PK/PD Simulation of the Analgesic Effects of Anti-EGFR Antibodies Panitumumab and Cetuximab using the Effect Compartment Model

• Shu Yuasa

  Department of Hospital Pharmacy, Nagoya Memorial Hospital, Japan

• Megumi Kabeya

  Department of Hospital Pharmacy, Nagoya Memorial Hospital, Japan and Palliative Care Team, Nagoya Memorial Hospital, Japan

• Chiharu Okamoto

  Department of Hospital Pharmacy, Nagoya Memorial Hospital, Japan

• Ryosuke Hayashi

  Department of Hospital Pharmacy, Nagoya Memorial Hospital, Japan and Palliative Care Team, Nagoya Memorial Hospital, Japan

• Ai Akeno

  Department of Hospital Pharmacy, Nagoya Memorial Hospital, Japan and Palliative Care Team, Nagoya Memorial Hospital, Japan

• Satoshi Hibi

  Department of Hospital Pharmacy, Nagoya Memorial Hospital, Japan

• Satoshi Kayukawa

  Department of Clinical Oncology, Nagoya Memorial Hospital, Japan

• Yui Tajima

  Palliative Care Team, Shinseikai Dai-ichi Hospital, Nagoya, Japan and Department of Hospital Pharmacy, Shinseikai Dai-ichi Hospital, Nagoya, Japan

• Yuka Minamikawa

  Palliative Care Team, Shinseikai Dai-ichi Hospital, Nagoya, Japan and Department of Hospital Pharmacy, Shinseikai Dai-ichi Hospital, Nagoya, Japan

• Chiaki Tokoro

  Palliative Care Team, Shinseikai Dai-ichi Hospital, Nagoya, Japan

• Yoshihiro Ohta

  Department of Renal Disease, Shinseikai Dai-ichi Hospital, Nagoya, Japan

• Kenji Ina

  Palliative Care Team, Shinseikai Dai-ichi Hospital, Nagoya, Japan

The analgesic effects of epidermal growth factor receptor (EGFR) inhibitors have been reported in several studies, and the underlying mechanisms of pain relief, particularly for neuropathic pain, have been gradually clarified. To explain the time profile of the analgesic effects of anti-EGFR antibodies, this study used the effect compartment model, which is currently applied to analgesics and sedatives, to explain the duration of pharmacologic effects. The findings indicate the compartmental pharmacological model can reliably predict the duration of the analgesic effects of anti-EGFR antibodies.

[1] Liu N, Sh Xi, Chen SR, et al. EGFR activation sensitizes trigeminal NMDA receptors to promote pain and morphine analgesic tolerance in oral cancer. Sci Signal 2026; 19(922): eadt3026.

[2] Kersten C, Cameron MG, Laird B, et al. Epidermal growth factor receptor-inhibition (EGFR-I) in the treatment of neuropathic pain. Br J Anaesth 2015; 115(5): 761-7.

[3] Kersten C, Cameron MG, Bailey AG, et al. Relief of Neuropathic Pain Through Epidermal Growth Factor Receptor Inhibition: A Randomized Proof-of-Concept Trial. Pain Med 2019; 20(12): 2495-2505.

[4] Cameron MG, Kersten C. Differential effects of epidermal growth factor receptor inhibitors in a single patient with neuropathic pain. BMJ Case Rep 2021; 26; 14(3): e239385.

[5] Kersten C, Cameron MG. Cetuximab alleviates neuropathic pain despite tumor progression. BMJ Case Rep 2012; 14: 2012: bcr1220115374.

[6] Yuasa S, Furuta R, Kabeya M, et al. The Relief of Nociceptive Pain Induced by Panitumumab Could be Sustainable during. J Anal Oncol 2024; 13: 59-63.

[7] Yuasa S, Kabeya M, Hibi S et al. Retrospective Evaluation of the Analgesic Effects of Molecular Target Agents Against Cancer Pain and Oxaliplatin-Induced Chemotherapy Chronic Peripheral Neuropathy. J Anal Oncol 2022; 11: 40-44.

