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Pharmacokinetics of Rapamycin and Tacrolimus in A Large Animal Model of Vascularized Composite Allotransplantation
Firuz Feturi, Pharm1, Deokyeol Kim, MD2, Tarek Elgendy, MD3, Matthias Waldner, MD2, Wensheng Zhang, MD, PhD2, Alan Zahorchak, PhD2, Mohamed Ezzelarab, MD3, Angus Thomson, PhD3, Raman Venkataramanan, PhD1,4§, Mario Solari, MD2§
University of Pittsburgh
2018-02-15
Presenter: Firuz Feturi, PhD
Affidavit:
I certify that Firuz Feturi is a fellow in plastic surgery at UPMC
Director Name: Mario Solari, MD
Author Category: Fellow Plastic Surgery
Presentation Category: Basic Science Research
Abstract Category: General Reconstruction
Purpose
Minipigs are currently used as large animal model for studies of vascularized composite allotransplantation due to their physiologic, immunologic, and anatomic similarities to humans. Rapamycin (RAPA) and tacrolimus (TAC) are commonly used immunosuppressants to prevent rejection. Pharmacokinetic (PK) parameters of TAC and RAPA in minipigs have not been reported. This study sought to determine an appropriate dosage regimen that achieves target drug exposures for an optimal immunosuppression using PK approach.
Method
Minipigs (n=3) with vertical rectus abdominis myocutaneous flap received a single intramuscular (I.M) dose of RAPA or TAC (0.05 and 0.1 mg/kg), and underwent 24-hour whole blood PK sampling. Additionally, daily I.M doses were administered for 7 days with blood troughs being collected on days 3, 5, and 7. TAC and RAPA levels were analyzed by UPLC-MS-MS. PK parameters were derived from noncompartmental analysis.
Results
Peak C max (72±17 and 23±4ng/ml) and trough C min (7±1.3 and 2.9±1.9ng/ml) blood levels, area under the curves AUC0-α (530±71 and 229±140 ng.h/ml), half-life T1/2 (7±1.3 and 8±1.7 h), clearance CL (2.3±1.17 and 5.4±3.4 l/h), and volume of distribution Vd (31.4±15 and 77.5±50 l) were determined for TAC and RAPA, and maintenance doses M.D of RAPA and TAC for trough levels of 10–15 ng/ml were estimated.
Conclusion
RAPA and TAC are low clearance drugs in minipigs. The half-life indicates twice a day or once a day dosing of these drugs in minipigs. A dosage regimen of 0.11±0.028/kg/day for TAC and 0.13±0.02 mg/kg/day for RAPA will maintain levels in therapeutic range.
