Arzneimittelforschung 2012; 62(04): 194-201
DOI: 10.1055/s-0031-1299772
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

The Observed Correlation between in vivo Clinical Pharmacokinetic Parameters and in vitro Potency of VEGFR-2 Inhibitors

Can this be used as a Prospective Guide for the Development of Novel Compounds?
B. Benjamin
1   Vanthys Pharmaceutical Development [P] Ltd., Phoenix Pinnacle, Ulsoor Road, Bangalore, India
,
M. Sahu
1   Vanthys Pharmaceutical Development [P] Ltd., Phoenix Pinnacle, Ulsoor Road, Bangalore, India
,
U. Bhatnagar
1   Vanthys Pharmaceutical Development [P] Ltd., Phoenix Pinnacle, Ulsoor Road, Bangalore, India
,
D. Abhyankar
1   Vanthys Pharmaceutical Development [P] Ltd., Phoenix Pinnacle, Ulsoor Road, Bangalore, India
,
N. R. Srinivas
1   Vanthys Pharmaceutical Development [P] Ltd., Phoenix Pinnacle, Ulsoor Road, Bangalore, India
› Author Affiliations
Further Information

Publication History

received 27 November 2011

accepted 22 December 2011

Publication Date:
30 January 2012 (online)

Abstract

Literature data on the clinical pharmacokinetics of various VEGFR-2 inhibitors along with in vitro potency data were correlated and a linear relationship was established in spite of limited data set. In this work, a model set comprised of axitinib, recentin, sunitinib, pazopanib, and sorafenib were used. The in vitro potencies of the model set compounds were correlated with the published unbound plasma concentrations (Cmax, Cavg, Ctrough). The established linear regression (r2>0.90) equation was used to predict Cmax, Cavg, Ctrough of the ‘prediction set’ (motesanib, telatinib, CP547632, vatalanib, vandetanib) using in vitro potency and unbound protein free fraction. Cavg and Ctrough of prediction set were closely matched (0.2–1.8 fold of reported), demonstrating the usefulness of such predictions for tracking the target related modulation and/or efficacy signals within the clinically optimized population average. In case of Cmax where correlation was least anticipated, the predicted values were within 0.1–1.1 fold of those reported. Such predictions of appropriate parameters would provide rough estimates of whether or not therapeutically relevant dose(s) have been administered when clinical investigations of novel agents of this class are being performed. Therefore, it may aid in increasing clinical doses to a desired level if safety of the compound does not compromise such dose increases. In conclusion, the proposed model may prospectively guide the dosing strategies and would greatly aid the development of novel compounds in this class.

