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Life-threatening toxicities upon Pembrolizumab intake: could pharmacokinetics be the bad guy?

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Abstract

Purpose

We report the case of an adult patient diagnosed with Hodgkin’s lymphoma who was scheduled for Pembrolizumab after failure of standard therapy. After three well-tolerated courses of Pembrolizumab, a PET scan showed a favorable outcome and a fourth course of Pembrolizumab was started. Unexpectedly, extremely severe toxicities (i.e., autoimmune peripheral hypothyroidism, rhabdomyolysis and severe acute renal failure) occurred after this last course, requiring transfer to the intensive care unit.

Methods

Therapeutic drug monitoring was performed to measure residual Pembrolizumab levels at intervals from the last dose (i.e., 120 and then 170 days), as well as pharmacogenetics investigations on the FCγR gene.

Results

Pembrolizumab plasma concentrations that were still pharmacologically active months after the last administration, suggesting impaired elimination of Pembrolizumab in this patient. Further pharmacokinetic modeling based on the population approach showed that both half-life (47.8 days) and clearance (0.12 L/day) values were significantly different from the standard values usually reported in patients. Further in silico simulations showed that pharmacologically active concentrations of Pembrolizumab were maintained for up to 136 days after the last dose. The search for possible polymorphisms affecting the genes coding for FCγR (i.e., rs1801274 on FCGR2A and rs396991 on FCGR3A gene) was negative. Further TDM showed that Pembrolizumab could be detected up to 263 days after the last administration.

Conclusion

This case report suggests that persistent overexposure in plasma could lead to life-threatening toxicities with Pembrolizumab.

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Availability of data and materials

Both clinical and biological raw data plus technical details regarding bioanalytical or genotyping procedures will be made available upon request to the Corresponding Author.

Availability of code

The source code we have used is available as a supplementary electronic file.

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Funding

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Author information

Authors and Affiliations

  1. SMARTc Unit, CRCM Inserm U1068, Aix Marseille Univ, Marseille, France

    Mourad Hamimed, Clémence Marin & Joseph Ciccolini

  2. COMPO, CRCM Inserm U1068 and INRIA Sophia Antipolis, Aix Marseille Univ, Marseille, France

    Mourad Hamimed & Joseph Ciccolini

  3. Hematology Unit, Paoli Calmettes Institute, Marseille, France

    Raynier Devillier, Pierre-Jean Weiller, Jean-Marc Schiano, Nawel Belmecheri & Samia Harbi

  4. Oncopharmacology Unit, Centre Antoine Lacassagne, Nice, France

    Marie-Christine Etienne-Grimaldi

  5. Clinical Pharmacokinetics Laboratory, La Timone University Hospital of Marseille, Marseille, France

    Clémence Marin & Joseph Ciccolini

Authors
  1. Mourad Hamimed
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  2. Raynier Devillier
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  3. Pierre-Jean Weiller
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  4. Clémence Marin
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  5. Jean-Marc Schiano
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  6. Nawel Belmecheri
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  7. Marie-Christine Etienne-Grimaldi
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  8. Joseph Ciccolini
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  9. Samia Harbi
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Contributions

Pharmacometrics, modeling and simulation: MH. Bioanalysis: CM, JC. Genotyping: MCEG. Data collection: RD, PJW, JMS, NB and SH. Manuscript drafting and writing: MH, RD, SH, JC. Manuscript final approval: all authors.

Corresponding author

Correspondence to Joseph Ciccolini.

Ethics declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest with the reported data or case presentation.

Ethical approval and consent to participate

Treatment, sampling for biological analyze including drug monitoring, and clinical evaluations were all performed following standard practice in our institute in all patients with cancer and not part of an experimental protocol. Genotyping was not part of routine care and written informed consent was thus obtained from the patient prior to perform germinal genotyping of the FCGR2A and FCGR3A genes, following the French Biomedicine Agency guidelines.

Patients authorization to publish the case

Authorization was waived because in this case report, no potentially identifiable images or data related to the patient are displayed.

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Hamimed, M., Devillier, R., Weiller, PJ. et al. Life-threatening toxicities upon Pembrolizumab intake: could pharmacokinetics be the bad guy?. Cancer Chemother Pharmacol 93, 627–632 (2024). https://doi.org/10.1007/s00280-023-04611-x

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  • DOI: https://doi.org/10.1007/s00280-023-04611-x

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