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Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers

Frank Stifft, Floris Vanmolkot, Ingrid Scheffers, Lucas Van Bortel, Cees Neef and Maarten Christiaans (2014) BRITISH JOURNAL OF CLINICAL PHARMACOLOGY. 78(5). p.996-1004
abstract
Aims: The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. Methods: Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3mg of powder obtained from oral capsules was applied under the tongue for a period of 15min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15mg of the oral powder was used. Oral administration consisted of 7mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. Results: Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. Conclusions: Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
pharmacokinetics, therapeutic drug monitoring, tacrolimus, novel formulation, LIVER-TRANSPLANT RECIPIENT, MULTIDRUG-RESISTANCE GENE, P-GLYCOPROTEIN, CLINICAL PHARMACOKINETICS, CYTOCHROME-P450 3A, EXPRESSION, ABSORPTION
journal title
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Br. J. Clin. Pharmacol.
volume
78
issue
5
pages
996 - 1004
Web of Science type
Article
Web of Science id
000344222100007
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
3.878 (2014)
JCR rank
46/255 (2014)
JCR quartile
1 (2014)
ISSN
0306-5251
DOI
10.1111/bcp.12420
language
English
UGent publication?
no
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
5836861
handle
http://hdl.handle.net/1854/LU-5836861
date created
2015-02-03 14:55:17
date last changed
2016-12-19 15:42:57
@article{5836861,
  abstract     = {Aims: The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. 
Methods: Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3mg of powder obtained from oral capsules was applied under the tongue for a period of 15min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15mg of the oral powder was used. Oral administration consisted of 7mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. 
Results: Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78\%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. 
Conclusions: Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered.},
  author       = {Stifft, Frank and Vanmolkot, Floris and Scheffers, Ingrid and Van Bortel, Lucas and Neef, Cees and Christiaans, Maarten},
  issn         = {0306-5251},
  journal      = {BRITISH JOURNAL OF CLINICAL PHARMACOLOGY},
  keyword      = {pharmacokinetics,therapeutic drug monitoring,tacrolimus,novel formulation,LIVER-TRANSPLANT RECIPIENT,MULTIDRUG-RESISTANCE GENE,P-GLYCOPROTEIN,CLINICAL PHARMACOKINETICS,CYTOCHROME-P450 3A,EXPRESSION,ABSORPTION},
  language     = {eng},
  number       = {5},
  pages        = {996--1004},
  title        = {Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers},
  url          = {http://dx.doi.org/10.1111/bcp.12420},
  volume       = {78},
  year         = {2014},
}

Chicago
Stifft, Frank, Floris Vanmolkot, Ingrid Scheffers, Lucas Van Bortel, Cees Neef, and Maarten Christiaans. 2014. “Rectal and Sublingual Administration of Tacrolimus: a Single-dose Pharmacokinetic Study in Healthy Volunteers.” British Journal of Clinical Pharmacology 78 (5): 996–1004.
APA
Stifft, F., Vanmolkot, F., Scheffers, I., Van Bortel, L., Neef, C., & Christiaans, M. (2014). Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 78(5), 996–1004.
Vancouver
1.
Stifft F, Vanmolkot F, Scheffers I, Van Bortel L, Neef C, Christiaans M. Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY. 2014;78(5):996–1004.
MLA
Stifft, Frank, Floris Vanmolkot, Ingrid Scheffers, et al. “Rectal and Sublingual Administration of Tacrolimus: a Single-dose Pharmacokinetic Study in Healthy Volunteers.” BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 78.5 (2014): 996–1004. Print.