TY - JOUR
T1 - Case report
T2 - Pharmacokinetics of pembrolizumab in a patient with stage IV non?small cell lung cancer after a single 200 mg administration
AU - de Vries, Fenna
AU - Smit, Adrianus A. J.
AU - Wolbink, Gertjan
AU - de Vries, Annick
AU - Loeff, Floris C.
AU - Franssen, Eric J. F.
N1 - Funding Information: This study was supported by OLVG, Subsidie Stichting Wetenschappelijk Onderzoek 2021. Publisher Copyright: Copyright © 2023 de Vries, Smit, Wolbink, de Vries, Loeff and Franssen.
PY - 2023/1/11
Y1 - 2023/1/11
N2 - Background: Pembrolizumab is a well-tolerated biologic agent with a potentially stable and durable anti-tumor response. Unfortunately, discontinuation of therapy can occur as a consequence of immune-related adverse effects (irAEs). These irAEs appear independent of dose and exposure. However, such irAEs might also result from pembrolizumab’s highly specific mechanism of action and current dosing regimens. However, the currently available pharmacokinetic (PK) and pharmacodynamic (PD) data to reassess dosing strategies are insufficient. To highlight the importance of additional PK/PD studies, we present a case describing the complexity of pembrolizumab’s PK/PD after a single 200 mg pembrolizumab dose in a treatment-naive patient with non–small cell lung cancer (NSCLC). Case description: A 72-year-old man with stage IV NSCLC presented hepatotoxic symptoms 19 days after receiving the first 200 mg pembrolizumab dose. Hence, pembrolizumab therapy was paused, and prednisolone therapy was initiated, which successfully inhibited the toxic effect of pembrolizumab. However, repeated flare-ups due to prednisolone tapering suggest that the toxic effect of pembrolizumab outlasts the presence of pembrolizumab in the bloodstream. This further suggests that the T-cell–mediated immune response outlasts the programmed cell death protein 1 (PD-1) receptor occupancy by pembrolizumab, which challenges the need for the current fixed-interval strategies and their stop criteria. Furthermore, a validated ELISA quantified pembrolizumab levels in 15 samples within 123 days after administration. A shift in the pembrolizumab clearance rate was evident ensuing day 77 (0.6 µg/mL) after administration. Pembrolizumab levels up to day 77 (9.1–0.6 µg/mL) strongly exhibited a linear, first-order clearance (R 2 = 0.991), whereas after day 77, an accelerated non-linear clearance was observed. This transition from a linear to non-linear clearance was most likely a result of full target receptor saturation to non-full target receptor saturation, in which the added effect of target-mediated drug disposition occurs. This suggests that pembrolizumab’s targets were fully saturated at levels above 0.6 µg/mL, which is 43 to 61 times lower than the steady-state trough levels (C trough,ss) of the currently registered fixed-dosing regimens (3–5).
AB - Background: Pembrolizumab is a well-tolerated biologic agent with a potentially stable and durable anti-tumor response. Unfortunately, discontinuation of therapy can occur as a consequence of immune-related adverse effects (irAEs). These irAEs appear independent of dose and exposure. However, such irAEs might also result from pembrolizumab’s highly specific mechanism of action and current dosing regimens. However, the currently available pharmacokinetic (PK) and pharmacodynamic (PD) data to reassess dosing strategies are insufficient. To highlight the importance of additional PK/PD studies, we present a case describing the complexity of pembrolizumab’s PK/PD after a single 200 mg pembrolizumab dose in a treatment-naive patient with non–small cell lung cancer (NSCLC). Case description: A 72-year-old man with stage IV NSCLC presented hepatotoxic symptoms 19 days after receiving the first 200 mg pembrolizumab dose. Hence, pembrolizumab therapy was paused, and prednisolone therapy was initiated, which successfully inhibited the toxic effect of pembrolizumab. However, repeated flare-ups due to prednisolone tapering suggest that the toxic effect of pembrolizumab outlasts the presence of pembrolizumab in the bloodstream. This further suggests that the T-cell–mediated immune response outlasts the programmed cell death protein 1 (PD-1) receptor occupancy by pembrolizumab, which challenges the need for the current fixed-interval strategies and their stop criteria. Furthermore, a validated ELISA quantified pembrolizumab levels in 15 samples within 123 days after administration. A shift in the pembrolizumab clearance rate was evident ensuing day 77 (0.6 µg/mL) after administration. Pembrolizumab levels up to day 77 (9.1–0.6 µg/mL) strongly exhibited a linear, first-order clearance (R 2 = 0.991), whereas after day 77, an accelerated non-linear clearance was observed. This transition from a linear to non-linear clearance was most likely a result of full target receptor saturation to non-full target receptor saturation, in which the added effect of target-mediated drug disposition occurs. This suggests that pembrolizumab’s targets were fully saturated at levels above 0.6 µg/mL, which is 43 to 61 times lower than the steady-state trough levels (C trough,ss) of the currently registered fixed-dosing regimens (3–5).
KW - immune-related adverse events
KW - immunotherapy
KW - pembrolizumab
KW - pharmacodynamic (PD)
KW - pharmacokinetic (PK)
KW - programmed cell death protein 1 (PD-1)
UR - http://www.scopus.com/inward/record.url?scp=85147035957&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fonc.2022.960116
DO - https://doi.org/10.3389/fonc.2022.960116
M3 - Article
C2 - 36713570
SN - 2234-943X
VL - 12
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 960116
ER -