Population Pharmacokinetics of Durvalumab in Cancer Patients and Association With Longitudinal Biomarkers of Disease Status

Abstract

The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, an anti‐PD‐L1 antibody, and quantify the impact of baseline and time‐varying patient/disease characteristics on PK. Pooled data from two studies (1,409 patients providing 7,407 PK samples) were analyzed with nonlinear mixed effects modeling. Durvalumab PK was best described by a two‐compartment model with both linear and nonlinear clearances. Three candidate models were evaluated: a time‐invariant clearance (CL) model, an empirical time‐varying CL model, and a semimechanistic time‐varying CL model incorporating longitudinal covariates related to disease status (tumor shrinkage and albumin). The data supported a slight decrease in durvalumab clearance with time and suggested that it may be associated with a decrease in nonspecific protein catabolic rate among cancer patients who benefit from therapy. No covariates were clinically relevant, indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following weight‐based and flat‐dosing regimens.

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

“…All covariates included in the final PopPK model for 23 mAbs, including the PK structural model, were summarized from the literature review (Table ) . The effect of covariates was evaluated specifically for the linear portion of CL for mAbs exhibiting linear or parallel linear and nonlinear CL.…”

“…It is also notable that the magnitude of effect of BW on CL was substantially higher for elotuzumab, rituximab and trastuzumab when compared with other mAbs. Along with several other mAbs included in the analysis (daratumumab, durvalumab and panitumumab), these 3 mAbs exhibit parallel linear and nonlinear kinetics; nevertheless, it should be noted that for elotuzumab, rituximab and trastuzumab, the effect of BW was included only on the linear component and not on the nonlinear part of CL. In our opinion, BW might also influence the nonlinear component of CL and, if not included as a covariate, this effect of BW on the nonlinear CL may be distributed to linear CL.…”

“…Additionally, the current analyses evaluated only the most common covariates that were included in PopPK models for more than 5 mAbs (of the 23 identified). Tumour size was included in the final PopPK model for 5 mAbs, whereby a larger tumour size was associated with higher CL . In addition to BW, ALB, and sex, other covariates might also influence PK of mAbs in oncology (e.g.…”

Nivolumab Clearance Is Stationary in Patients With Resected Melanoma on Adjuvant Therapy: Implications of Disease Status on Time‐Varying Clearance

“…If baseline CL is reflective of disease status, then it is reasonable to conclude that as patients respond to therapy, this will have a positive impact on overall disease status, as measured by reduced tumor burden, and CL would decrease. Consistent with the idea that reduction in CL can effect a biomarker of response, a recent report describing time‐varying CL for durvalumab included longitudinal time‐varying biomarkers in the PopPK model to determine if these could sufficiently account for the empirical time‐varying CL term in the model. Time‐varying biomarkers, such as lactate dehydrogenase (LDH), albumin, neutrophil‐to‐lymphocyte ratio, and tumor size were evaluated in the PopPK model and compared with an empirical time‐varying CL model similar to the one described here.…”

“…Nivolumab clearance (CL) has been shown to decrease with time, with ~ 25% maximum reduction within 3 months after nivolumab treatment . This change in CL after treatment has also been reported for other checkpoint inhibitors and is believed to be associated with improved disease status . Additionally, baseline nivolumab CL was different among tumor types, with values 20% higher and 25% lower in patients with gastric cancer and classical Hodgkin's lymphoma, respectively, compared with patients with NSCLC or MEL…”