The pharmacokinetics of 3-fluoroamphetamine following delivery using clinically relevant routes of administration

Abstract

3-Fluoroamphetamine (also called PAL-353) is a synthetic amphetamine analog that has been investigated for cocaine use disorder (CUD), yet no studies have characterized its pharmacokinetics (PK). In the present study, we determined the PK of PAL-353 in male Sprague Dawley rats following intravenous bolus injection (5 mg/kg). Plasma samples were analyzed using a novel bioanalytical method that coupled liquid-liquid extraction and LC-MS/MS. The primary PK parameters determined by WinNonlin were a C₀ (ng/mL) of 1412.09 ± 196.12 and a plasma half-life of 2.27 ± 0.67 h. As transdermal delivery may be an optimal approach to delivering PAL-353 for CUD, we assessed its PK profile following application of 50 mg of transdermal gel (10% w/w drug over 5 cm²). The 10% w/w gel resulted in a short lag time, sustained delivery, and a rapid clearance in plasma immediately after removal. The rodent PK data were verified by examining in vitro permeation through human epidermis mounted on Franz diffusion cells. An in vitro-in vivo correlation (IVIVC) analysis was performed using the Phoenix IVIVC toolkit to assess the predictive relationship between rodent and human skin absorption/permeation. The in vitro permeation study revealed a dose-proportional cumulative and steady-state flux with ~ 70% of drug permeated. The fraction absorbed in vivo and fraction permeated in vitro showed a linear relationship. In conclusion, we have characterized the PK profile of PAL-353, demonstrated that it has favorable PK properties for transdermal administration for CUD, and provided preliminary evidence of the capacity of rodent data to predict human skin flux.

Keywords: 3-Fluoroamphetamine; Cocaine use disorder; In vitro-in vivo correlation; Intravenous; Pharmacokinetics; Transdermal.

Fig. 1

A representative chromatogram of PAL-353 at the transition of 154.3–109.2 m/z for spiked plasma extraction sample at 0.5 ng/mL (signal-to-noise ratio=10.5).

Fig. 2

Plasma profile of PAL-353 following intravenous bolus injection and transdermal administration of 10% w/w gel (n=3, mean ± SD).

Fig. 3

The in vitro permeation profile of PAL-353 from 5 and 10% w/w gels. The percentage of delivery at 9 h and 24 h were labeled under the symbol corresponding to those sample points. (n=4, mean ± SD).

Fig. 4

The analysis of the predictive relationship between in vitro permeation and in vivo absorption of PAL-353.