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

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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.

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References

  1. Vocci FJ, Acri J, Elkashef A. Medication development for addictive disorders: the state of the science. Am J Psychiatry. 2005;162:1432–40.

    Article  PubMed  Google Scholar 

  2. Vocci FJ, Appel NM. Approaches to the development of medications for the treatment of methamphetamine dependence. Addiction. 2007;102:96–106.

    Article  PubMed  Google Scholar 

  3. Volkow ND, Li T-K. Drug addiction: the neurobiology of behaviour gone awry. Nat Rev Neurosci. 2004;5(12):963–70.

    Article  CAS  PubMed  Google Scholar 

  4. Howell LL, Murnane KS. Nonhuman primate neuroimaging and the neurobiology of psychostimulant addiction. Ann N Y Acad Sci. 2008;1141(1):176–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Andersen ML, Kessler E, Murnane KS, McClung JC, Tufik S, Howell LL. Dopamine transporter-related effects of modafinil in rhesus monkesy. Psychopharmacology. 2010;210(3):439–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Murnane KS, Howell LL. Neuroimaging and drug taking in primates. Psychopharmacology. 2011;216(2):153–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Howell LL, Murnane KS. Nonhuman primate positron emission tomography neuroimaging in drug abuse research. J Pharmacol Exp Ther. 2011;337(2):324–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Howell LL, Kimmel HL. Monoamine transporters and psychostimulant addiction. Biochem Pharmacol. 2008;75(1):196–217.

    Article  CAS  PubMed  Google Scholar 

  9. Reith MEA, Meisler BE, Sershen H, Lajtha A. Structural requirements for cocaine congeners to interact with dopamine and serotonin uptake sites in mouse brain and to induce stereotyped behavior. Biochem Pharmacol. 1986;35(7):1123–9.

    Article  CAS  PubMed  Google Scholar 

  10. Bergman J, Madras BK, Johnson SE, Spealman RD. Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys. J Pharmacol Exp Ther. 1989.

  11. Banks ML, Blough BE, Negus SS. Effects of monoamine releasers with varying selectivity for releasing dopamine/norepinephrine versus serotonin on choice between cocaine and food in rhesus monkeys. Behav Pharmacol. 2011;22(8):824–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Negus SS, Baumann MH, Rothman RB, Mello NK, Blough BE. Selective suppression of cocaine- versus food-maintained responding by monoamine releasers in rhesus monkeys: benzylpiperazine, (+)phenmetrazine, and 4-benzylpiperidine. J Pharmacol Exp Ther. 2009;329(1):272–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Negus SS, Mello NK. Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a second-order schedule in rhesus monkeys. Drug Alcohol Depend. 2003;70(1):39–52.

    Article  CAS  PubMed  Google Scholar 

  14. Banks ML, Blough BE, Fennell TR, Snyder RW, Negus SS. Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys. Neuropsychopharmacology. 2013;38(13):2698–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kimmel HL, Manvich DF, Blough BE, Negus SS, Howell LL. Behavioral and neurochemical effects of amphetamine analogs that release monoamines in the squirrel monkey. Pharmacol Biochem Behav. 2009;94(2):278–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Grabowski J, Shearer J, Merrill J, Negus SS. Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav. 2004;29(7):1439–64.

    Article  PubMed  Google Scholar 

  17. Negus SS, Henningfield J. Agonist medications for the treatment of cocaine use disorder. Neuropsychopharmacology. 2015;40:1815–25.

    Article  PubMed  Google Scholar 

  18. Puri A, Murnane KS, Blough BE, Banga AK. Effects of chemical and physical enhancement techniques on transdermal delivery of 3-fluoroamphetamine hydrochloride. Int J Pharm. 2017;528(1–2):452–62.

    Article  CAS  PubMed  Google Scholar 

  19. Jiang Y, Murnane KS, Bhattaccharjee SA, Blough BE, Banga AK. Skin delivery and irritation potential of phenmetrazine as a candidate transdermal formulation for repurposed indications. AAPS J. 2019;21(4):70.

    Article  PubMed  Google Scholar 

  20. Ganti SS, Bhattaccharjee SA, Murnane KS, Blough BE, Banga AK. Formulation and evaluation of 4-benzylpiperidine drug-in-adhesive matrix type transdermal patch. Int J Pharm. 2018;550(1–2):71–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Volkow ND, Swanson JM. Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am J Psychiatry. 2003;160(11):1909–18.

    Article  PubMed  Google Scholar 

  22. de Wit H, Bodker B, Ambre J. Rate of increase of plasma drug level influences subjective response in humans. Psychopharmacology. 1992;107(2–3):352–8.

    Article  PubMed  Google Scholar 

  23. Chambers E, Wagrowski-Diehl DM, Lu Z, Mazzeo JR. Systematic and comprehensive strategy for reducing matrix effects in LC/MS/MS analyses. J Chromatogr B Anal Technol Biomed Life Sci. 2007;852(1–2):22–34.

    Article  CAS  Google Scholar 

  24. Zhang L, Jiang Y, Jing G, Tang Y, Chen X, Yang D, et al. A novel UPLC–ESI-MS/MS method for the quantitation of disulfiram, its role in stabilized plasma and its application. J Chromatogr B. 2013;937:54–9.

    Article  CAS  Google Scholar 

  25. Bakshi P, Jiang Y, Nakata T, Akaki J, Matsuoka N, Banga AK. Formulation development and characterization of nanoemulsion-based formulation for topical delivery of heparinoid. J Pharm Sci. 2018;107(11):2883–90.

