Skip to main content
SpringerLink
Log in

Practical Considerations for Clinical Pharmacology in Drug Development: A Survey of 44 FDA Oncology Approvals

  • Chapter
  • First Online:
Pharmacokinetics in Drug Development

Abstract

This chapter presents the practical challenges facing the oncology clinical pharmacologist by surveying the cancer chemotherapies approved by the FDA in the period between January 2009 and June 2015. For each new medicine, the contents of the review summaries published by the FDA in the Drugs@FDA database at the time of first approval are examined. The comments of reviewers in the areas of subject and patient selection, dose and regimen justification, characterization of food and pH-altering drug interactions, evaluation of dose adjustment for organ impaired populations, and QTc assessment of new oncology therapeutics are presented. The information gleaned from the 44 approvals for new oncology drugs during this period provides the reader with an insight into the expectations and requirements for initial approval and provide practical information for how regulatory guidance is applied in clinical pharmacology.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abbas R, Hug BA, Leister C, El Gaaloul M, Chalon S, Sonnichsen D (2012) A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects. Cancer Chemother Pharmacol 69:221–227

    Article  CAS  PubMed  Google Scholar 

  • Afinitor® (everolimus) Prescribing Information (Label) (2010) http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022334s001lbl.pdf, May 2010

  • Agus DB, Gordon MS, Taylor C, Natale RB, Karlan B, Mendelson DS, Press MF, Allison DE, Sliwkowski MX, Lieberman G, Kelsey SM, Fyfe G (2005) Phase I clinical study of Pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Onc 23(11):2534–2543

    Article  CAS  Google Scholar 

  • Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E, Clark J, Cooper CS, Kaye SB, Dearnaley D, Lee G, de Bono JS (2008) Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 26:4563–4571

    Article  CAS  PubMed  Google Scholar 

  • Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, Tobler S, Heusser C, O’Reilly T, Stolz B, Marti A, Thomas G, Lane HA (2004) Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 54:252–261

    Article  Google Scholar 

  • Caprelsa® (vandetanib) Prescribing Information (Label) (2014) http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022405s007lbl.pdf, March 2014

  • DiMasi JA, Grabowski HG (2007) Economics of new oncology drug development. J Clin Oncol 25(2):209–216. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids/Panel on Macronutrients, Panel on the Definition of Dietary Fiber, Subcommittee on Upper Reference Levels of Nutrients, Subcommittee on Interpretation and Uses of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board (2005) https://www.nal.usda.gov/fnic/DRI/DRI_Energy/energy_full_report.pdf

  • Drugs@FDA http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

  • Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, Niederle B, Cohen EE, Wirth LJ, Ali H, Hessel C, Yaron Y, Ball D, Nelkin B, Sherman SI (2013) Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 31(29):3639–3646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erivedge® (vismodegib) Prescribing Information (Label) (2015) http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203388s005s006s007s008lbl.pdf, May 2015

  • Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H, van Doorn L, Burger H, Stopfer P, Verweij J, de Vries EG (2008) A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer 98(1):80–85

    Article  CAS  PubMed  Google Scholar 

  • Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau HT, Brown MP, Hamid O, Infante JR, Millward M, Pavlick A, Chin MT (2014) Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436). Clini Can Res 20(17):4449–58

    Article  CAS  Google Scholar 

  • Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies Food (2002) http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm070241.pdf

  • Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function (2010) http://www.fda.gov/downloads/Drugs/Guidances/UCM204959.pdf

  • Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic Function (2003) http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072123.pdf

  • Guideline on the Investigation of Drug Interactions (2012) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf, 21 June 2012

  • Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics (2014) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf, May 2014

  • Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds) SEER Cancer Statistics Review, 1975–2012, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015

  • Hurwitz HI, Dowlati A, Saini S, Savage S, Suttle AB, Gibson DM, Hodge JP, Merkle EM, Pandite L (2009) Phase I trial of Pazopanib in patients with advanced cancer. Clin Cancer Res 15(12):4220–4227

