Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 3/2020

01-03-2020 | Checkpoint Inhibitors | Review Article

Setting the Dose of Checkpoint Inhibitors: The Role of Clinical Pharmacology

Authors: Etienne Chatelut, Félicien Le Louedec, Gérard Milano

Published in: Clinical Pharmacokinetics | Issue 3/2020

Login to get access

Abstract

Cancer immunotherapy is based on checkpoint inhibitors (CPIs) that significantly improve the clinical outcome of several malignant diseases. These inhibitors are monoclonal antibodies (mAbs) directed at cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), or programmed death-ligand 1 (PD-L1), sharing most of the clinical pharmacokinetic characteristics of mAb targeted therapies, all of which differ from those of cytotoxics and small molecules. Establishing the labeled dose of mAbs, and particularly of the CPIs, represents a true challenge. This review therefore examines the main criteria used for dose selection, along with their limits. The relationships between CPI pharmacokinetic parameters and treatment outcome (efficacy and/or toxicity) differ somewhat among the various drugs, but general features can be identified. Nevertheless, the interpretation of these relationships remains quite controversial. A first interpretation asserts that inter-individual pharmacokinetic variability in clearance has an impact on outcome and should be taken into consideration for dosing individualization. The second considers that higher clearance values observed in some patients result from characteristics associated with poor predictive factors of efficacy. Finally, the schedule, and particularly its frequency of administration, merits rethinking.
Literature
1.
Liu JKH. The history of monoclonal antibody development—progress, remaining challenges and future innovations. Ann Med Surg. 2014;3:113–6.
2.
Ecker DM, Jones SD, Levine HL. The therapeutic monoclonal antibody market. mAbs. 2015;7:9–14.PubMed
3.
Imamura CK. Therapeutic drug monitoring of monoclonal antibodies: applicability based on their pharmacokinetic properties. Drug Metab Pharmacokinet. 2019;34:14–8.PubMed
4.
Wong H, Chow TW. Physiologically based pharmacokinetic modeling of therapeutic proteins. J Pharm Sci. 2017;106:2270–5.PubMed
5.
Tabrizi MA, Tseng CML, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11:81–8.PubMed
6.
Berinstein NL, Grillo-Lopez AJ, White CA, Bence-Bruckler I, Maloney D, Czuczman M, et al. Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol. 1998;9:995–1001.PubMed
7.
Azzopardi N, Lecomte T, Ternant D, Boisdron-Celle M, Piller F, Morel A, et al. Cetuximab pharmacokinetics influences progression-free survival of metastatic colorectal cancer patients. Clin Cancer Res. 2011;17:6329–37.PubMed
8.
Caulet M, Lecomte T, Bouché O, Rollin J, Gouilleux-Gruart V, Azzopardi N, et al. Bevacizumab pharmacokinetics influence overall and progression-free survival in metastatic colorectal cancer patients. Clin Pharmacokinet. 2016;55:1381–94.PubMed
9.
Feng Y, Roy A, Masson E, Chen T-T, Humphrey R, Weber JS. Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin Cancer Res. 2013;19:3977–86.PubMed
10.
Basak EA, Koolen SLW, Hurkmans DP, Schreurs MWJ, Bins S, Oomen-de Hoop E, et al. Correlation between nivolumab exposure and treatment outcomes in non–small-cell lung cancer. Eur J Cancer. 2019;109:12–20.PubMed
11.
Kim H-D, Park S-H. Immunological and clinical implications of immune checkpoint blockade in human cancer. Arch Pharm Res. 2019;42:567–81.PubMed
12.
Sheng J, Srivastava S, Sanghavi K, Lu Z, Schmidt BJ, Bello A, et al. Clinical pharmacology considerations for the development of immune checkpoint inhibitors. J Clin Pharmacol. 2017;57:S26–42.PubMed
13.
14.
Centanni M, Moes DJAR, Trocóniz IF, Ciccolini J, van Hasselt JGC. Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet. 2019;58:835–57.PubMedPubMedCentral
15.
Tosi D, Laghzali Y, Vinches M, Alexandre M, Homicsko K, Fasolo A, et al. Clinical development strategies and outcomes in first-in-human trials of monoclonal antibodies. J Clin Oncol. 2015;33:2158–65.PubMed
16.
Viala M, Vinches M, Alexandre M, Mollevi C, Durigova A, Hayaoui N, et al. Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection. Br J Cancer. 2018;118:679–97.PubMedPubMedCentral
17.
Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017;18:611–22.PubMed