    Article  CAS  PubMed  Google Scholar 

  26. Badkar AV, Smith AM, Eppstein JA, Banga AK. Transdermal delivery of interferon alpha-2b using microporation and iontophoresis in hairless rats. Pharm Res. 2007;24(7):1389–95.

    Article  CAS  PubMed  Google Scholar 

  27. McGough JJ, Wigal SB, Abikoff H, Turnbow JM, Posner K, Moon E. A randomized, double-blind, placebo-controlled, laboratory classroom assessment of methylphenidate transdermal system in children with ADHD. J Atten Disord. 2006;9(3):476–85.

    Article  PubMed  Google Scholar 

  28. White S, Laurenzana E, Hendrickson H, Gentry WB, Owens SM. Gestation time-dependent pharmacokinetics of intravenous (+)-methamphetamine in rats. Drug Metab Dispos. 2011;39(9):1718–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gal J, Hodshon BJ, Pintauro C, Flamm BL, Cho AK. Pharmacokinetics of methylphenidate in the rat using single-ion monitoring GLC-mass spectrometry. J Pharm Sci. 1977;66(6):866–9.

    Article  CAS  PubMed  Google Scholar 

  30. Czoty PW, Tran P, Thomas LN, Martin TJ, Grigg A, Blough BE, et al. Effects of the dopamine/norepinephrine releaser phenmetrazine on cocaine self-administration and cocaine-primed reinstatement in rats. Psychopharmacology. 2015;232(13):2405–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zimmer BA, Chiodo KA, Roberts DCS. Reduction of the reinforcing effectiveness of cocaine by continuous d-amphetamine treatment in rats: Importance of active self-administration during treatment period. Psychopharmacology. 2014;231(5):949–54.

    Article  CAS  PubMed  Google Scholar 

  32. Saroha K, Yadav B, Sharma B. Transdermal patch: a discrete dosage form. Int J Curr Pharm Res. 2011;3(3):98–108.

    CAS  Google Scholar 

  33. Banga AK. Transdermal and intradermal delivery of therapeutic agents application of physical technologies. Boca Raton, Florida: CRC press; 2011.

  34. Elias PM. Epidermal lipids, barrier function, and desquamation. J Investig Dermatol. 1983;80(s6):44s–9s.

    Article  CAS  PubMed  Google Scholar 

  35. Schiffer WK, Volkow ND, Fowler JS, Alexoff DL, Logan J, Dewey SL. Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine. Synapse. 2006;59(4):243–51.

    Article  Google Scholar 

  36. Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL. Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs. J Pharmacol Exp Ther. 2005;313(2):848–54.

    Article  CAS  PubMed  Google Scholar 

  37. Yang Y, Manda P, Pavurala N, Khan MA, Krishnaiah YSR. Development and validation of in vitro–in vivo correlation (IVIVC) for estradiol transdermal drug delivery systems. J Control Release. 2015;210:58–66.

    Article  CAS  PubMed  Google Scholar 

  38. Shin SH, Thomas S, Raney SG, Ghosh P, Hammell DC, El-Kamary SS, et al. In vitro–in vivo correlations for nicotine transdermal delivery systems evaluated by both in vitro skin permeation (IVPT) and in vivo serum pharmacokinetics under the influence of transient heat application. J Control Release. 2018;270:76–88.

    Article  CAS  PubMed  Google Scholar 

  39. Ghosh P, Milewski M, Paudel K. In vitro/in vivo correlations in transdermal product development. Ther Deliv. 2015;6:1117–24.

    Article  CAS  PubMed  Google Scholar 

  40. Milewski M, Paudel KS, Brogden NK, Ghosh P, Banks SL, Hammell DC, et al. Microneedle-assisted percutaneous delivery of naltrexone hydrochloride in yucatan minipig: in vitro-in vivo correlation. Mol Pharm. 2013;10(10):3745–57.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work received financial support from the Georgia Research Alliance based in Atlanta, Georgia by grant number GRA.VL17.11 (Murnane and Banga - Multiple Principal Investigators) as well as by the National Institute on Drug Abuse by grant number DA12970 (Blough - Principal Investigator).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Mercer University Health Sciences Center, 3001 Mercer University Dr., Atlanta, GA, 30341, USA

    Ying Jiang, Azizi Ray, Mohammad Shajid Ashraf Junaid, Sonalika Arup Bhattaccharjee, Kayla Kelley, Ajay K. Banga & Kevin S. Murnane

  2. Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, Durham, NC, 27709, USA

    Bruce E. Blough

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  1. Ying Jiang
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  2. Azizi Ray
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  6. Ajay K. Banga
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  8. Kevin S. Murnane
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Corresponding author

Correspondence to Kevin S. Murnane.

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All institutional and national guidelines for the care and use of laboratory animals were followed.

Conflict of interest

None of the authors has a financial relationship with the sponsor of the research, which was the Georgia Research Alliance. The Georgia Research Alliance is a state government funded agency. Ajay Banga and Kevin Murnane are cofounders of DD Therapeutics, a for-profit startup company that aims to commercialize drug-delivery technology. Ajay Banga, Kevin Murnane, and Ying Jiang are co-inventors on a patent pending for transdermal use of phenethylamine monoamine releasers that is owned by Mercer University. Azizi Ray, Mohammad Shajid Ashraf Junaid, Sonalika Arup Bhattaccharjee, Kayla Kelley, and Bruce Blough have no conflicts of interest to declare.

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Jiang, Y., Ray, A., Junaid, M.S.A. et al. The pharmacokinetics of 3-fluoroamphetamine following delivery using clinically relevant routes of administration. Drug Deliv. and Transl. Res. 10, 271–281 (2020). https://doi.org/10.1007/s13346-019-00685-4

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