    Article  CAS  PubMed  Google Scholar 

  • Iclusig® (idelalisib) Prescribing Information (Label) (2014) http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203469s009lbl.pdf, July 2014

  • Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, Cox DS, Xu Y, Morris SR, Peddareddigari VG, Le NT, Hart L, Bendell JC, Eckhardt G, Kurzrock R, Flaherty K, Burris HA, Messersmith WA (2012 Aug) (2012) Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 13(8):773–781

    Article  CAS  PubMed  Google Scholar 

  • International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (2005) The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrythmic Drugs. E14. May 2005 http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Guideline.pdf

  • Jardim DL, Hess KR, LoRusso P, Kurzrock R, Hong DS (2014) Predictive value of phase I trials for safety in later trials and final approved dose: analysis of 61 approved cancer drugs. Clin Can Res 20(2):281–288

    Article  CAS  Google Scholar 

  • Kletzl H, Giraudon M, Ducray PS, Abt M, Hamilton M, Lum BL (2015) Effect of gastric pH on erlotinib pharmacokinetics in healthy individuals: omeprazole and ranitidine. Anticancer Drugs 26(5):565–572

    Article  CAS  PubMed  Google Scholar 

  • Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, Hopper TM, Miller CG, Harrington LE, Onori JA, Mullin RJ, Gilmer TM, Truesdale AT, Epperly AH, Boloor A, Stafford JA, Luttrell DK, Cheung M (2007) Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6:2012–2021

    Article  CAS  PubMed  Google Scholar 

  • Lewis N, Marshall J, Amelsberg A, Cohen RB, Stopfer P, Hwang J, Malik S (2006) A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a 3 week on 1 week off schedule in patients with advanced solid tumors. ASCO Meet Abstr 24 (18_suppl):3091

    Google Scholar 

  • LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Chang I, Darbonne WC, Graham RA, Zerivitz KL, Low JA, Von Hoff DD (2011a) Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res 17:2502–2511

    Article  CAS  PubMed  Google Scholar 

  • Lorusso PM, Jimeno A, Dy G, Adjei A, Berlin J, Leichman L, Low JA, Colburn D, Chang I, Cheeti S, Jin JY, Graham RA (2011b) Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors. Clin Cancer Res 17:5774–5782

    Article  CAS  PubMed  Google Scholar 

  • Martell RE, Sermer D, Getz K, Kaitin K (2013) Oncology drug development and approval of systemic anticancer therapy by the U.S. Food and Drug Administration. Oncologist 18:104–111

    Article  PubMed  Google Scholar 

  • Minasian L, Rosen O, Auclair D, Rahman A, Pazdur R, Schilsky R (2014) Optimizing dosing in oncology drugs. Clin Pharmacol Ther 96(5):572–579

    Article  CAS  PubMed  Google Scholar 

  • National Cancer Institute (NCI) Common Toxicity Criteria (CTC) (1999) Version 2.0: April 1999 http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf

  • O’Donnell A, Judson I, Dowsett M, Raynaud F, Dearnaley D, Mason M, Harland S, Robbins A, Halbert G, Nutley B, Jarman M (2004) Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) inpatients with prostate cancer. Br J Cancer 90:2317–2325

    PubMed  PubMed Central  Google Scholar 

  • 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) A phase I pharmacokinetic and pharmacodynamic study of the oral mTOR inhibitor everolimus (RAD001) in patients with advanced solid tumors. J Clin Oncol 26:1588–1595

    Article  PubMed  Google Scholar 

  • Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, Drengler R, Chen C, Smith L, Espino G, Gergich K, Delgado L, Daud A, Lindia JA, Li XN, Pierce RH, Yearley JH, Wu D, Laterza O, Lehnert M, Lannone R, Tolcher AW (2015) Phase I study of Pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 21(19):1–8

    Article  Google Scholar 

  • Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR (2013) A phase III study of gemtuzumab ozogamicin during induction and post-consolidation therapy in younger patients with acute myeloid leukemia. Blood 121(24):4854–4860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384(9948):1109–1117

