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Pharmacokinetics and Biodistribution of Tacrolimus after Topical Administration: Implications for Vascularized Composite Allotransplantation

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Abstract

Aim

The high doses of oral tacrolimus (TAC) (1,2) necessary to prevent acute rejection (AR) after vascularized composite allotransplantation (VCA) are associated with systemic adverse effects. The skin is the most antigenic tissue in VCA and the primary target of AR. However, the short-term use of topical TAC (Protopic®), as an off-label adjunct to oral TAC, to treat AR episodes pro re nata (PRN), has yielded inconsistent results. There is lack of data on the pharmacokinetics and tissue distribution of topical TAC in VCA, that hampers our understanding of the reasons for unreliable efficacy. Toward this goal, we evaluated the ability of topical TAC to achieve high local tissue concentrations at the site of application with low systemic concentrations.

Materials and Methods

We assessed the pharmacokinetics and tissue distribution of topical TAC (Protopic®, 0.03%) after single or repeated topical application in comparison to those after systemic delivery in rats. Animals received a single topical application of TAC ointment (Group 1) or an intravenous (IV) injection of TAC (Group 2) at a dose of 0.5 mg/kg. In another experiment, animals received daily topical application of TAC ointment (Group 3), or daily intraperitoneal (IP) injection of TAC (Group 4) at a dose of 0.5 mg/kg for 7 days. TAC concentrations in blood and tissues were analyzed by Liquid Chromatography–Mass Spectrometry (LC/MS-MS).

Results

Following single topical administration, TAC was absorbed slowly with a Tmax of 4 h and an absolute bioavailability of 11%. The concentrations of TAC in skin and muscle were several folds higher than whole blood concentrations. Systemic levels remained subtherapeutic (< 3 ng/ml) with repeated once daily applications.

Conclusion

Topical application of TAC ointment (Protopic®, 0.03%) at a dose of 0.5 mg/kg/day provided high concentrations in the local tissues with low systemic exposure. Repeated topical administration of TAC is well tolerated with no local or systemic adverse effects. This study confirms the feasibility of topical application of TAC for site specific graft immunosuppression and enables future applications in VCA.

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Funding

This study was supported by extramural funding from the American Society of Surgery of the Hand (Award # 0043416) and intramural support from the Department of Pharmaceutical Sciences, Department of Plastic Surgery, University of Pittsburgh.

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Author notes

  1. Vijay S. Gorantla and Raman Venkataramanan contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Room 4103, PTC 700 Technology Drive, Pittsburgh, Pennsylvania, 15219, USA

    Firuz G. Feturi & Raman Venkataramanan

  2. Department of Plastic and Reconstructive Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Jonas T. Schnider, Paolo M. Fanzio, Jignesh M. Unadkat, Alexander M. Spiess & Mario G. Solari

  3. Department of Plastic, Reconstructive and Aesthetic Surgery, Gulhane Military Medical Academy, Ankara, Turkey

    Vasil E. Erbas

  4. Department of Plastic, Reconstructive and Aesthetic Surgery, Medicalpark Gaziantep Hospital, Gaziantep, Turkey

    Sinan Oksuz

  5. Private Cagsu Hospital, Duzce, Turkey

    Huseyin Sahin

  6. Plastic and Aesthetic Surgery Department, XiJing Hospital, Xi’an, Shaanxi, China

    Liwei Dong

  7. Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland

    Jan A. Plock

  8. Departments of Surgery, Ophthalmology and Bioengineering, Wake Forest Baptist Medical Center, Wake Forest Institute for Regenerative Medicine, Richard H. Dean Biomedical Building, Suite 333, 391 Technology Way, Winston-Salem, North Carolina, 27101, USA

    Vijay S. Gorantla

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  1. Firuz G. Feturi
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Contributions

Overall research idea (VG); conceptual approach, hypothesis (VG, RV, FF); experimental design (FF, VG, RV, MS); protocol development (FF, RV, VG); In vivo experiments and collection of data (FF, JS, PF, VE, SO, HS and LD); Tissue processing for drug level measurement (FF); Manuscript drafting (FF), Extensive manuscript editing (RV, VG), Additional input (MS, AS, JP, JU); Analysis of data and interpretation of results (RV, VG, FF, MS);. All authors read and approved the manuscript.

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Correspondence to Vijay S. Gorantla or Raman Venkataramanan.

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Vijay S. Gorantla and Raman Venkataramanan are the Co-Corresponding Authors

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Feturi, F.G., Schnider, J.T., Fanzio, P.M. et al. Pharmacokinetics and Biodistribution of Tacrolimus after Topical Administration: Implications for Vascularized Composite Allotransplantation. Pharm Res 37, 222 (2020). https://doi.org/10.1007/s11095-020-02921-w

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