[8] Martin LJ, Smith SB, Khoutorsky A, et al. Epiregulin and EGFR interactions are involved in pain processing. J Clin Invest 2017; 127(9): 3353-3366.

[9] Borges JP, Mekhail K, Fairn GD, et al. Modulation of Pathological Pain by Epidermal Growth Factor Receptor. Front Pharmacol 2021; 12: 642820.

[10] Yuasa S, Kabeya M, Furuta R, et al. A Case of Sigmoid Colon Cancer in which Somatic Pain was Rapidly Alleviated after Panitumumab Administration despite Tumor Progression. J Anal Oncol 2016; 5: 38-41.

[11] Santi MD, Zhang M, Liu N, et al. Repurposing EGFR Inhibitors for Oral Cancer Pain and Opioid Tolerance. Pharmaceuticals (Basel) 2023; 16(11): 1558.

[12] Yuasa S, Nagao S, Kabeya M, et al. PK/PD of Opioids: Simulation of Oxycodone Concentrations in Plasma and Effect Site after Intravenous Injection, and Comparisons with that of Morphine and Fentanyl. Jpn J Pharm Health Care Sci 2015; 41(7): 497-505 (in Japanese).

[13] Lötsch J. Pharmacokinetic-Pharmacodynamic modeling opioids. J Pain Symptom Manage 2005; 29(5 Suppl): S90-103.

[14] Dershwitz M, Walsh JL, Morishige RJ, et al. Pharmacokin-etics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers. Anesth 2000; 93(3): 619-628.

[15] Ebling WF, Lee EN, Stanski DR Understanding pharmacokinetics and pharmacodynamics through computer stimulation: I. The comparative clinical profiles of fentanyl and alfentanil. Anesth 1990; 72(4): 650-658.

[16] Eleveld J, Colin P, Absalom AR, et al. Pharmacokinetic-pharmacodynamic model for propofol for broad application in anaesthesia and sedation. Br J Anaesth 2018; 120(5): 942-959.

[17] Mould DR, DeFeo TM, Reele S, et al. Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam. Clin Pharmacol Ther 1995; 58(1): 35-43.

[18] Sheiner LB, Stanski DR, Vozeh S, et al. Simultaneous modeling of pharmacokinetics and pharmacodynamics application to d-tubocurarine. Clin Pharmacol Ther 1979; 25(3): 358-71.

[19] Stanski DR, Ham J, Miller RD, et al. Pharmacokinetics and pharmacodynamics of d-tubocurarine during nitrous oxide-narcotic and halothane anesthesia in man. Anesth 1979; 51(3): 235-241.

[20] Shinoda S, Aoyama T, Aoyama Y, et al. Pharmacokinetic-Pharmacodynamic Simulation of Acetaminophen Analgesia in Patients with Chronic Pain. Biol Pharm Bull 2007; 30, 157-161.

[21] Kersten C, Cameron MG, Bailey AG, et al. Relief of Neuropathic Pain Through Epidermal Growth Factor Receptor Inhibition: A Randomized Proof-of-Concept Trial. Pain Med 2019; 20(12): 2495-2505.

[22] Wilkinson GR. Pharmacokinetics: The dynamics of drug absorption, distribution, and elimination. In Brunton LL, Lazo JS, Parker KL, (Eds.), Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). McGraw-Hill 2006; pp. 1-39.

[23] Doi T, Ohtsu A, Tahara T, et al. Safety and pharmacokinetics of panitumumab in Japanese patients with advanced solid tumors. Int J Clin Oncol 2009; 14(4): 307-14.

[24] Tabernero J, Ciardiello F, Rivera F, et al. Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/ pharmacodynamic phase I dose-escalation study. Ann Oncol 2010; 21(7): 1537-1545.

[25] Kersten C, Cameron MG, Mjåland S, et al. Epithelial growth factor receptor (EGFR)-inhibition for relief of neuropathic pain- A case series. Scand J Pain 2013; 4(1): 3-7.

• PDF

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.