Effects of Hepatic Impairment on the Pharmacokinetics of Everolimus: A Single-Dose, Open-Label, Parallel-Group Study

Clinical Therapeutics

Volumn 35, Issue 3, 2013, Pages 215-225

  Peveling Oberhag, Jan ^a   Zeuzem, Stefan ^a   Yong, Wei Peng ^b   Kunz, Tiffany ^c   Paquet, Thierry ^c   Bouillaud, Emmanuel ^c   Urva, Shweta ^c   Anak, Oezlem ^c   Sellami, Dalila ^c   Kobalava, Zhanna ^d  

^a UNIVERSITY HOSPITAL FRANKFURT   (Germany)

^b National University Cancer Institute   (Singapore)

^c NOVARTIS PHARMA AG   (Switzerland)

^d PEOPLES FRIENDSHIP UNIVERSITY OF RUSSIA   (Russian Federation)

Author keywords

Healthy subjects; Hepatic impairment; Molecular therapeutics; Pharmacokinetics

Indexed keywords

ALBUMIN; BILIRUBIN; EVEROLIMUS;

ADULT; AGED; AREA UNDER THE CURVE; ARTICLE; BLOOD SAMPLING; CHILD PUGH SCORE; CLINICAL ARTICLE; CONFIDENCE INTERVAL; CONTROLLED STUDY; DOSE CALCULATION; DRUG DOSE REDUCTION; DRUG EXPOSURE; DRUG HYPERSENSITIVITY; DRUG SAFETY; FEMALE; HUMAN; INTERNATIONAL NORMALIZED RATIO; LIVER DYSFUNCTION; LIVER FUNCTION; MALE; MULTICENTER STUDY; PHASE 1 CLINICAL TRIAL; POST HOC ANALYSIS; SINGLE DRUG DOSE; VOLUNTEER;

ADULT; AREA UNDER CURVE; FEMALE; HUMANS; IMMUNOSUPPRESSIVE AGENTS; LIVER; MALE; MIDDLE AGED; SIROLIMUS;

EID: 84874979447     PISSN: 01492918     EISSN: 1879114X     Source Type: Journal    
DOI: 10.1016/j.clinthera.2013.02.007     Document Type: Article

References (20)

1. Houghton P.J. Everolimus. Clin Cancer Res 2010, 16:1368-1372.
2. Bjornsti M.A., Houghton P.J. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004, 4:335-348.
3. Menon S., Manning B.D. Common corruption of the mTOR signaling network in human tumors. Oncogene 2008, 27(Suppl 2):S43-S51.
4. Meric-Bernstam F., Gonzalez-Angulo A.M. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009, 27:2278-2287.
5. Faivre S., Kroemer G., Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006, 5:671-688.
6. Motzer R.J., Escudier B., Oudard S., et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010, 116:4256-4265.
7. Yao J.C., Shah M.H., Ito T., et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011, 364:514-523.
8. Baselga J., Campone M., Piccart M., et al. Everolimus in postmenopausal hormone receptor-positive advanced breast cancer. N Engl J Med 2012, 366:520-529.
9. Franz D.N., Belousova E., Sparagna S., et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013, 381:125-132.
10. Bissler J.J., Kingswood J.C., Radzikowska E., et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicenter, randomized, double-blind, placebo-controlled trial. Lancet 2013 Jan 10, [Epub ahead of print]. 10.1016/S0140-6736(12)61767-X.
11. Kirchner G.I., Meier-Wiedenbach I., Manns M.P. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet 2004, 43:83-95.
12. Kovarik J.M., Sabia H.D., Figueiredo J., et al. Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment. Clin Pharmacol Ther 2001, 70:425-430.
13. O'Donnell A., Faivre S., Burris H.A., et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008, 26:1588-1595.
14. Tabernero J., Rojo F., Calvo E., et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008, 26:1603-1610.
15. Okamoto I., Doi T., Ohtsu A., et al. Phase I clinical and pharmacokinetic study of RAD001 (everolimus) administered daily to Japanese patients with advanced solid tumors. Jpn J Clin Oncol 2010, 40:17-23.
16. Jacobsen W., Serkova N., Hausen B., et al. Comparison of the in vitro metabolism of the macrolide immunosuppressants sirolimus and RAD. Transplant Proc 2001, 33:514-515.
17. Guidance for industry: pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling, 2003 US Food and Drug Administration (FDA), Accessed December 19, 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072123.pdf.
18. Guideline on evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function, 2005 European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), Accessed December 19, 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003122.pdf.
19. Guidance for industry: bioanalytical method validation, 2001 US Department of Health and Human Services, Food and Drug Administration (FDA), Accessed December 19, 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf.
20. Afinitor (everolimus) tablets for oral administration [prescribing information] 2012, Novartis Pharmaceuticals Corporation, East Hanover, NJ.