Reduced variability in tacrolimus pharmacokinetics following intramuscular injection compared to oral administration in cynomolgus monkeys: Investigating optimal dosing regimens

J Pharmacol Sci. 2019 Feb;139(2):65-71. doi: 10.1016/j.jphs.2018.05.013. Epub 2018 Dec 11.


Tacrolimus is one of the most commonly used immunosuppressive agents in animal models of transplantation. However, in these models, oral administration is often problematic due to the lowered compliance associated with highly invasive surgery and due to malabsorption in the intestinal tract. Therefore, we carried out a study to determine the pharmacokinetics of tacrolimus after intramuscular (IM) injection and to determine the optimal IM dosing regimens in primate models. Six male cynomolgus monkeys (Macaca fascicularis) were used in the study. Doses of 0.1 mg/kg and 5 mg were administered via IM injection and oral administration, respectively, once to determine single-dose pharmacokinetics and once daily for 5 days to determine multiple-dose pharmacokinetics. According to pharmacokinetic model estimates, the inter- and intra-individual variabilities in bioavailability following IM injection were remarkably reduced compared with those following oral administration. Monte Carlo simulations revealed that Cpeak, Ctrough and AUC would also have less variability following IM injection compared with oral administration. In this study, we found that the pharmacokinetic characteristics of tacrolimus were more constant following IM injection compared with oral administration. These results suggest that IM injection can be an alternative route of administration fin non-human primate model studies.

Keywords: Cynomolgus monkey; Intra-individual variability; Intramuscular injection; Tacrolimus.

MeSH terms

  • Administration, Oral
  • Animals
  • Area Under Curve
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / pharmacokinetics*
  • Immunosuppressive Agents / toxicity
  • Injections, Intramuscular
  • Macaca fascicularis
  • Male
  • Models, Biological
  • Tacrolimus / administration & dosage*
  • Tacrolimus / pharmacokinetics*
  • Tacrolimus / toxicity


  • Immunosuppressive Agents
  • Tacrolimus