18.
Deng R, Bumbaca D, Pastuskovas CV, Boswell CA, West D, Cowan KJ, et al. Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor. mAbs. 2016;8:593–603.PubMedPubMedCentral
19.
Stroh M, Winter H, Marchand M, Claret L, Eppler S, Ruppel J, et al. Clinical pharmacokinetics and pharmacodynamics of atezolizumab in metastatic urothelial carcinoma. Clin Pharmacol Ther. 2017;102:305–12.PubMed
20.
Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21:4286–93.PubMed
21.
Elassaiss-Schaap J, Rossenu S, Lindauer A, Kang S, de Greef R, Sachs J, et al. Using model-based “learn and confirm” to reveal the pharmacokinetics-pharmacodynamics relationship of pembrolizumab in the KEYNOTE-001 trial. CPT Pharmacometr Syst Pharmacol. 2017;6:21–8.
22.
Baverel PG, Dubois VFS, Jin CY, Zheng Y, Song X, Jin X, et al. Population pharmacokinetics of durvalumab in cancer patients and association with longitudinal biomarkers of disease status. Clin Pharmacol Ther. 2018;103:631–42.PubMedPubMedCentral
23.
Bajaj G, Wang X, Agrawal S, Gupta M, Roy A, Feng Y. Model-based population pharmacokinetic analysis of nivolumab in patients with solid tumors. CPT Pharmacometr Syst Pharmacol. 2017;6:58–66.
24.
Agrawal S, Feng Y, Roy A, Kollia G, Lestini B. Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy. J Immunother Cancer. 2016;4:72.PubMedPubMedCentral
25.
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti–programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75.PubMedPubMedCentral
26.
Heery CR, O’Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18:587–98.PubMedPubMedCentral
27.
28.
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49:1012–24.PubMed
29.
Li J, Zhi J, Wenger M, Valente N, Dmoszynska A, Robak T, et al. Population pharmacokinetics of rituximab in patients with chronic lymphocytic leukemia. J Clin Pharmacol. 2012;52:1918–26.PubMed
30.
Dirks NL, Nolting A, Kovar A, Meibohm B. Population pharmacokinetics of cetuximab in patients with squamous cell carcinoma of the head and neck. J Clin Pharmacol. 2008;48:267–78.PubMed
31.
Bruno R, Washington CB, Lu J-F, Lieberman G, Banken L, Klein P. Population pharmacokinetics of trastuzumab in patients With HER2 + metastatic breast cancer. Cancer Chemother Pharmacol. 2005;56:361–9.PubMed
32.
Passot C, Azzopardi N, Renault S, Baroukh N, Arnoult C, Ohresser M, et al. Influence of FCGRT gene polymorphisms on pharmacokinetics of therapeutic antibodies. mAbs. 2013;5:614–9.PubMedPubMedCentral
33.
Wilkins JJ, Brockhaus B, Dai H, Vugmeyster Y, White JT, Brar S, et al. Time-varying clearance and impact of disease state on the pharmacokinetics of avelumab in merkel cell carcinoma and urothelial carcinoma. CPT Pharmacometr Syst Pharmacol. 2019;8(6):415–27. https://​doi.​org/​10.​1002/​psp4.​12406.CrossRef
34.
Li H, Yu J, Liu C, Liu J, Subramaniam S, Zhao H, et al. Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response. J Pharmacokinet Pharmacodyn. 2017;44:403–14.PubMed
35.
36.
37.
Le Louedec F, Alix-Panabières C, Lafont T, Allal BC, Garrel R, Digue L, et al. Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients. Br J Clin Pharmacol. 2019;85:1357–66.PubMed
38.
Han K, Peyret T, Marchand M, Quartino A, Gosselin NH, Girish S, et al. Population pharmacokinetics of bevacizumab in cancer patients with external validation. Cancer Chemother Pharmacol. 2016;78:341–51.PubMedPubMedCentral
39.
Garg A, Quartino A, Li J, Jin J, Wada DR, Li H, et al. Population pharmacokinetic and covariate analysis of pertuzumab, a HER2-targeted monoclonal antibody, and evaluation of a fixed, non-weight-based dose in patients with a variety of solid tumors. Cancer Chemother Pharmacol. 2014;74:819–29.PubMed
40.
Turner DC, Kondic AG, Anderson KM, Robinson AG, Garon EB, Riess JW, et al. Pembrolizumab exposure–response assessments challenged by association of cancer cachexia and catabolic clearance. Clin Cancer Res. 2018;24:5841–9.PubMed
41.
Liu C, Yu J, Li H, Liu J, Xu Y, Song P, et al. Association of time-varying clearance of nivolumab with disease dynamics and its implications on exposure response analysis. Clin Pharmacol Ther. 2017;101:657–66.PubMed
42.
Bins S, Koolen SLW, Mathijssen RHJ. Pembrolizumab exposure–response assessments challenged by association of cancer cachexia and catabolic clearance—letter. Clin Cancer Res. 2019;25:3192–3192.PubMed
43.
