Skip to content
2000
image of A Physiologically-Based Pharmacokinetic Model to Characterize Dasotraline Pharmacokinetics and CYP-mediated Drug-Drug Interactions

Abstract

Introduction

Dasotraline is an investigational inhibitor of dopamine and norepinephrine reuptake transporters that has completed pivotal studies in Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED). Preclinical studies show dasotraline is well absorbed, well distributed, and highly metabolized in animal models, though absorption is prolonged with slow overall elimination in humans. Dasotraline is a substrate of multiple Cytochrome P450s (CYP). The metabolism of dasotraline is largely determined by CYP2B6 (fraction of metabolism f: 0.63) and, to a lesser extent, by CYP2D6 (f: 0.12), CYP2C19 (f: 0.11), and CYP3A4/5 (f: 0.14). Dasotraline is not a CYP inducer but is an inhibitor of CYP2B6, CYP2C19, CYP2D6, and CYP3A4/5.

Methods

A dasotraline PBPK model was established by a middle-out approach based on and clinical results. Simulations were performed to evaluate CYP-mediated drug-drug interactions (DDI) with dasotraline as a victim and perpetrator, the impact of polymorphic CYP2B6 on dasotraline PK, as well as the role CYP2B6 autoinhibition on dasotraline accumulation at steady state.

Results

The PBPK model well described clinically observed PK not only after a single dose, but also predicted substantial accumulation of dasotraline due to auto-inhibition of CYP2B6-mediated clearance. In addition, the simulated CYP2B6-mediated DDI precisely depicted the clinically observed DDI. Although hepatic elimination of dasotraline is primarily mediated by CYP2B6, simulations suggest that the impact of CYP2B6 polymorphism on pharmacokinetics is minimal, likely due to compensatory auto-inhibition of the enzyme. As a result, dose adjustment based on CYP2B6 phenotype is likely unnecessary.

Discussion

A PBPK model was developed via the middle-out approach to predict CYP-mediated DDI with dasotraline as either a victim or a perpetrator and the impact of polymorphic CYP2B6 on dasotraline PK. The PBPK model was developed assuming the hepatic metabolism of dasotraline is only determined by CYP enzymes based on the in vitro studies. Although the minor contribution of non-CYP enzymes may not be ruled out, the simulations on CYP mediated DDI with dasotraline as the victim will unlikely be significantly different.

Conclusion

The PBPK model developed the middle-out approach provides a quantitative tool to predict CYP-mediated DDI with dasotraline as either a victim or a perpetrator and the impact of polymorphic CYP2B6 on dasotraline PK. This model may aid in optimizing dosing strategies to minimize the risks associated with CYP-mediated interactions and significant accumulation following repeated dosing.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/dmbl/10.2174/0118723128376630250618102129
2025-06-27
2025-08-16

