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Repeat-dose sirolimus pharmacokinetics and pharmacodynamics in patients with hepatic allografts

  • Pharmacodynamics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To determine sirolimus steady-state pharmacokinetics, and to assess the relationship between time-normalized trough sirolimus concentration (Cmin,TN) and evidence of efficacy (rejection and death) and adverse reactions (stomatitis and pneumonia) in liver allograft patients.

Methods

Dense sampling of sirolimus was performed over a single daily-dosing interval in 11 hepatic allograft recipients on day 28 and at 3 months after start of treatment. Serial trough concentration sampling was performed in 380 hepatic allograft recipients on days 1, 7, 14, 28, 42, 60, 90, 180, 270 and 360 after start of treatment. Occurrence of stomatitis, pneumonia, rejection, and death were collected for 360 days after start of treatment. Noncompartmental pharmacokinetic parameters were analyzed in the 11 densely sampled patients; Cmin,TN was determined in the 380 patients.

Results

Mean maximum concentration (Cmax), time to Cmax (tmax), area under the curve for the given dose interval (AUCtau), and whole blood oral clearance at 3 months were 20.8 ± 7.6 ng/mL, 3 ± 1 h, 338 ± 144 ng·h/mL, and 10.0 ± 5.6 L/hr, respectively. In the 11 densely sampled patients, linear regression showed that Cmin,TN was highly predictive of AUCtau (r2 = 0.77, P < 0.0001) at each analysis time point. Logistic regression showed a relationship between Cmin,TN in the 380 patients and pneumonia occurrence, but not between Cmin,TN and stomatitis, rejection, or death.

Conclusions

In this study, the pharmacokinetic profile of sirolimus in hepatic allograft patients was consistent with that of renal transplantation recipients. With the exception of pneumonia, no correlation was observed between Cmin,TN and the occurrence of adverse events of interest.

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Abbreviations

ANOVA:

Analysis of variance

AUC:

Area under the concentration–time curve

AUCtau :

Area under the curve for the given dose interval

CI:

Confidence interval

Cmax :

Maximum concentration

Cmin,TN :

Time-normalized trough concentration

CNI:

Calcineurin inhibitor

OR:

Odds ratio

tmax :

Time to maximum concentration

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Acknowledgements

We thank the patients and their families, the study nurses, and clinical staff who cared for patients while in the trial, and the study coordinators, research support staff, and research and data management personnel for their participation in this study. We gratefully acknowledge Roberto J. Firpi-Morell of the University of Florida for assuming the role of principal investigator from February 2006 to completion. We also thank Albert Balkiewicz, MSc, of Peloton Advantage for medical writing and editorial assistance, and Pfizer Inc, which provided funding for editorial/medical writing support of this manuscript through Peloton Advantage, LLC.

We would like to recognize the following investigators (listed alphabetically) and their study centers for participation in this trial as members of the Sirolimus Liver Conversion Trial Study Group:

