Determining Equivalence Dose for Oral Versus Sublingual Administration of Tacrolimus in Hepatic Receptors

Evidence of Liver Transplantation Clinical Trial

— FKosl  

Official title:

Determining Equivalence Dose for Oral Versus Sublingual Administration of Tacrolimus in Hepatic Receptors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02608606
• Other study ID #: FKoral-sl
• Status: Completed
• Phase: N/A
• First received: November 3, 2015
• Last updated: October 10, 2016
• Start date: March 2015
• Est. completion date: March 2016

Study information

• Verified date: October 2016
• Source: Pontificia Universidad Catolica de Chile
• Contact: n/a
• Is FDA regulated: No
• Health authority: Chile: Comité de Ética Científico
• Study type: Interventional

Clinical Trial Summary

After liver transplantation one of the most important cost, for both patients and their health insurance system, is immunosuppressive drug therapy. Tacrolimus (FK 506) is considered the cornerstone of immunosuppressive therapy in solid organ transplantation. Oral administration is the usual route, however, sublingual (SL) administration has been recently reported. This method of administration avoids first pass metabolism and allows an alternative route after transplant surgery, particularly in those patients who should extend the period of fasting (prolonged intubation, ileus, etc). Interestingly, in some studies, the dose of tacrolimus SL required to maintain similar plasma concentrations compared with oral administration, is significantly lower, even up to 50%, which can result in considerable savings in short and long term. Among these studies, only one was conducted in liver recipients. This study suggest that SL administration of tacrolimus could allow to obtain similar concentrations compared with oral administration. The design of this study did not assess the existence of differences in the dose required and only included six patients.

Description:

The patient will be scheduled fasting to liver transplant unit where the pharmacokinetic study was performed. After installation of the venous needle, blood samples will be collected on 4 ml tubes with EDTA as an anticoagulant at the following intervals of time in hours: 0 (immediately before the oral administration of tacrolimus); 0.5; 1.0; 1.5; 2; 4; 6; 9 and 12 h. post-dose. Once the blood samples taken, the tubes will be plugged, invest gently to mix with anticoagulant and stored at -20 ° C until analysis.

Subsequently, tacrolimus administration was change to sublingual route and dose was adjusted to obtain similar trough levels to those determined on per oral administration. The capsule be opened and its contents shall be deposited in the sublingual mucosa. To be ensure that drug will be absorted the patient will be instructed to insistently that after sublingual placement of the drug, should not swallow the capsule content for at least 15 minutes. The same pharmacokinetic study described for the oral route will be performed.

Breakfast will be administered 2 hours after ingesting the drug and lunch and dinner 6 and 10 hours after respectively. Fluid intake is discretionary.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: March 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Outline of immunosuppression that includes tacrolimus dosing every 12 hours.

• Stable plasma levels of tacrolimus in 3 consecutive measurements.

• Stable blood tests: biochemical profile, creatinine and liver profile.

• Absence of treatment with drugs that have interaction with tacrolimus (antifungal and diltiazem) and use of grapefruit juice.

• Absence of active bacterial or viral infection and rejection episodes within 8 weeks prior.

Exclusion Criteria:

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Effects of Immunosuppressant Therapy
• Evidence of Liver Transplantation

Intervention

Drug:
• Tacrolimus
compared oral administration versus sublingual administration of tacrolimus.

Locations

Country	Name	City	State
Chile	Pontificia Universidad Catolica de Chile	Santiago

Sponsors (1)

Lead Sponsor	Collaborator
Pontificia Universidad Catolica de Chile

Country where clinical trial is conducted

Chile, 

References & Publications (11)

Agopian VG, Petrowsky H, Kaldas FM, Zarrinpar A, Farmer DG, Yersiz H, Holt C, Harlander-Locke M, Hong JC, Rana AR, Venick R, McDiarmid SV, Goldstein LI, Durazo F, Saab S, Han S, Xia V, Hiatt JR, Busuttil RW. The evolution of liver transplantation during 3 — View Citation

Collin C, Boussaud V, Lefeuvre S, Amrein C, Glouzman AS, Havard L, Billaud EM, Guillemain R. Sublingual tacrolimus as an alternative to intravenous route in patients with thoracic transplant: a retrospective study. Transplant Proc. 2010 Dec;42(10):4331-7. — View Citation

Nasiri-Toosi Z, Dashti-Khavidaki S, Nasiri-Toosi M, Khalili H, Jafarian A, Irajian H, Abdollahi A, Sadrai S. Clinical pharmacokinetics of oral versus sublingual administration of tacrolimus in adult liver transplant recipients. Exp Clin Transplant. 2012 D — View Citation

Rabkin JM, Corless CL, Rosen HR, Olyaei AJ. Pharmacoeconomic study of tacrolimus-based versus cyclosporine-based immunosuppressive therapy following liver transplantation. Transplant Proc. 2001 Feb-Mar;33(1-2):1532-4. — View Citation

Reams BD, Palmer SM. Sublingual tacrolimus for immunosuppression in lung transplantation: a potentially important therapeutic option in cystic fibrosis. Am J Respir Med. 2002;1(2):91-8. Review. — View Citation

Reams D, Rea J, Davis D, Palmer S. Utility of sublingual tacrolimus in cystic fibrosis patients after lung transplantation. J Heart Lung Transplant. 2001 Feb;20(2):207-208. — View Citation

Romero I, Jiménez C, Gil F, Escuin F, Ramirez E, Fudio S, Borobia A, Carcas A. Sublingual administration of tacrolimus in a renal transplant patient. J Clin Pharm Ther. 2008 Feb;33(1):87-9. doi: 10.1111/j.1365-2710.2008.00884.x. — View Citation

Srinarong P, Pham BT, Holen M, van der Plas A, Schellekens RC, Hinrichs WL, Frijlink HW. Preparation and physicochemical evaluation of a new tacrolimus tablet formulation for sublingual administration. Drug Dev Ind Pharm. 2012 Apr;38(4):490-500. doi: 10.3 — View Citation

Tsapepas D, Saal S, Benkert S, Levine D, Delfin M, Cremers S, Amann S, Dadhania D, Kapur S, Aull M. Sublingual tacrolimus: a pharmacokinetic evaluation pilot study. Pharmacotherapy. 2013 Jan;33(1):31-7. doi: 10.1002/phar.1149. — View Citation

van de Plas A, Dackus J, Christiaans MH, Stolk LM, van Hooff JP, Neef C. A pilot study on sublingual administration of tacrolimus. Transpl Int. 2009 Mar;22(3):358-9. doi: 10.1111/j.1432-2277.2008.00779.x. Epub 2008 Oct 30. — View Citation

Watkins KD, Boettger RF, Hanger KM, Leard LE, Golden JA, Hoopes CW, Singer JP. Use of sublingual tacrolimus in lung transplant recipients. J Heart Lung Transplant. 2012 Feb;31(2):127-32. doi: 10.1016/j.healun.2011.10.015. Epub 2011 Dec 16. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Compare tacrolimus exposure using per oral and sublingual administration employing AUC (Area Under the Curve).	compared oral administration versus sublingual administration of tacrolimus	30 days	Yes
Secondary	Compare tacrolimus dose necessary to obtain similar trough levels employing per oral and sublingual administration	compared oral administration versus sublingual administration of tacrolimus	30 days	Yes