Optimizing Anti-PD1 Immunotherapy: An Overview of Pharmacokinetics, Biomarkers, and Therapeutic Drug Monitoring
Abstract
Simple Summary
Abstract
1. Introduction
2. Pharmacokinetics of Anti-PD-1
2.1. Disposition Mechanisms of Anti-PD-1 mAbs
2.1.1. Target-Mediated Drug Disposition
2.1.2. Non-Selective Mechanisms
Neonatal Fc Receptor
Gamma Fc Receptor
Tissue Proteolysis
Autoantibodies
2.1.3. Anti-Drug Antibodies
2.2. Pharmacokinetic Models
2.3. Factors Influencing Pharmacokinetics of Anti-PD-1
2.3.1. Albumin and Cachexia
2.3.2. Disease Burden
3. Pharmacokinetic–Pharmacodynamic Relations
3.1. Exposure–Efficacy Relations
3.2. Exposure–Safety Relations
3.3. Clearance–Efficacy and/or Safety Relationships
4. Biomarkers for Anti-PD-1 Therapies
5. Rethinking Dosing Strategies for Anti-PD-1: The Role of TDM
6. Clinical Implications and Future Directions
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Abbreviations
ADAs | Anti-drug antibodies |
ADCC | Antibody-dependent cellular citotoxicity |
ALB | Albumin |
Anti-TIM3 | Anti-T cell mucin domain 3 |
Anti-TIGIT | Anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains |
AUC | Area under plasmatic concentration versus time curve |
BW | Body weight |
CL | Clearance |
CL0 | Baseline clearance |
CL–R | Clearance–response |
Cmin, ss | Steady-state trough concentrations |
CTLA4 | Cytotoxic T- lymphocyte-associated antigen 4 |
DCs | Dendritic cells |
ELISA | Enzyme-linked immunosorbent assay |
ECM | Extracellular matrix |
E–R | Exposure–Response |
FcRn | Neonatal Fc receptor |
FcRs | Fc receptors |
FcγR | Gamma Fc receptor |
ICIs | Immune checkpoint inhibitors |
IFN-γ | Gamma-interferon |
Ig | Immunoglobulin |
IL-1 | Interleukin 1 |
irAEs | Immune-related adverse events |
LC-MS/MS | Liquid chromatography tandem mass spectrometry |
mAbs | Monoclonal antibodies |
MMP | Matrix metalloproteinases |
NK | Natural killer |
NSCLC | Non-small cell lung cancer |
OS | Overall survival |
PB | Peripheral blood |
PBPK | Physiologically based pharmacokinetic |
PD | Pharmacodynamics |
PD-1 | Programmed cell death protein 1 |
PD-L1 | Programmed death-ligand 1 |
PK | Pharmacokinetics |
PK–PD | Pharmacokinetic–Pharmacodynamic |
PopPK | Population pharmacokinetics |
PS | Performance status |
TDM | Therapeutic drug monitoring |
TMB | Tumor mutational burden |
TMDD | Target-mediated drug disposition |
TNF-α | Tumor necrosis factor-alpha |
Vd | Volume of distribution |
ΔCL | Change in clearance over time |
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Pharmacokinetic | Pembrolizumab [21,23] | Nivolumab [21,24] | Cemiplimab [25] |
---|---|---|---|
Model | Two-compartment model with first-order elimination, zero-order iv infusion rate, and time-varying change in CL | ||
Linear | Doses range: 2–10 mg/kg t1/2β = 22–27.3 days CL = 0.2–0.22 L/day Vdss = 6 L | Dose range: 0.1 to 20 mg/kg t1/2α = 32.5 h, t1/2β = 25 days CL = 0.226 L/day Vc = 3.63 L; Vp = 2.78 L Tmáx = 1–4 h (Normalized to BW of 80 kg) | Dose range: 1 to 10 mg/kg CL = 0.246 L/day t1/2β = 19.7 days Vdss = 5.89 L |
Non-linear | Time-varying CL = 16–19 weeks | Time-varying CL = 12–16 weeks |
Biomarker | Category | Status | References |
---|---|---|---|
Effectiveness | |||
PD-L1 expression | Protein (tumor/immune) | Approved | [142,143,144] |
TMB | Genomic | Approved (TMB ≥10 mut/1 Mb) | [144,145] |
dMMR/MSI-H | Genomic | Approved | [146,147,148] |
Tumor-infiltrating lymphocytes | Histological | Investigational | [149] |
Gene expression signatures | Transcriptomic | Investigational | [135] |
Antibiotic use | Clinical factors | Observational | [150] |
miRNA signatures (germline) | Epigenetic | Exploratory | [151] |
Effectiveness and/or Safety | |||
Lymphocyte counts/NLR | Hematologic | Investigational | [152,153,154] |
Circulating cytokines and other inflammatory markers | Soluble proteins | Investigational | [155,156,157] |
Clearance monitoring (CL0 and ΔCL) | Pharmacokinetics | Investigational | This work * [123] |
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Monteiro, J.F.; Fernandes, A.; Tato, D.G.; Moreira, E.; Ribeiro, R.; Reguengo, H.; Gonçalves, J.; Fresco, P. Optimizing Anti-PD1 Immunotherapy: An Overview of Pharmacokinetics, Biomarkers, and Therapeutic Drug Monitoring. Cancers 2025, 17, 3262. https://doi.org/10.3390/cancers17193262
Monteiro JF, Fernandes A, Tato DG, Moreira E, Ribeiro R, Reguengo H, Gonçalves J, Fresco P. Optimizing Anti-PD1 Immunotherapy: An Overview of Pharmacokinetics, Biomarkers, and Therapeutic Drug Monitoring. Cancers. 2025; 17(19):3262. https://doi.org/10.3390/cancers17193262
Chicago/Turabian StyleMonteiro, Joaquim Faria, Alexandrina Fernandes, Diogo Gavina Tato, Elias Moreira, Ricardo Ribeiro, Henrique Reguengo, Jorge Gonçalves, and Paula Fresco. 2025. "Optimizing Anti-PD1 Immunotherapy: An Overview of Pharmacokinetics, Biomarkers, and Therapeutic Drug Monitoring" Cancers 17, no. 19: 3262. https://doi.org/10.3390/cancers17193262
APA StyleMonteiro, J. F., Fernandes, A., Tato, D. G., Moreira, E., Ribeiro, R., Reguengo, H., Gonçalves, J., & Fresco, P. (2025). Optimizing Anti-PD1 Immunotherapy: An Overview of Pharmacokinetics, Biomarkers, and Therapeutic Drug Monitoring. Cancers, 17(19), 3262. https://doi.org/10.3390/cancers17193262