Skip to main content

Dose Escalation Study to Assess the Pharmacokinetic Parameters of a Nano-amorphous Oral Sirolimus Formulation in Healthy Volunteers

Abstract

Background and Objectives

Sirolimus (Rapamune®) exhibits low bioavailability, high variability and moderate food effect following oral administration. This makes therapeutic blood monitoring of sirolimus concentrations necessary for kidney transplant patients. Furthermore, reaching therapeutic blood sirolimus concentrations in renal cancer patients was found to be challenging when the marketed drug was administered alone. A novel, nano-amorphous formulation of the compound was developed and its pharmacokinetic properties were investigated in a dose escalation study in a first-in-human clinical trial. The effect of food at the highest dose on the pharmacokinetic parameters was also assessed.

Methods

Each group received one of the escalating doses (0.5–2–10–40 mg) of sirolimus as the novel formulation in the fasted state. Following a 2- to 3-week washout period, the 40-mg group then also received another 40 mg dose in the fed state. Sirolimus whole blood concentrations were determined for up to 48 h. To avoid degradation of sirolimus in the acidic environment in the stomach, 40 mg famotidine was administered 3 h pre-dose in all regimens. The main pharmacokinetic parameters were calculated and data were compared with pharmacokinetic data reported for dose escalation studies for Rapamune®.

Results

Thirty-two healthy volunteers were divided into 4 cohorts of 8 volunteers. Dose increments resulted in approximately dose-proportional increases of maximal plasma concentrations (Cmax) and area under the concentration–time curve (AUC)0–48 h up to 10 mg, while less than dose-proportional increases were observed when the dose was increased from 10 to 40 mg. Mean AUCinf at the 40 mg dose in the fasted state was 4,300 ± 1,083 ng·h/ml, which is 28% higher than the AUC reported following the administration of 90 (2 × 45) mg Rapamune® and 11% higher than the exposure reported for 25 mg intravenous pro-drug temsirolimus (3,810 ng·h/ml). At the 40 mg dose, food reduced Cmax by 35.5%, but it had no statistically significant effect on AUC. Inter-individual variability of the pharmacokinetic parameters mostly fell in the 20–30% (CV) range showing that sirolimus administered as the nano-amorphous formulation is a low-to-moderate variability drug.

Conclusion

Based on the pharmacokinetic profiles observed, the nano-amorphous formulation could be a better alternative to Rapamune® for the treatment of mammalian target of rapamycin-responsive malignancies. Therapeutically relevant plasma concentrations and exposures can be achieved by a single 40 mg oral dose. Furthermore, the low variability observed might make therapeutic blood monitoring unnecessary for transplant patients taking sirolimus as an immunosuppressant.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003;35:7S–14S.

    CAS  Article  Google Scholar 

  2. Napoli KL, Taylor PJ. From beach to bedside: history of the development of sirolimus. Ther Drug Monit. 2001;23:559–86.

    CAS  Article  Google Scholar 

  3. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov. 2011;10:868–80. https://doi.org/10.1038/nrd3531.

    CAS  Article  PubMed  Google Scholar 

  4. Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005;16:525–37. https://doi.org/10.1093/annonc/mdi113.

    CAS  Article  PubMed  Google Scholar 

  5. Law BK. Rapamycin: an anti-cancer immunosuppressant? Crit Rev Oncol Hematol. 2005;56:47–60. https://doi.org/10.1016/j.critrevonc.2004.09.009.

    Article  PubMed  Google Scholar 

  6. Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol. 2010;7:209–19. https://doi.org/10.1038/nrclinonc.2010.21.

    CAS  Article  PubMed  Google Scholar 

  7. Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet. 2001;40:573–85.

    CAS  Article  Google Scholar 

  8. Wyeth Pharmaceuticals (2017) Rapamune® (sirolimus) Oral Solution and Tablets Product Label, NDA 21-083/S-030/038.

  9. Kelly PA, Napoli K, Kahan BD. Conversion from liquid to solid rapamycin formulations in stable renal allograft transplant recipients. Biopharm Drug Dispos. 1999;20:249–53.

    CAS  Article  Google Scholar 

  10. Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol. 1997;37:405–15.

    CAS  Article  Google Scholar 

  11. Yatscoff RW. Pharmacokinetics of rapamycin. Transplant Proc. 1996;28:970–3.

    CAS  PubMed  Google Scholar 

  12. Sun M, Si L, Zhai X, et al. The influence of co-solvents on the stability and bioavailability of rapamycin formulated in self-microemulsifying drug delivery systems. Drug Dev Ind Pharm. 2011;37:986–94. https://doi.org/10.3109/03639045.2011.553618.

    CAS  Article  PubMed  Google Scholar 

  13. Kim M-S, Kim Jeong-Soo, Park Hee Jun, et al. Enhanced bioavailability of sirolimus via preparation of solid dispersion nanoparticles using a supercritical antisolvent process. Int J Nanomedicine. 2011. https://doi.org/10.2147/ijn.s26546.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lampen A, Zhang Y, Hackbarth I, et al. Metabolism and transport of the macrolide immunosuppressant sirolimus in the small intestine. J Pharmacol Exp Ther. 1998;285:1104–12.

    CAS  PubMed  Google Scholar 

  15. Stenton SB, Partovi N, Ensom MHH. Sirolimus the evidence for clinical pharmacokinetic monitoring. Clin Pharmacokinet. 2005;44:469–789.

    Article  Google Scholar 

  16. Cohen EEW, Wu K, Hartford C, et al. Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients. Clin Cancer Res. 2012;18:4785–93. https://doi.org/10.1158/1078-0432.CCR-12-0110.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Jimeno A, Rudek MA, Kulesza P, et al. Pharmacodynamic-guided modified continuous reassessment method-based, dose-finding study of rapamycin in adult patients with solid tumors. J Clin Oncol. 2008;26:4172. https://doi.org/10.1200/JCO.2008.16.2347.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Solymosi T, Angi R, Basa-Dénes O, et al. Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method. Eur J Pharm Biopharm. 2015. https://doi.org/10.1016/j.ejpb.2015.05.010.

    Article  PubMed  Google Scholar 

  19. Yatscoff R, Raraci C, Bolingbroke P. Measurement of rapamycin in whole blood using reverse-phase high-performance liquid chromatography. Ther Drug Monit. 1992;14:138–41. https://doi.org/10.1097/00007691-199204000-00011.

    CAS  Article  PubMed  Google Scholar 

  20. Doligalski CT, Logan AT, Silverman A. Drug interactions: a primer for the gastroenterologist. Gastroenterol Hepatol. 2012;8:376–83.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hristos Glavinas.

Ethics declarations

Funding

No source of funding was used to conduct this study.

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the NHS/HSC Research Ethics Committee.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 12 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Basa-Dénes, O., Angi, R., Kárpáti, B. et al. Dose Escalation Study to Assess the Pharmacokinetic Parameters of a Nano-amorphous Oral Sirolimus Formulation in Healthy Volunteers. Eur J Drug Metab Pharmacokinet 44, 777–785 (2019). https://doi.org/10.1007/s13318-019-00562-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-019-00562-y