Tardivon C, Desmée S, Kerioui M, Bruno R, Wu B, Mentré F, et al. Association between tumor size kinetics and survival in patients with urothelial carcinoma treated with atezolizumab: implication for patient follow-up. Clin Pharmacol Ther. 2019;106:810–20.PubMed
44.
Hertz DL, McLeod HL. Use of pharmacogenetics for predicting cancer prognosis and treatment exposure, response and toxicity. J Hum Genet. 2013;58:346–52.PubMed
45.
46.
47.
Iafolla MAJ, Selby H, Warner K, Ohashi PS, Haibe-Kains B, Siu LL. Rational design and identification of immuno-oncology drug combinations. Eur J Cancer. 2018;95:38–51.PubMed
48.
49.
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.PubMedPubMedCentral
50.
Hammers HJ, Plimack ER, Infante JR, Rini BI, McDermott DF, Lewis LD, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol. 2017;35:3851–8.PubMed
51.
Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.PubMedPubMedCentral
52.
Weber JS, O’Day S, Urba W, Powderly J, Nichol G, Yellin M, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26:5950–6.PubMed
53.
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116–27.PubMed
54.
Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19:405–15.PubMedPubMedCentral
55.
Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019;20:1083–97.PubMed
56.
57.
Coosemans A, Vankerckhoven A, Baert T, Boon L, Ruts H, Riva M, et al. Combining conventional therapy with immunotherapy: a risky business? Eur J Cancer. 2019;113:41–4.PubMed
58.
59.
Lala M, Li M, Sinha V, de Alwis D, Chartash E, Jain L. A six-weekly (Q6 W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation. J Clin Oncol. 2018;36:3062–3062.
60.
Ratain MJ, Goldstein DA. Time is money: optimizing the scheduling of nivolumab. J Clin Oncol. 2018;36:3074–6.
61.
62.
Feng Y, Masson E, Dai D, Parker SM, Berman D, Roy A. Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma: clinical pharmacology profiling of ipilimumab in advanced melanoma. Br J Clin Pharmacol. 2014;78:106–17.PubMedPubMedCentral
63.
Wang X, Feng Y, Bajaj G, Gupta M, Agrawal S, Yang A, et al. Quantitative characterization of the exposure-response relationship for cancer immunotherapy: a case study of nivolumab in patients with advanced melanoma. CPT Pharmacometr Syst Pharmacol. 2017;6:40–8.
64.
Chatterjee M, Elassaiss-Schaap J, Lindauer A, Turner D, Sostelly A, Freshwater T, et al. Population pharmacokinetic/pharmacodynamic modeling of tumor size dynamics in pembrolizumab-treated advanced melanoma. CPT Pharmacometr Syst Pharmacol. 2017;6:29–39.
65.
Center for Drug Evaluation and Research (CDER), US FDA. Clinical pharmacology and biopharmaceutics review(s): atezolizumab. Silver Springs: US FDA; 2016.
66.
Center for Drug Evaluation and Research (CDER), US FDA. Clinical pharmacology and biopharmaceutics review(s): avelumab. Silver Springs: US FDA; 2017.
67.
Jin C, Zheng Y, Jin X, Mukhopadhyay P, Gupta AK, Dennis PA, et al. Exposure-efficacy and safety analysis of durvalumab in patients with urothelial carcinoma (UC) and other solid tumors. J Clin Oncol. 2017;35:2568–2568.
Metadata
Title
Setting the Dose of Checkpoint Inhibitors: The Role of Clinical Pharmacology
Authors
Etienne Chatelut
Félicien Le Louedec
Gérard Milano
Publication date
01-03-2020
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 3/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-019-00837-2

Other articles of this Issue 3/2020

Clinical Pharmacokinetics 3/2020 Go to the issue

Review Article

Clinical Pharmacology of Elagolix: An Oral Gonadotropin-Releasing Hormone Receptor Antagonist for Endometriosis

Original Research Article

Amisulpride: Real-World Evidence of Dose Adaptation and Effect on Prolactin Concentrations and Body Weight Gain by Pharmacokinetic/Pharmacodynamic Analyses

Original Research Article

Vancomycin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis

Original Research Article

An Open-Label, Single-Period, Two-Stage, Single Oral Dose Pharmacokinetic Study of Remogliflozin Etabonate Tablet 100 and 250 mg in Healthy Asian Indian Male Subjects Under Fasting and Fed Conditions

Original Research Article

Exposure-Response Analyses of the Effects of Venetoclax, a Selective BCL-2 Inhibitor, on B-Lymphocyte and Total Lymphocyte Counts in Women with Systemic Lupus Erythematosus

Original Research Article

Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly