Pharmacokinetic Simulation Analysis of Less Frequent Nivolumab and Pembrolizumab Dosing: Pharmacoeconomic Rationale for Dose Deescalation

被引:20
作者
Peer, Cody J. [1 ]
Heiss, Brian L. [2 ,3 ]
Goldstein, Daniel A. [4 ,5 ]
Goodell, Jennifer C. [1 ]
Figg, William D. [1 ]
Ratain, Mark J. [2 ,3 ]
机构
[1] NCI, Clin Pharmacol Program, 10 Ctr Dr,Room 5A03, Bethesda, MD 20892 USA
[2] Univ Chicago, Dept Med, Sect Hematol Oncol, Chicago, IL 60637 USA
[3] Univ Chicago, Comm Clin Pharmacol & Pharmacogen, Chicago, IL 60637 USA
[4] Rabin Med Ctr, Davidoff Canc Ctr, Tel Aviv, Israel
[5] Tel Aviv Univ, Fac Med, Tel Aviv, Israel
基金
美国国家卫生研究院;
关键词
clinical trials; immunopharmacology; modeling and simulation; oncology; population pharmacokinetics; CANCER; SAFETY; TUMOR; TIME; REMISSION; SCHEDULE; EFFICACY; ANTIBODY; TRIALS; PD-1;
D O I
10.1002/jcph.1984
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Nivolumab and pembrolizumab, anti-programmed cell death protein 1 monoclonal antibodies, have revolutionized oncology but are expensive. Using an interventional pharmacoeconomic approach, these drugs can be administered less often to reduce costs and increase patient convenience while maintaining efficacy. Both drugs are good candidates for less frequent dosing because of long half-lives and no evidence of a relationship of dose to efficacy. Established population pharmacokinetic models for both nivolumab and pembrolizumab were used to simulate profiles for multiple dosing regimens on 1000 randomly generated virtual patients. Simulations were initially performed on standard dose regimens to validate these in silico predictions. Next, simulations of nivolumab 0.3 mg/kg every 3 weeks revealed that >95% of patients maintained >= 1.5 mu g/mL at steady state, which was inferred as the minimum effective concentration (MEC) for both drugs. Various alternative dosing regimens were simulated for both drugs to determine which regimen(s) can maintain this MEC in >95% of patients. Extended dosing regimens of nivolumab 240 mg every 4 weeks and 480 mg every 8 weeks along with pembrolizumab 200 mg every 6 weeks were simulated, showing that >95% of patients maintained MEC or greater. These simulations demonstrate the potential to reduce drug exposure by at least 50%, thus substantially reducing patient visits (as well as costs), while maintaining equivalent efficacy. These models provide the scientific justification for an ongoing prospective randomized clinical trial comparing standard interval fixed dosing with extended interval fixed dosing, and ultimately an efficacy-driven comparative trial.
引用
收藏
页码:532 / 540
页数:9
相关论文
共 41 条
  • [1] Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy
    Agrawal, Shruti
    Feng, Yan
    Roy, Amit
    Kollia, Georgia
    Lestini, Brian
    [J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2016, 4
  • [2] [Anonymous], Application Number 125554Orig1-000
  • [3] Bajaj G, 2017, CPT-PHARMACOMET SYST, V6, P58, DOI 10.1002/psp4.12143
  • [4] Model-informed drug development approach supporting approval of the 4-week (Q4W) dosing schedule for nivolumab (Opdivo) across multiple indications: a regulatory perspective
    Bi, Y.
    Liu, J.
    Furmanski, B.
    Zhao, H.
    Yu, J.
    Osgood, C.
    Ward, A.
    Keegan, P.
    Booth, B. P.
    Rahman, A.
    Wang, Y.
    [J]. ANNALS OF ONCOLOGY, 2019, 30 (04) : 644 - 651
  • [5] Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway
    Boussiotis, Vassiliki A.
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2016, 375 (18) : 1767 - 1778
  • [6] Low-dose pembrolizumab for relapsed/refractory Hodgkin lymphoma: high efficacy with minimal toxicity
    Chan, Thomas S. Y.
    Luk, Tsan-Hei
    Lau, June S. M.
    Khong, Pek-Lan
    Kwong, Yok-Lam
    [J]. ANNALS OF HEMATOLOGY, 2017, 96 (04) : 647 - 651
  • [7] Optimising the dose of clonidine to achieve sedation in intensive care unit patients with population pharmacokinetics
    Cloesmeijer, Michael E.
    van den Oever, Huub L. A.
    Mathot, Ron A. A.
    Zeeman, Marieke
    Kruisdijk-Gerritsen, Arriette
    Bles, Carmen M. A.
    Nassikovker, Polina
    de Meijer, Arthur R.
    van Steveninck, Fred L.
    Arbouw, Maurits E. L.
    [J]. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2020, 86 (08) : 1620 - 1631
  • [8] Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor
    Deng, Rong
    Bumbaca, Daniela
    Pastuskovas, Cinthia V.
    Boswell, C. Andrew
    West, David
    Cowan, Kyra J.
    Chiu, Henry
    McBride, Jacqueline
    Johnson, Clarissa
    Xin, Yan
    Koeppen, Hartmut
    Leabman, Maya
    Iyer, Suhasini
    [J]. MABS, 2016, 8 (03) : 593 - 603
  • [9] Population Pharmacokinetics of Isavuconazole from Phase 1 and Phase 3 (SECURE) Trials in Adults and Target Attainment in Patients with Invasive Infections Due to Aspergillus and Other Filamentous Fungi
    Desai, Amit
    Kovanda, Laura
    Kowalski, Donna
    Lu, Qiaoyang
    Townsend, Robert
    Bonate, Peter L.
    [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2016, 60 (09) : 5483 - 5491
  • [10] Clinical Trial Simulations and Pharmacometric Analysis in Pediatrics: Application to Inhaled Loxapine in Children and Adolescents
    Dong, Min
    Fukuda, Tsuyoshi
    Selim, Sally
    Smith, Mark A.
    Rabinovich-Guilatt, Laura
    Cassella, James V.
    Vinks, Alexander A.
    [J]. CLINICAL PHARMACOKINETICS, 2017, 56 (10) : 1207 - 1217