Manal Abdelmalek, University of Florida, Gainesville, FL, USA; Angel Alsina, LifeLink HealthCare Institute, Tampa, Florida, USA; Pietro Andreone, University of Bologna, Bologna, Italy; Prabhakar Baliga, Medical University of South Carolina, Charleston, SC, USA; Rafael Bárcena, Hospital Ramón y Cajal, Madrid, Spain; David S. Barnes, Cleveland Clinic, Cleveland, OH, USA; Eduardo Barroso, Hospital Curry Cabral, Lisbon, Portugal; Alex S. Befeler, Saint Louis University Health Sciences Center, St Louis, MO, USA; Itxarone Bilbao, Hospital Vall d’Hebrón, Barcelona, Spain; Karim Boudjema, Hôpital Pontchaillou, Rennes, France; Adel Bozorgzadeh, University of Rochester, Rochester, NY, USA; Matthew Brown, Hartford Hospital, Hortford, CT, USA; Erwin Buckel, Clínica Las Condes, Santiago, Chile; Yon Calmus, Hôpital Cochin, Paris, France; Luis Campos-de la Borbolla, University of Maryland Medical Center, Baltimore, MD, USA; Guido PC Cantisani, Irmandade Santa Casa de Misericórdia de Porte Alegre, Porto Alegre, Brazil; Pierre-Alain Clavien, UniversitätsSpital Zürich, Zurich, Switzerland; Davide D’Amico, Istituto di Clinical Chirurgica I, Universita degli Studi di Padova, Padova, Italy; Juan del Rio Martin, Mount Sinai School of Medicine, New York, NY, USA; Marcelo P de Miranda, Hepato Ltda, Paraíso, Brazil; Valeria Descalzi, Fundación Favaloro, Buenos Aires, Argentina; Francois Durand, Hôpital Beaujon, Clichy, France; Elmahdi Elkhammas, Ohio State University Medical Center, Columbus, OH, USA; Jonathan Fawcett, Princess Alexandria Hospital, Wooloongabba, Queensland, Australia; Roberto J. Firpi-Morell, University of Florida, Gainesville, FL, USA; Lutz Fischer, Universitätsklin Hamburg-Eppendorf, Hamburg, Germany; Adrian Gadano, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Edward Gane, Auckland City Hospital, Auckland, New Zealand; Alexander Gerbes, Ludwig-Maximilians-Universität München, Munich, Germany; John Goss, Baylor College of Medicine, Houston, TX, USA; Jean Gugenheim, CHU Nice-Hôpital de l’Archet, Nice, France; Jose I. Herrero, Unidad de Hepatologia, Pamplona, Spain; Abhinav Humar, University of Minnesota, Minneapolis, MN, USA; Oscar Imventarza, Hospital General de Agudos Dr. Cosme Argerich, Ciudad de Buenos Aires, Argentina; Robert McLaren Jones, Austin Health, Heidelberg, VIC, Australia; Ki H. Kim, Asan Medical Center, Seoul, Korea; Norman Kneteman, University of Alberta Hospital Site, Walter C. McKenzie Health Centre, Edmonton, AB, Canada; Baburao Koneru, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA; Suk-Koo Lee, Samsung Medical Center, Seoul, Korea; Josh Levitsky; Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Leslie Lilly, Toronto General Hospital, Toronto, ON, Canada; Alistair MacGilchrist, The Royal Infirmary of Edinburgh, Edinburgh, Scotland; John Magee, University of Michigan Medical Center, Ann Arbor, MI, USA; Martin L. Mai, Mayo Clinic Jacksonville, Jacksonville, FL, USA; Lo C. Mau, Queen Mary Hospital, Hong Kong; Vivian McAlister, London Health Sciences Centre, London, ON, Canada; Geoff W. McCaughan, Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Luis A. Mieles, University of Texas Medical School, Houston, TX, USA; Charles Millson, St James University Hospital, Leeds, UK; Maria C. Moerlli, Oespedale Policlinico S. Orsola-Malpighi, Bologna, Italy; Guy Neff, University of Cincinnati Medical Center (formerly University Internal Medicine), Cincinnati, OH, USA; Peter Neuhaus, Charité Universitätsmedizin Berlin, Berlin, Germany; Robert Osorio, California Pacific Medical Center, San Francisco, CA, USA; Robert Padbury, Flinders Medical Centre, Bedford Park, SA, Australia; Lee Po-Huang, Taiwan University Hospital, Taiwan, ROC; Elizabeth A. Pomfret, Lahey Clinic, Burlington, MA, USA; Martin Prieto, Hospital Universitario La Fe, Valencia, Spain; Emilio Ramos, Hospital de Bellvitge, Barcelona, Spain; Dinesh Ranjan, University of Kentucky Medical Center, Lexington, KY, USA; K. Rajender Reddy, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Paolo Reggiani, IRCCS Ospedale Maggiori di Milano, Milan, Italy; Antoni Rimola, Hospital Clinic I Provincial, Barcelona, Spain; John Roberts, University of California, San Francisco, San Francisco, CA, USA; Luis C. Rodriguez Sancho, The Guadalajara Public Hospital, Guadalajara, Jalisco, Mexico; Ephrem Salamé, Hôpital Côte de Nacre, Caen, France; Didier Samuel, Hôpital Paul Brousse, Villejuif, France; Charles Scudamore, British Columbia Transplant Society, Vancouver, BC, Canada; Surendra Shenoy, Washington University School of Medicine, St Louis, MO, USA; Linda Sher, University Hospital USC, Los Angeles, CA, USA; Marcelo O. Silva, Hospital Universitario Austral, Buenos Aires, Argentina; Nuno Silva, Hospitais da Universidade de Coimbra, Coimbra, Portugal; Debra L. Sudan, University of Nebraska Medical Center (formerly Organ Transplantation Center), Omaha, NE, USA; Louis W. Teperman, New York University Medical Center, New York, NY, USA; Douglas Thorburn, Queen Elizabeth Hospital, Birmingham, UK; Paul Thuluvath, The Johns Hopkins Hospital, Baltimore, MD, USA; Lorenzo Toselli, CRAI Norte, San Martin, Buenos Aires, Argentina; Bart van Hoek, Leiden University Medical Center, Leiden, The Netherlands; Hans van Vlierberghe, Allgemeines Krankenhaus der Stadt Wien, Wien, Austria; Evaristo Varo-Perez, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain; Michael Voigt, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Russell H. Wiesner, Mayo Clinic, Rochester, MN, USA; Atsushi Yoshida, Henry Ford Transplant Institute, Detroit, MI, USA.

Funding disclosure

This study was sponsored by Wyeth Research, which also provided financial support for medical writing and editorial assistance in the preparation of this manuscript. Wyeth was acquired by Pfizer Inc in October 2009. At the time of this study, Indranil Bhattacharya, Kyle Matschke, Eric Maller, and Joan Korth-Bradley were employees and stockholders of Wyeth. Jürg Reichen and Felix Stickel received no honoraria or other form of financial support related to the development of this manuscript and report no potential financial conflicts relevant to this manuscript.

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Authors and Affiliations

  1. University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital, Berne, Switzerland

    Jürg Reichen & Felix Stickel

  2. Pfizer Inc, 500 Arcola Road, Collegeville, PA, 19426, USA

    Indranil Bhattacharya, Kyle Matschke, Eric Maller & Joan Korth-Bradley

Authors
  1. Jürg Reichen
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  2. Felix Stickel
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  3. Indranil Bhattacharya
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  4. Kyle Matschke
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  5. Eric Maller
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  6. Joan Korth-Bradley
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Corresponding author

Correspondence to Joan Korth-Bradley.

Additional information

ClinicalTrials.gov identifier number: NCT00038948

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Reichen, J., Stickel, F., Bhattacharya, I. et al. Repeat-dose sirolimus pharmacokinetics and pharmacodynamics in patients with hepatic allografts. Eur J Clin Pharmacol 68, 589–597 (2012). https://doi.org/10.1007/s00228-011-1172-7

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  • DOI: https://doi.org/10.1007/s00228-011-1172-7

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