Case report: Pharmacokinetics of pembrolizumab in a patient with stage IV non–small cell lung cancer after a single 200 mg administration
BackgroundPembrolizumab 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 irA...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.960116/full |
| _version_ | 1797956043595055104 |
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| author | Fenna de Vries Adrianus A. J. Smit Gertjan Wolbink Annick de Vries Floris C. Loeff Eric J. F. Franssen |
| author_facet | Fenna de Vries Adrianus A. J. Smit Gertjan Wolbink Annick de Vries Floris C. Loeff Eric J. F. Franssen |
| author_sort | Fenna de Vries |
| collection | DOAJ |
| description | BackgroundPembrolizumab 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 descriptionA 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 (R2 = 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 (Ctrough,ss) of the currently registered fixed-dosing regimens (3–5). |
| first_indexed | 2024-04-10T23:42:43Z |
| format | Article |
| id | doaj.art-80f9f5ef5d7443cb95508f45902e8801 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-10T23:42:43Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj.art-80f9f5ef5d7443cb95508f45902e88012023-01-11T06:00:47ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-01-011210.3389/fonc.2022.960116960116Case report: Pharmacokinetics of pembrolizumab in a patient with stage IV non–small cell lung cancer after a single 200 mg administrationFenna de Vries0Adrianus A. J. Smit1Gertjan Wolbink2Annick de Vries3Floris C. Loeff4Eric J. F. Franssen5Department of Pharmacy, OLVG Hospital, Amsterdam, NetherlandsDepartment of Pulmonary Medicine, OLVG Hospital, Amsterdam, NetherlandsDepartment of Rheumatology, Amsterdam Rheumatology and Immunology Centre, Amsterdam, NetherlandsDiagnostic Services, Sanquin Health Solutions, Amsterdam, NetherlandsDiagnostic Services, Sanquin Health Solutions, Amsterdam, NetherlandsDepartment of Pharmacy, OLVG Hospital, Amsterdam, NetherlandsBackgroundPembrolizumab 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 descriptionA 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 (R2 = 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 (Ctrough,ss) of the currently registered fixed-dosing regimens (3–5).https://www.frontiersin.org/articles/10.3389/fonc.2022.960116/fullpembrolizumabimmunotherapyimmune-related adverse eventsprogrammed cell death protein 1 (PD-1)pharmacodynamic (PD)pharmacokinetic (PK) |
| spellingShingle | Fenna de Vries Adrianus A. J. Smit Gertjan Wolbink Annick de Vries Floris C. Loeff Eric J. F. Franssen Case report: Pharmacokinetics of pembrolizumab in a patient with stage IV non–small cell lung cancer after a single 200 mg administration Frontiers in Oncology pembrolizumab immunotherapy immune-related adverse events programmed cell death protein 1 (PD-1) pharmacodynamic (PD) pharmacokinetic (PK) |
| title | Case report: Pharmacokinetics of pembrolizumab in a patient with stage IV non–small cell lung cancer after a single 200 mg administration |
| title_full | Case report: Pharmacokinetics of pembrolizumab in a patient with stage IV non–small cell lung cancer after a single 200 mg administration |
| title_fullStr | Case report: Pharmacokinetics of pembrolizumab in a patient with stage IV non–small cell lung cancer after a single 200 mg administration |
| title_full_unstemmed | Case report: Pharmacokinetics of pembrolizumab in a patient with stage IV non–small cell lung cancer after a single 200 mg administration |
| title_short | Case report: Pharmacokinetics of pembrolizumab in a patient with stage IV non–small cell lung cancer after a single 200 mg administration |
| title_sort | case report pharmacokinetics of pembrolizumab in a patient with stage iv non small cell lung cancer after a single 200 mg administration |
| topic | pembrolizumab immunotherapy immune-related adverse events programmed cell death protein 1 (PD-1) pharmacodynamic (PD) pharmacokinetic (PK) |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.960116/full |
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