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

Eur J Drug Metab Pharmacokinet. 2019 Dec;44(6):777-785. doi: 10.1007/s13318-019-00562-y.


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.

Publication types

  • Clinical Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Biological Availability
  • Female
  • Healthy Volunteers
  • Humans
  • Immunosuppressive Agents / pharmacokinetics
  • Kidney Transplantation
  • Male
  • Middle Aged
  • Sirolimus / administration & dosage
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacokinetics


  • Immunosuppressive Agents
  • temsirolimus
  • Sirolimus