  • From This Site

    /content/journals/dmbl/10.2174/0118723128376630250618102129
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Findling R.L. Adler L.A. Spencer T.J. Goldman R. Hopkins S.C. Koblan K.S. Kent J. Hsu J. Loebel A. Dasotraline in children with attention-deficit/hyperactivity disorder: A six-week, placebo-controlled, fixed-dose trial. J. Child Adolesc. Psychopharmacol. 2019 29 2 80 89 10.1089/cap.2018.0083 30694697
    [Google Scholar]
  2. Koblan K.S. Hopkins S.C. Sarma K. Jin F. Goldman R. Kollins S.H. Loebel A. Dasotraline for the treatment of attention-deficit/hyperactivity disorder: A randomized, double-blind, placebo-controlled, proof-of-concept trial in adults. Neuropsychopharmacology 2015 40 12 2745 2752 10.1038/npp.2015.124 25948101
    [Google Scholar]
  3. Wigal S.B. Hopkins S.C. Koblan K.S. Childress A. Kent J.M. Tsai J. Hsu J. Loebel A. Goldman R. Efficacy and safety of dasotraline in children with ADHD: A laboratory classroom study. J. Atten. Disord. 2020 24 2 192 204 10.1177/1087054719864644 31375051
    [Google Scholar]
  4. Maiti R. Mishra A. Jena M. Maji S. Padhan M. Mishra B.R. Efficacy and safety of dasotraline in attention-deficit hyperactivity disorder: A systematic review and meta-analysis. Indian J. Psychiatry 2024 66 4 326 335 10.4103/indianjpsychiatry.indianjpsychiatry_3_24 38778858
    [Google Scholar]
  5. Appolinario J.C. Nardi A.E. McElroy S.L. Investigational drugs for the treatment of binge eating disorder (BED): An update. Expert Opin. Investig. Drugs 2019 28 12 1081 1094 10.1080/13543784.2019.1692813 31714807
    [Google Scholar]
  6. Dasotraline IND 2017
  7. Hopkins S.C. Sunkaraneni S. Skende E. Hing J. Passarell J.A. Loebel A. Koblan K.S. Pharmacokinetics and exposure-response relationships of dasotraline in the treatment of attention-deficit/hyperactivity disorder in adults. Clin. Drug Investig. 2016 36 2 137 146 10.1007/s40261‑015‑0358‑7 26597180
    [Google Scholar]
  8. Chen Y.L. Skende E. Lin J. Yi Y. Wang P.L. Wills S. Wilkinson H.S. Koblan K.S. Hopkins S.C. Absorption, distribution, metabolism, and excretion of [14C]-dasotraline in humans. Pharmacol. Res. Perspect. 2017 5 1 e00281 10.1002/prp2.281 28596833
    [Google Scholar]
  9. In vitro drug interaction studies-cytochrome P450 enzyme- and transporter-mediated drug interactions. 2020 Available from: https://www.fda.gov/media/135587/download
  10. In vivo drug interaction studies-cytochrome P450 enzyme- and transporter-mediated drug interactions. 2020
  11. Fahmi O.A. Shebley M. Palamanda J. Sinz M.W. Ramsden D. Einolf H.J. Chen L. Wang H. Evaluation of CYP2B6 induction and prediction of clinical drug–drug interactions: Considerations from the IQ consortium induction working group—an industry perspective. Drug Metab. Dispos. 2016 44 10 1720 1730 10.1124/dmd.116.071076 27422672
    [Google Scholar]
  12. Meyer zu Schwabedissen H.E. Oswald S. Bresser C. Nassif A. Modess C. Desta Z. Ogburn E.T. Marinova M. Lütjohann D. Spielhagen C. Nauck M. Kroemer H.K. Siegmund W. Compartment-specific gene regulation of the CAR inducer efavirenz in vivo. Clin. Pharmacol. Ther. 2012 92 1 103 111 10.1038/clpt.2012.34 22588604
    [Google Scholar]
  13. Robertson S.M. Maldarelli F. Natarajan V. Formentini E. Alfaro R.M. Penzak S.R. Efavirenz induces CYP2B6-mediated hydroxylation of bupropion in healthy subjects. J. Acquir. Immune Defic. Syndr. 2008 49 5 513 519 10.1097/QAI.0b013e318183a425 18989234
    [Google Scholar]
  14. Haas D.W. Ribaudo H.J. Kim R.B. Tierney C. Wilkinson G.R. Gulick R.M. Clifford D.B. Hulgan T. Marzolini C. Acosta E.P. Pharmacogenetics of efavirenz and central nervous system side effects: An adult aids clinical trials group study. AIDS 2004 18 18 2391 2400 15622315
    [Google Scholar]
  15. Kirchheiner J. Klein C. Meineke I. Sasse J. Zanger U.M. Mürdter T.E. Roots I. Brockmöller J. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics 2003 13 10 619 626 10.1097/00008571‑200310000‑00005 14515060
    [Google Scholar]
  16. Wang J. Zhang Z.Y. Lu S. Powers D. Kansra V. Wang X. Effects of rolapitant administered orally on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects. Support. Care Cancer 2019 27 3 819 827 10.1007/s00520‑018‑4331‑x 30084103
    [Google Scholar]
  17. Watanabe T. Saito T. Rico E.M.G. Hishinuma E. Kumondai M. Maekawa M. Oda A. Saigusa D. Saito S. Yasuda J. Nagasaki M. Minegishi N. Yamamoto M. Yamaguchi H. Mano N. Hirasawa N. Hiratsuka M. Functional characterization of 40 CYP2B6 allelic variants by assessing efavirenz 8-hydroxylation. Biochem. Pharmacol. 2018 156 420 430 10.1016/j.bcp.2018.09.010 30201214
    [Google Scholar]
  18. Park G. Bae S.H. Park W.S. Han S. Park M.H. Shin S.H. Shin Y.G. Yim D.S. Drug–drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer. Drug Des. Devel. Ther. 2017 11 1043 1053 10.2147/DDDT.S131797 28408803
    [Google Scholar]