    Article  CAS  PubMed  Google Scholar 

  • Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL, Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium (2010) Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 375(9724):1437–1446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, Shah MH, Hoff AO, Gianoukakis AG, Kiyota N, Taylor MH, Kim SB, Krzyzanowska MK, Dutcus CE, de las Heras B, Zhu J, Sherman SI (2015) Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621–663

    Google Scholar 

  • Sharma M, Karrison TG, Kell B, Wu K, Turcich M, Geary D, Kang SP, Takebe N, Graham RA, Maitland ML, Schilsky RL, Ratain MJ, Cohen EE (2013) Evaluation of food effect on pharmacokinetics of vismodegib in advanced solid tumor patients. Clin Cancer Res 19(11):3059–3067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E, Ramon y Cajal S, Jones S, Vidal L, Shand N, Macarulla T, Ramos FJ, Dimitrijevic S, Zoellner U, Tang P, Stumm M, Lane HA, Lebwohl D, Baselga J (2008) Dose- and schedule-dependent inhibition of the mTOR pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced tumors. J Clin Oncol 26:1603–1610

    Google Scholar 

  • Tan AR, Gibbon DG, Stein MN, Lindquist D, Edenfield JW, Martin JC, Gregory C, Suttle AB, Tada H, Botbyl J, Stephenson J (2013) Effects of ketoconazole and esomepresole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol 71:1635–1643

    Article  CAS  PubMed  Google Scholar 

  • 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 H (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(10):1596–1602

    CAS  PubMed  Google Scholar 

  • Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal R, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Eng J Med 366(26):2443–2454

    Article  CAS  Google Scholar 

  • Webb HK (2010) Clinical pharmacokinetics of CAL 101, a p110d isoform-selective PI3K inhibitor, following single- and multiple-dose administration in healthy volunteers and patients with hematological malignancies. Blood 116(121):1774

    Google Scholar 

  • Wu Y, Benet L (2005) Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 22(1):11–23

    Article  CAS  PubMed  Google Scholar 

  • Xalkori® (crizotinib) Prescribing Information (Label) (2015) http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202570s013lbl.pdf, March 2015

  • Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, Yu CJ, Chang GC, Ho CL, Sequist LV, Dudek AZ, Shahidi M, Cong XJ, Lorence RM, Yang PC, Miller VA (2012) Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol 13(5):539–548

    Article  CAS  PubMed  Google Scholar 

  • Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, Forero-Torres A (2012) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363(19):1812–1821

    Article  Google Scholar 

  • Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H, Ang J, Temple G, Bell S, Shahidi M, Uttenreuther-Fischer M, Stopfer P, Futreal A, Calvert H, de Bono J, Plummer R (2010) Phase I trial of the irrevisible ErbB1 (EGFR) and ErbB2 (HER2) kinase inhibitor BIBW 2992 in patients with advanced solid tumours. J Clin Oncol 28(25):3965–3972

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Wu F, Lee SC, Zhao H, Zhang L (2014) pH-dependent drug–drug interactions for weak base drugs: potential implications for new drug development. Nature 96(2):266–277

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Novartis Pharmaceuticals, Oncology Clinical Pharmacology, One Health Plaza, East Hanover, NJ, 07936-1080, USA

    Danny R. Howard

Authors
  1. Danny R. Howard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Danny R. Howard .

Editor information

Editors and Affiliations

  1. Pharmacokinetics/Modeling/Simulation 2N.184 Astellas, Global Clinical Pharmacology and Exploratory Development, Northbrook, Illinois, USA

    Peter L. Bonate

  2. Oncology Clinical Pharmacology Novartis, East Hanover, New Jersey, USA

    Danny R. Howard

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Howard, D.R. (2016). Practical Considerations for Clinical Pharmacology in Drug Development: A Survey of 44 FDA Oncology Approvals. In: Bonate, P., Howard, D. (eds) Pharmacokinetics in Drug Development. Springer, Cham. https://doi.org/10.1007/978-3-319-39053-6_12

Download citation

Publish with us

Policies and ethics

Search

Navigation