 
  • References

  • 1 Bria E, Di Maio M, Carlini P et al. Targeting targeted agents: Open issues for clinical trial design. J Exp Clin Canc Res 2009; 28: 66
  • 2 Parulerkar WR, Eisenhauer EA. Phase 1 trial design for solid tumor studies of targeted non-cytotoxic agents: Theory and practice. J Nat Canc Inst 2004; 96: 990-997
  • 3 Folkman J. Tumor Angiogenesis: Therapeutic implications. New Eng J Med 1971; 285: 1182-1186
  • 4 Cebe-Suarez S, Fjallman ZA, Hofer BK. The Role of VEGF receptors in angiogenesis; Complex partnerships. Cell Mol Life Sci 2006; 63: 601-615
  • 5 Kuhnert F, Tam BYY, Sennino B et al. Soluble receptor-mediated selective inhibition of VEGFR and PDGFR beta signaling during physiologic and tumor angiogenesis. Proc Nat Acad Sci USA 2008; 105: 10185-10190
  • 6 Ma WW, Adjei AA. Novel agents on the horizon for cancer therapy. CA: A Canc J Clinicians 2009; 59: 111-137
  • 7 Fox E, Curt GA, Ballis FM. Clinical trial design for target-based therapy. The Oncologist 2002; 7: 401-409
  • 8 De Buck SS, Sinha VK, Fenu LA et al. Prediction of human pharmacokinetics using physiologically based Modeling: A retrospective analysis of 26 clinically tested drugs. Drug Metab Disp 2007; 35: 1766-1780
  • 9 Jain RK, Lee JJ, Hong D et al. . Phase 1 oncology studies: Evidence that in the era of targeted therapies, patients on lower doses do not fare worse. Clin Canc Res 2010; 16: 1289-1297
  • 10 Undevia SD, Gomez-Abuin G, Ratain MJ. Pharamcokinetic variability of anticancer agents. Nat Reviews Canc 2005; 5: 447-458
  • 11 Huang SR, Ratain MJ. Pharamcogenetics and Pharmacogenomics of anticancer agents. CA: A Canc J Clinicians 2009; 59: 42-55
  • 12 Scripture CD, Figg WD. Drug interactions In cancer therapy. Nat Rev Canc 2006; 6: 546-558
  • 13 Yu Dk. The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions. J Clin Pharmacol 1999; 39: 1203-1211
  • 14 Strumberg D, Schultheis B, Adamietz IA et al. Phase I dose escalation study Of telatinib (BAY 57-9352) in patients with advanced solid tumours. Br J Canc 2008; 99: 1579-1585
  • 15 Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 2009; 6: 465-477
  • 16 Liebler DC, Guengerich FP. Elucidating mechanisms of drug-induced toxicity. Nat Rev Drug Discov 2005; 4: 410-420
  • 17 Karamen MW, Herrgard S, Treiber DK et al. A quantitative analysis Of kinase inhibitor selectivity. Nat Biotech 2008; 26: 127-132
  • 18 Kumar R, Crouthamel MC, Rominger DH et al. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Canc 2009; 101: 1717-1723
  • 19 GENENTEC. fda.gov [Online]; 2009 [cited 2010 August 31. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0168lbl.pdf
  • 20 Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irnotican, fluorouracil and leucovorin for metastatic colorectal cancer. New Eng J Med 2004; 350: 2335-2342
  • 21 Lind JSW, Smit EF. Angiogenesis inhibitors in the treatment of non small cell lung cancer. Ther Ad Med Oncol 2009; 1: 95-107
  • 22 Adjei AA. Novel small molecule inhibitors of the Vascular Endothelial Growth Factor Receptor. Clin Lung Canc 2007; 8: S74-S78
  • 23 Ma J, Waxman DJ. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol Canc Ther 2008; 3670-3684
  • 24 Rugo HS, Herbst RS, Liu G et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: Pharmacokinetic and clinical results. J Clin Oncol 2005; 23: 5474-5483
  • 25 Tortorici MA, Toh M, Rahavendran SV et al. Investigational New Drugs: Open Access. [Online]; 2010 DOI: 10.1007/s10637-010-9477-4 Available from http://www.springerlink.com/content/p56k6qn636l24067/fulltext.html
  • 26 Dana D, Zou HY, Grazzini ML et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of Vascular Endothelial Growth Factor Receptor tyrosine kinases 1,2,3. Clin Canc Res 2008; 14: 7272-7283
  • 27 Drevs J, Siegert P, Medinger M et al. Phase I Clinical Study of AZD2171, an oral vascular Endothelial Growth Factor signaling inhibitor, in patients with advanced solid tumors. J Clinl Oncol 2007; 25: 3045-3054
  • 28 Radiation Therapy Oncology group, American College of Radiology . Randomnized, Phase II, Double Blinded, Placebo-Controlled Trial of Conventional Chemoradiation and Adjuvant Temozolomide Plus Cediranib Versus Conventional Chemoradiation and Adjuvant Temozolomide Plus Placebo in Patients With Newly Diagnosed Glioblastoma.. 2010;
  • 29 Stephen RW, Jane K, Laurent FH et al. AZD 2171: A highly potent, orally bioavailable, Vascular Endothelial Growth Factor Receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Canc Res 2005; 65: 4389-4400
  • 30 Rosen LS, Kurzock R, Mulay M et al. Safety, pharmacokinetics and efficacy of AMG706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 2007; 26: 2369-2376
  • 31 Polverino A, Coxon A, Starnes C et al. AMG 706, an oral, multikinase inhibitor that selectively targets Vascular Endothelial Growth Factor, Platelet-Derived Growth Factor and Kit Receptors, potently inhibits angiogenesis and induces tumor regression in tumor xenografts. Canc Res 2006; 66: 8715-8721
  • 32 Ramanathan RK, Trump DL, Eiseman JL et al. Phase I pharmacokinetic-pharmacodynamic study of 17-(Allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of Heat Shock Protein 90, in patients with refractory advanced cancers. Clin Canc Res 2005; 11: 3385-3391
  • 33 Steeghs N, Gelderblom H, Roodt J et al. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Canc Res 2008; 14: 3470-3476
  • 34 Faivre S, Delbaldo c, Vera K et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clinl Oncol 2006; 24: 25-35
  • 35 Bello CL, Garrett M, Sherman L et al. Pharmacokinetics of Sunitinib malate in Subjects with hepatic impairment. Canc Chemother Pharmacol 2010; 66: 699-707
  • 36 Cohen RB, Langer CJ, Simon GR et al. A Phase I/randomnised Phase II, non-comparative, multicenter, open label trial of CP-547632 in combination with Paclitaxel and Carboplatin or Paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC). Canc Chemother Pharmacol 2007; 60: 81-89
  • 37 Hurwitz HI, Dowlati A, Saini S et al. Phase I trial of pazopanib in patients with advanced cancer. Clin Canc Res 2009; 15: 4220-4227
  • 38 Drabkin HA. Pazopanib and anti-VEGF Therapy. J Urol 2010; 2: 35-40
  • 39 Thomas AL, Morgan B, Horsfield MA et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol 2005; 23: 4162-4171
  • 40 Scott EN, Meinhardt G, Jacques C et al. Vatalanib: The clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumors. Exp Opin Investig Drugs 2007; 16: 367-379
  • 41 Tamura T, Minami H, Yamada Y et al. A Phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors. J Thorac Oncol 2006; 1: 1002-1009
  • 42 Zsila F, Fitos I, Bencze G et al. Determination of human serum alpha 1-acid glycoprotein and albumin binding of Various marketed and preclinical kinase Inhibitors. Curr Med Chem 2009; 16: 1964-1977
  • 43 Holden SN, Eckhardt SG, Basser R et al. Clinical evaluation of ZD 6474, an orally active inhibitor of VEGF and EGF receptor signalling, in patients with solid, malignant tumors. Ann Oncol 2005; 16: 1391-1397
  • 44 Strumberg D, Richly H, Hilger RA et al. Phase I clinical and pharmacokinetic study of the novel Raf Kinase and Vascular Endothelial Growth Factor Receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Pharmacol 2005; 23: 965-972
  • 45 Miller AA, Murry DJ, Owzar K et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 2009; 27: 1800-1805
  • 46 Wilhelm SM, Carter C, Tang L et al. Bay 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Canc Res 2004; 64: 7099-7109
  • 47 Genentech. fda.gov [Online]; 2004 [cited 2011 July 28]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf
  • 48 labs P. Pfizer.com [Online]; 2006 [cited 2011 July1 28]. Available from: http://labeling.pfizer.com/ShowLabeling.aspx?id=607
  • 49 Inc BHP. fda.gov [Online]; 2005 [cited 2011 July 28]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021923s008s009lbl.pdf
  • 50 GlaxoSmithkline. fda.gov [Online]; 2009 [cited 2011 July 28]. Availablefrom: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022465lbl.pdf
  • 51 Ramalingam SS, Belani CP, Mack PC et al. Phase II study of Cediranib(AZD 2171), an inhibitor of the Vascular Epidermal Growth Factor Receptor, for second line therapy of small cell lung cancer (National Cancer Institute#7097). J Thorac Oncol 2010; 5: 1279-1284
  • 52 Medindia. Medindia [Online]; 2006 [cited 2011 July 28]. Available from: http://www.medindia.net/news/view_news_main.asp?str=1&x=7656
  • 53 today Mn. Medical news today [Online]; 2009 [cited 2011 July 28]. Available from: http://www.medicalnewstoday.com/releases/137485.php
  • 54 Pharmastrategyblog [Online]; 2010 [cited 2011 July 29]. Available from: http://pharmastrategyblog.com/2010/03/antisoma-and-novartis-lung-cancer-drug-asa404-flops-in-phase-iii.html/
  • 55 Sherman SI, Wirth LJ, Droz JP et al. Motesanib diphosphate in progressive differentiated thyroid cancer. New Eng J Med 2008; 359: 31-42
  • 56 Langenberg MHG, Petronella WO, Jeanine RM et al. Phase I evaluation of Telatinib, a vasular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irnotecan and capecitabine in patients with advanced solid tumors. Clin Canc Res 2010; 16: 2187-2197
  • 57 Actbiotech/pipeline [Online] [cited 2011 July 29]. Available from: http://actbiotech.com/pipeline.html
  • 58 Strumberg D, Schultheis B, Adamietz IA et al. Phase I dose escalation study of telatinib (BAY57-9352) in patients with advanced solid tumors. Br J Canc 2008; 99: 1579-1585