Work

SP03. Pharmacokinetics of Rapamycin and Tacrolimus in Swine Model of Vascularized Composite Allotransplantation

Year: 2023

Type: article

Abstract: PURPOSE: Tacrolimus (Tac) and Rapamycin (Rapa) are effective immunosuppressive drugs that has been widely used in experimental animals including minipigs; however, the pharmacokinetic properties of Tac and Rapa in minipigs have not been investigated. The objectives of this study were: first, to describe the pharmacokinetic properties of Tac and Rapa in minipigs following single and multiple-dose intramuscular administration and secondly, to determine the optimal intramuscular doses required to reach the target trough concentrations of 10-15ng/mL for the prevention of rejection with a minimal risk of drug related side effects in minipigs. METHODS: Minipigs (n=3) received either Tac (0.1mg/kg) or Rapa (0.05mg/kg) as a single intramuscular injection; blood samples were obtained before and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours after administration. Blood Tac and Rapa concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay and analyzed with non-compartmental analysis (NCA) using Phoenix WinNonlin® 8.3 to estimate pharmacokinetic parameters. Simulations from single-dose to multiple-dose were performed using a nonparametric superposition method to estimate steady state concentrations and to determine optimal doses. RESULTS: The estimated values (mean±S.D.) of the single dose pharmacokinetic parameters derived from the blood concentrations-time data after intramuscular administration including absorption rate constant (Ka), elimination rate constant (Kel), half-life (T1/2), apparent total body clearance (CL/F), and apparent volume of distribution (Vd/F) were 1.9 ± 0.8 1/h, 0.07±0.017 1/h, 9.5±1.9h, 3.4±0.3L/h, and 48.7±11.5L, respectively, for Tac (0.1mg/kg), and, 3.04±0.8 1/h, 0.07±0.03 1/h, 11±6.5h, 1.05±0.29L/h, and 15±3.7L, respectively, for Rapa (0.05mg/kg). Simulations showed that intramuscular administration of 0.11 ± 0.03 mg/kg of Tac and 0.023±0.007 mg/kg of Rapa at 24 h intervals to minipigs weighing 21-25 kg achieved target trough concentrations of 10-15 ng/mL. An intramuscular administration of Tac or/and Rapa was well tolerated with no systemic adverse effects. CONCLUSION: Pharmacokinetic analysis of Tac and Rapa in minipigs has been performed. A dosage regimen that is administered according to human VCA protocols, is not appropriate for minipigs due to inter-species variability in the pharmacokinetics of Tac and Rapa. A dosage regimen that achieves target trough drug concentrations in minipigs was determined for an optimal immunosuppression and without drug related side effects.

Source: Plastic & Reconstructive Surgery Global Open

DOI: 10.1097/01.gox.0000938356.27509.9a