Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

Abstract

Aims The development of monoclonal antibodies (mAbs) requires an understanding of the interindividual variability (IIV) in pharmacokinetics (PK) at the population level facilitated by population PK (PopPK) modelling. However, there is no clear rationale for selecting which covariates to screen during PopPK model development. Here, we compare the effect of covariates on PK parameters for mAbs in oncology and identify the most commonly used covariates affecting PK parameters. Methods All 25 mAbs approved for therapeutic use in oncology until December 2017 by the Food and Drug Administration and the European Medicines Agency were selected for study. Literature searches revealed 23 available PopPK models for these mAbs. To understand the magnitude and types of covariate effect on PK parameters, all covariates included in the final PopPK model for each mAb were summarized. Results The most commonly identified covariates were baseline body weight (BW; 17 mAbs), baseline serum albumin (8 mAbs), and sex (7 mAbs) on clearance; and BW (16 mAbs) and sex (12 mAbs) on central volume of distribution. A reduced PopPK model was developed for nivolumab and ipilimumab using these covariates, and the percentage of explained IIV from the reduced model (20.3% and 16.8%, respectively) was compared with that from the full model (24.5% and 27.9%, respectively). Conclusions This analysis provides a uniform platform for selecting covariates and suggests that the effect of BW, albumin and sex should be included during the development of PopPK models for mAbs in oncology. The reduced model was able to explain IIV to a similar extent as the full model.

Population Pharmacokinetics of Trastuzumab Deruxtecan in Patients With HER2‐Positive Breast Cancer and Other Solid Tumors

“…Body weight, albumin, tumor size, sex, and country were identified as statistically significant covariates for intact trastuzumab deruxtecan. Trastuzumab deruxtecan clearance increases with increasing body weight; this is expected and consistent with current knowledge about monoclonal antibodies 22 . However, because trastuzumab deruxtecan is administered by weight‐based dosing (i.e., drug amount administered increases with increasing weight), the apparent net effect of increased body weight is slightly increased exposure.…”

Identifying biophysical assays and in silico properties that enrich for slow clearance in clinical-stage therapeutic antibodies

“…Furthermore, the clearance reported in well-designed clinical PK studies, as used in this dataset, filters out the effect of ADA, either by focusing on the first weeks after first dosing in drug naïve subjects, or by the design of the PK study and analysis itself, excluding ADA positive subjects or by investigating ADA positivity as a covariate in a population PK analysis. 30,31 A high incidence of clearing ADA was not observed in clinical PK studies in drug-naïve subjects, for the fast clearing antibodies in our dataset. [32][33][34] As consequently we can exclude ADAs, we attribute the difference we observe (Figure 2a) to different sequence motifs or biophysical properties of the chimeric antibodies.…”

Is weight-based IV dosing of trastuzumab preferable to SC fixed-dose in some patients? A systematic scoping review

“…PopPK models are widely used to determine the influence of different covariates, including body weight, on interindividual variability in PK [ 2 ]. PopPK models for trastuzumab consistently identified body weight [ 7 , 15 , [27] , [28] , [29] , [30] , [31] , [32] ] or BMI [ 33 ] as a significant covariate for linear clearance (point estimate > 0.5 [ 1 ]) in HER2-positive EBC, MBC and metastatic gastric cancer (MGC).…”

“…Optimizing the therapeutic index across a target patient population requires understanding of the exposure–effect relationship and interindividual variability in the PK of the therapeutic [ 2 ]. The optimal efficacy of monoclonal antibodies (mAbs) requires saturation of the accessible target sites [ 3 ].…”