Population pharmacokinetic models of anti-PD-1 mAbs in patients with multiple tumor types: A systematic review

Our plain-English summary of Population pharmacokinetic models of anti-PD-1 mAbs in patients with multiple tumor types: A systematic review, by J. Shang, L. Huang, J. Huang, et al (Frontiers in Immunology, 2022).

The study

• Authors: J. Shang, L. Huang, J. Huang, X. Ren, Y. Liu, Y. Feng
• Journal: Frontiers in Immunology
• Published: 2022;13:871372
• Type of article: Systematic review
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Aims And Background: A number of population pharmacokinetic (PPK) models of anti-programmed cell death-1 (PD-1) monoclonal antibodies (mAbs) in multiple tumor types have been published to characterize the influencing factors of their pharmacokinetics. This review described PPK models of anti-PD-1 mAbs that investigate the magnitude and types of covariate effects in PK parameters, provide a reference for building PPK models of other anti-PD-1 mAbs, and identify areas requiring additional research to facilitate the application of PPK models.

Methods: A systematic search for analyses of PPK models of eleven anti-PD-1 mAbs on the market that were carried out in humans was conducted using PubMed, Embase, and the Cochrane Library. The search covered the period from the inception of the databases to April 2022.

Results: Currently, there are fourteen analyses on PPK models of anti-PD-1 mAbs summarized in this review, including seven models that refer to nivolumab, four referring to pembrolizumab, one referring to cemiplimab, one referring to camrelizumab, and one referred to dostarlimab. Most analyses described the pharmacokinetics of anti-PD-1 mAbs with a two-compartment model with time-varying clearance (CL) and a sigmoidal maximum effect. The estimated CL and volume of distribution in the central (VC) ranged from 0.179 to 0.290 L/day and 2.98 to 4.46 L, respectively. The median (range) of interindividual variability (IIV) for CL and VC was 30.9% (8.7%-50.8%) and 29.0% (4.32%-40.7%), respectively. The commonly identified significant covariates were body weight (BW) on CL and VC, and albumin (ALB), tumor type, sex, and performance status (PS) on CL. Other less assessed significant covariates included lactate dehydrogenase (LDH), immunoglobulin G (IgG), ipilimumab coadministration (IPICO) on CL, and body mass index (BMI), malignant pleural mesothelioma (MESO) on VC.

Conclusion: This review provides detailed information about the characteristics of PPK models of anti-PD-1 mAbs, the effects of covariates on PK parameters, and the current status of the application of the models. ALB, BW, specific tumor type, sex, and PS should be considered for the future development of the PPK model of anti-PD-1 mAbs. Other potential covariates that were assessed less frequently but still have significance (e.g., LDH, IgG, and IPICO) should not be ignored. Thus, further research and thorough investigation are needed to assess new or potential covariates, which will pave the way for personalized anti-PD-1 mAbs therapy.

Copyright © 2022 Shang, Huang, Huang, Ren, Liu and Feng.

In plain English

This article was a systematic review; it did not study asbestos exposure. The authors searched three databases up to April 2022 for population pharmacokinetic models (descriptions of how the body handles a drug) of anti-PD-1 antibodies, a type of cancer immunotherapy. Of 279 documents retrieved, fourteen analyses were included: seven on nivolumab, four on pembrolizumab, and one each on cemiplimab, camrelizumab and dostarlimab. Across the thirteen analyses that used a two-compartment model, the median estimated clearance (how fast the drug is removed) was 0.249 L/day. Lower albumin was linked to higher clearance in ten analyses, and higher body weight was linked to higher clearance in eight. One real-world pembrolizumab analysis, which used a one-compartment model, reported a lower volume of distribution in patients with malignant pleural mesothelioma than in patients with other tumor types (median effect of 42.0%). None of the models had been externally validated. The authors concluded that albumin, body weight, specific tumor type, sex and performance status should be considered in future models. They noted that details were missing from some publications and that only English-language publications were included.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Systematic review of published population pharmacokinetic (PPK) model analyses
• Who was studied: Fourteen published PPK analyses, selected from 279 documents found in PubMed, Embase and the Cochrane Library from database inception to April 2022. The analyses involved cancer patients with multiple tumor types, with a median of 1,137 patients per analysis. Twelve analyses used clinical trial data and two used real-world cohorts.
• Exposure: Anti-PD-1 monoclonal antibody cancer drugs (nivolumab, pembrolizumab, cemiplimab, camrelizumab, dostarlimab), given by intravenous infusion at weight-based or fixed doses. No asbestos exposure was studied.
• Main results:
  • Thirteen of the fourteen analyses used a two-compartment model.
  • Across the thirteen two-compartment analyses, median estimated clearance was 0.249 L/day (range 0.179 to 0.290 L/day).
  • The one analysis that used a one-compartment model could not estimate central and peripheral volumes separately. It estimated clearance at 0.257 L/day and volume of distribution at 6.8 L.
  • Clearance increased as albumin decreased. This effect was significant in ten analyses, with a median effect ranging from 22.7 to 67.3%.
  • In eight analyses, clearance increased with body weight, with a median effect ranging from 21.1 to 29.8%.
  • In the one-compartment, real-world pembrolizumab analysis, patients with malignant pleural mesothelioma (MESO) had a lower volume of distribution than patients with other tumor types (median effect of 42.0%). The review labels this volume VC in this passage.
  • All analyses used internal evaluation only; none had been externally validated.
• The authors' conclusion: The authors concluded that albumin, body weight, specific tumor type, sex and performance status should be considered when developing future PPK models of anti-PD-1 antibodies. They also concluded that further research is needed on new or potential covariates.
• Limitations the authors state:
  • Some model information was missing because of a lack of detail in some publications.
  • Most analyses used clinical trial data; only two used real-world data.
  • The covariates available or investigated varied widely among publications.
  • No PPK analyses were available for six other marketed anti-PD-1 antibodies.
  • Only English-language publications were included, so research published in other languages may have been missed.

Topics

Medical terms in this study, explained in our Lexicon: Systematic Review, Monoclonal Antibody, Nivolumab (Opdivo), Pembrolizumab (Keytruda), Performance Status, Lactate Dehydrogenase (LDH), Ipilimumab (Yervoy), Pleural Mesothelioma.

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