  19. Glass S.M. Martell C.M. Oswalt A.K. Osorio-Vasquez V. Cho C. Hicks M.J. Mills J.M. Fujiwara R. Glista M.J. Kamath S.S. Furge L.L. CYP2D6 allelic variants *34, *17-2, *17-3, and *53 and a Thr309Ala mutant display altered kinetics and NADPH coupling in metabolism of bufuralol and dextromethorphan and altered susceptibility to inactivation by SCH 66712. Drug Metab. Dispos. 2018 46 8 1106 1117 10.1124/dmd.117.079871 29784728
    [Google Scholar]
  20. Storelli F. Matthey A. Lenglet S. Thomas A. Desmeules J. Daali Y. Impact of CYP2D6 functional allelic variations on phenoconversion and drug–drug interactions. Clin. Pharmacol. Ther. 2018 104 1 148 157 10.1002/cpt.889 28940476
    [Google Scholar]
  21. Hanke N. Frechen S. Moj D. Britz H. Eissing T. Wendl T. Lehr T. PBPK models for CYP3A4 and P‐gp DDI Prediction: A modeling network of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin. CPT Pharmacometrics Syst. Pharmacol. 2018 7 10 647 659 10.1002/psp4.12343 30091221
    [Google Scholar]
  22. Townsend R. Dietz A. Hale C. Akhtar S. Kowalski D. Lademacher C. Lasseter K. Pearlman H. Rammelsberg D. Schmitt-Hoffmann A. Yamazaki T. Desai A. Pharmacokinetic evaluation of CYP3A4‐mediated drug‐drug interactions of isavuconazole with rifampin, ketoconazole, midazolam, and ethinyl estradiol/norethindrone in healthy adults. Clin. Pharmacol. Drug Dev. 2017 6 1 44 53 10.1002/cpdd.285 27273461
    [Google Scholar]
  23. Sugiyama I. Murayama N. Kuroki A. Kota J. Iwano S. Yamazaki H. Hirota T. Evaluation of cytochrome P450 inductions by anti-epileptic drug oxcarbazepine, 10-hydroxyoxcarbazepine, and carbamazepine using human hepatocytes and HepaRG cells. Xenobiotica 2016 46 9 765 774 10.3109/00498254.2015.1118774 26711482
    [Google Scholar]
  24. Nirogi R. Palacharla R.C. Uthukam V. Manoharan A. Srikakolapu S.R. Kalaikadhiban I. Boggavarapu R.K. Ponnamaneni R.K. Ajjala D.R. Bhyrapuneni G. Chemical inhibitors of CYP450 enzymes in liver microsomes: Combining selectivity and unbound fractions to guide selection of appropriate concentration in phenotyping assays. Xenobiotica 2015 45 2 95 106 10.3109/00498254.2014.945196 25070627
    [Google Scholar]
  25. Palacharla R.C. Nirogi R. Uthukam V. Manoharan A. Ponnamaneni R.K. Kalaikadhiban I. Quantitative in vitro phenotyping and prediction of drug interaction potential of CYP2B6 substrates as victims. Xenobiotica 2018 48 7 663 675 10.1080/00498254.2017.1354267 28737446
    [Google Scholar]
  26. Richter T. Mürdter T.E. Heinkele G. Pleiss J. Tatzel S. Schwab M. Eichelbaum M. Zanger U.M. Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J. Pharmacol. Exp. Ther. 2004 308 1 189 197 10.1124/jpet.103.056127 14563790
    [Google Scholar]
  27. Lamorde M. Wang X. Neary M. Bisdomini E. Nakalema S. Byakika-Kibwika P. Mukonzo J.K. Khan W. Owen A. McClure M. Boffito M. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of efavirenz 400 mg once daily during pregnancy and post-partum. Clin. Infect. Dis. 2018 67 5 785 790 10.1093/cid/ciy161 30124823
    [Google Scholar]
  28. Podany A.T. Bao Y. Swindells S. Chaisson R.E. Andersen J.W. Mwelase T. Supparatpinyo K. Mohapi L. Gupta A. Benson C.A. Kim P. Fletcher C.V. Team A.C.T.G.A.S. Efavirenz pharmacokinetics and pharmacodynamics in HIV-infected persons receiving rifapentine and isoniazid for tuberculosis prevention. Clin. Infect. Dis. 2015 61 8 1322 1327 10.1093/cid/civ464 26082504
    [Google Scholar]
  29. Saitoh A. Fletcher C.V. Brundage R. Alvero C. Fenton T. Hsia K. Spector S.A. Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism. J. Acquir. Immune Defic. Syndr. 2007 45 3 280 285 10.1097/QAI.0b013e318040b29e 17356468
    [Google Scholar]
  30. Zhu A.Z.X. Cox L.S. Nollen N. Faseru B. Okuyemi K.S. Ahluwalia J.S. Benowitz N.L. Tyndale R.F. CYP2B6 and bupropion’s smoking-cessation pharmacology: The role of hydroxybupropion. Clin. Pharmacol. Ther. 2012 92 6 771 777 10.1038/clpt.2012.186 23149928
    [Google Scholar]
  31. Høiseth G. Haslemo T. Uthus L.H. Molden E. Effect of CYP2B6*6 on steady-state serum concentrations of bupropion and hydroxybupropion in psychiatric patients. Ther. Drug Monit. 2015 37 5 589 593 10.1097/FTD.0000000000000183 25565674
    [Google Scholar]
  32. Li Y. Jackson K.A. Slon B. Hardy J.R. Franco M. William L. Poon P. Coller J.K. Hutchinson M.R. Currow D.C. Somogyi A.A. CYP2B6* 6 allele and age substantially reduce steady‐state ketamine clearance in chronic pain patients: Impact on adverse effects. Br. J. Clin. Pharmacol. 2015 80 2 276 284 10.1111/bcp.12614 25702819
    [Google Scholar]
/content/journals/dmbl/10.2174/0118723128376630250618102129
Loading
A Physiologically-Based Pharmacokinetic Model to Characterize Dasotraline Pharmacokinetics and CYP-mediated Drug-Drug Interactions
Bentham Science Publishers ; https://doi.org/10.2174/0118723128376630250618102129
/content/journals/dmbl/10.2174/0118723128376630250618102129
/content/journals/dmbl/10.2174/0118723128376630250618102129
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: PBPK model ; dasotraline ; drug interactions ; CYP2B6 ; Autoinhibition ; auto-inhibition

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test