Abstract
Purpose
Everolimus is a drug used successfully in a number of different oncology indications, but significant on-target toxicities exist. We explored the possibility of improving the therapeutic index (TI) by studying alternative means of administering the drug based upon low continuous dosing.
Methods
All studies were performed using naïve nude mice or nude mice bearing s.c. human renal 786-O tumours or human breast MDA-MB-468 tumours. Everolimus was administered via a standard emulsion, either i.v., p.o., i.p., s.c., or via s.c. osmotic mini-pumps (MP) or via poly-lactic-co-glycolic (PLGA)-microparticles (PLGA-µP) prepared from everolimus powder injected s.c. Total-drug levels in blood, plasma or tissues were quantified ex vivo by LC–MS/MS. Efficacy studies were performed over 2–3 weeks and toxicity assessed by changes in body weight, glucose and white blood cell count. Effects on tumour activity biomarkers were quantified using reverse-phase protein array.
Results
Everolimus administration s.c. in an emulsion decreased the absorption rate but increased the C max and bio-availability of everolimus compared to standard approaches of administration p.o. or i.p. Everolimus administration s.c. via MP or PLGA-µP reduced the C max and provided continuous low concentrations of everolimus in the plasma, which inhibited tumour pS6/S6 to a similar degree to oral administration. Toxicities such as changes in body weight or white blood cell count were unaffected. Provided the everolimus concentration was above the free unbound IC50 for proliferation of the tumour cell line, efficacy could be achieved equivalent to that provided by standard oral administration. However, an overall improvement in the TI could not be demonstrated.
Conclusions
Continuous low plasma concentrations of everolimus can provide strong efficacy in preclinical models, which if translatable to the clinic may reduce on-target toxicities and so increase the TI.
References
Lebwohl D, Anak O, Sahmoud T, Klimovsky J, Elmroth I, Haas T, Posluszny J, Saletan S, Berg W (2013) Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases. Ann NY Acad Sci 1291:14–32
Tanaka C, O’Reilly T, Kovarik JM, Shand N, Hazell K, Judson I, Raymond E, Zumstein-Mecker S, Stephan C, Boulay A, Hattenberger M, Thomas G, Lane HA (2008) Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 26:1596–1602
O’Donnell A, Faivre S, Burris HA 3rd, Rea D, Papadimitrakopoulou V, Shand N, Lane HA, Hazell K, Zoellner U, Kovarik JM, Brock C, Jones S, Raymond E, Judson I (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26:1588–1595
Ravaud A, Urva SR, Grosch K, Cheung WK, Anak O, Sellami DB (2014) Relationship between everolimus exposure and safety and efficacy: meta-analysis of clinical trials in oncology. Eur J Cancer 50:486–495
Thiery-Vuillemin A, Mouillet G, Nguyen Tan Hon T, Montcuquet P, Maurina T, Almotlak H, Stein U, Montange D, Foubert A, Nerich V, Pivot X, Royer B (2014) Impact of everolimus blood concentration on its anti-cancer activity in patients with metastatic renal cell carcinoma. Cancer Chemother Pharmacol 73:999–1007
de Wit D, Schneider TC, Moes DJ, Roozen CF, den Hartigh J, Gelderblom H, Guchelaar HJ, van der Hoeven JJ, Links TP, Kapiteijn E, van Erp NP (2016) Everolimus pharmacokinetics and its exposure-toxicity relationship in patients with thyroid cancer. Cancer Chemother Pharmacol 78:63–71
Patel JK, Kobashigawa JA (2006) Everolimus: an immunosuppressive agent in transplantation. Expert Opin Pharmacother 7:1347–1355
Deppenweiler M, Falkowski S, Saint-Marcoux F et al (2017) Towards therapeutic drug monitoring of everolimus in cancer? Results of an exploratory study of exposure-effect relationship. Pharmacol Res 121:138–144
Tabernero J, Rojo F, Calvo E et al (2008) 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 26:1603–1610
FDA (2003) Guidance for industry: exposure-response relationships, p. 14. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064982.htm. Accessed 03 Aug 2017
Aapro M, Andre F, Blackwell K et al (2014) Adverse event management in patients with advanced cancer receiving oral everolimus: focus on breast cancer. Ann Oncol 25:763–773
Shi J, Kantoff PW, Wooster R, Farokhzad OC (2017) Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 17:20–37
Smith DA, Di L, Kerns EH (2010) The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov 9:929–939
Petersen H, Bizec JC, Schuetz H, Delporte ML (2011) Pharmacokinetic and technical comparison of Sandostatin® LAR® and other formulations of long-acting octreotide. BMC Res Notes 9:344
O’Reilly T, McSheehy PM, Kawai R, Kretz O, McMahon L, Brueggen J, Bruelisauer A, Gschwind HP, Allegrini PR, Lane HA (2010) Comparative pharmacokinetics of RAD001 (everolimus) in normal and tumor-bearing rodents. Cancer Chemother Pharmacol 65:625–639
Royce ME, Osman D (2015) Everolimus in the treatment of metastatic breast cancer. Breast Cancer Basic Clin Res 9:73–79
O’Reilly T, McSheehy PM (2010) Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): Processes, limitations, and further proposals. Transl Oncol 3:65–79
O’Reilly T, Wartmann M, Brueggen J et al (2008) Pharmacokinetic profile of the microtubule stabilizer patupilone in tumor-bearing rodents and comparison of anti-cancer activity with other MTS in vitro and in vivo. Cancer Chemother Pharm 62:1045–1054
Tunçay M, Caliş S, Kaş HS, Ercan MT, Peksoy I, Hincal AA (2000) Diclofenac sodium incorporated PLGA (50:50) microspheres: formulation considerations and in vitro/in vivo evaluation. Int J Pharm 195:179–188
Pacifici GM, Viani A (1992) Methods of determining plasma and tissue binding of drugs. Clin Pharmacokinet 23:449–468
Pawlak M, Schick E, Bopp MA, Schneider MJ, Oroszlan P, Ehrat M (2002) Zeptosens’ protein microarrays: a novel high performance microarray platform for low abundance protein analysis. Proteomics 2:383–393
van Oostrum J, Calonder C, Rechsteiner D, Ehrat M, Mestan J, Fabbro D, Voshol H (2009) Tracing pathway activities with kinase inhibitors and reverse phase protein arrays. Proteom Clin Appl 3:412–422
Lane HA, Wood JM, McSheehy PM et al (2009) mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res 15:1612–1622
Apryshkina O, Manukyants A, Romen F, Elzenga C, Collins L, Morgan (2015) Everolimus novartis investigator’s brochure, edn 14. Tables 5.2 and 5.3, p. 65
O’Reilly T, McSheehy PM, Wartmann M, Lassota P, Brandt R, Lane HA (2011) Evaluation of the mTOR inhibitor, everolimus, in combination with cytotoxic antitumor agents using human tumor models in vitro and in vivo. Anticancer Drugs 22:58–78
Acknowledgements
It is a pleasure to thank Dr Michael Jensen for the provision of in vivo facilities, and Dr. Terry O’Reilly for statistical advice.
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All procedures involving animals were conducted in strict adherence to the Swiss law for animal care and handling.
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All authors are employees and/or share-holders of Novartis.
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Laborde, L., Oz, F., Ristov, M. et al. Continuous low plasma concentrations of everolimus provides equivalent efficacy to oral daily dosing in mouse xenograft models of human cancer. Cancer Chemother Pharmacol 80, 869–878 (2017). https://doi.org/10.1007/s00280-017-3407-5
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DOI: https://doi.org/10.1007/s00280-017-3407-5