Sixty Japanese men between 20 and 45 years of age took part (30 men per study).  

  • Study 1 measured the concentration of fentanyl in the blood with increasing doses of Lafenta (1.38, 2.75, 5.5, 8.25, and 11.0 mg patches), called dose-proportionality. 
  • Study 2 compared the pharmaceutical similarities, called bioequivalence, of 11.0 mg Lafenta versus 16.8 mg Durotep, a commercially available fentanyl patch in Japan.

Both studies also assessed how well the patches adhered to the skin, the residual amount of fentanyl after use, and the side effects the volunteers had. 

What were the results?

Study 1: Dose-proportionality

Analysis of over 1,300 blood samples showed that:

  • Higher blood concentrations of fentanyl were seen with increasing doses of Lafenta.
  • Concentrations plateaued 18-48 hours after Lafenta application. 
  • The absorption rate and the maximum concentration of fentanyl in the blood were higher with increasing doses.

Overall, the results showed that dose-proportionality was achieved.

Study 2: Bioequivalence

  • The amount of fentanyl that reached the bloodstream was similar between the 2 treatments (Lafenta, 7.46 mg; Durotep, 6.96 mg).
  • Blood concentrations of fentanyl plateaued 18-72 hours after application of both patches.
  • The absorption rate and the maximum concentration of fentanyl in the blood were similar for both patches.

Overall, the results showed that the 11.0 mg Lafenta and 16.8 mg Durotep were bioequivalent. 

Residual fentanyl amount

In both studies, approximately 20-30% fentanyl remained on the Lafenta patch after use, compared with 59% on the Durotep patch during Study 2.

Adhesion analysis 

The ability of the patches to adhere to the skin was scored on a scale where ≥90% adhesion meant no lifting of the patch from the skin, and 0% adhesion meant the patch lifted off the skin.

In Study 1, Lafenta had, on average, ≥75% surface area adhesion across all doses.  During Study 2, fewer Lafenta patches (40-60%) had ≥90% surface area adhesion than Durotep patches (87-100%).

Was Lafenta safe in healthy Japanese volunteers?

Lafenta was considered safe and well-tolerated in healthy Japanese volunteers.  No serious, severe, or significant adverse events occurred during either study, and no volunteer stopped taking part due to adverse events. 

  • In Study 1, 19 out of 30 volunteers (63%) reported adverse events.  
  • In Study 2, 16 out of 30 volunteers (53%) in the Lafenta group and 14 out of 30 volunteers (47%) in the Durotep group reported adverse events.

The most common events in the Lafenta group in both studies were nausea, dizziness, drowsiness, abdominal pain, headache, constipation, and a decrease in appetite. The most common events in the Durotep group were nausea, dizziness, decreased appetite, and a skin rash where the patch had been applied.  Most of the adverse events in both studies were mild. 

How has this research helped patients and researchers?

Lafenta patches are safe and well-tolerated in healthy Japanese men and provide reliable dose-proportional delivery of fentanyl with good adhesion.  The patches deliver an equivalent amount of drug into the bloodstream as Durotep but at a lower dose.  Furthermore, adverse events experienced by volunteers were consistent with those usually reported after fentanyl patch administration.  Collectively, these results provide encouraging data to support further studies of Lafenta in Japan.

Read the full publication on the Clinical Pharmacology in Drug Development Journal.

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