Opportunities for using in silico‐based extended dosing regimens for monoclonal antibody immune checkpoint inhibitors

Abstract

Therapeutic drug monitoring (TDM) involves frequent measurements of drug concentrations to ensure levels remain within a therapeutic window, and it is especially useful for drugs with narrow therapeutic indices or extensive interindividual pharmacokinetic variability. This technique has never been applied to immuno‐oncology drugs, but, given recent examinations of clinical data (both exposure and response) on a number of these drugs, further investigations into TDM may be justified to reduce costs as well as potentially reducing the severity and/or duration of immune‐related adverse events. Specifically, all but one of the approved PD‐1 and PD‐L1 inhibitors (pembrolizumab, nivolumab, cemiplimab‐rwlc, atezolizumab, avelumab, durvalumab) have been shown to exhibit a plateaued exposure‐response (E‐R) curve at doses evaluated extensively to date, as well as time‐dependent changes in drug exposure. Furthermore, responders have a greater decrease in drug clearance over time and would, therefore, have supratherapeutic serum concentrations. With frequent trough measurements, it is possible to use pharmacokinetic modelling and simulation to estimate drug clearance via Bayesian methods. Based on patient‐specific estimates for clearance, optimal alternative dosing strategies can be simulated to lower drug and cost burden yet maintain therapeutic levels, especially as the clearance of the drug decreases over time. This review will comprehensively discuss each of the FDA approved PD‐1, PD‐L1/2 and CTLA‐4 inhibitors regarding their indications and current recommended dosing, with evidence supporting the investigation of these types of TDM strategies.

Cross-Validation of a Multiplex LC-MS/MS Method for Assaying mAbs Plasma Levels in Patients with Cancer: A GPCO-UNICANCER Study

“…For example, TDM of immune checkpoint inhibitors (ICIs), could be interesting, not necessarily as an attempt to tailor dosing to increase efficacy, but at least to customize the frequency of administrations, in a drug cost saving perspective [ 16 ]. Indeed, TDM-based determination of individual PK parameters could allow simulating the time to reach the efficacy threshold, and to determine when the next dose should be administered for a given patient [ 41 ]. A new bioanalytical method for TDM application in routine should meet different analytical requirements such as sensitivity, precision, and accuracy, in addition to ease of use, cost and time effectiveness considerations.…”

Direct analysis in real time-mass spectrometry for rapid quantification of five anti-arrhythmic drugs in human serum: application to therapeutic drug monitoring

“…Therapeutic drug monitoring prevents the drug concentration-dependent adverse reactions (ADR) and monitors the compliance. The concentrations of clinical TDM samples above the upper limits may have increased risks of ADRs 32 , 33 . The reported effective plasma concentration range was from 40 to over 3,000 ng/mL for propafenone and 500 to 2,500 ng/mL for amiodarone 32 .…”

The Right Dose: From Phase I to Clinical Practice

“…Modeling and simulation have been used to support label changes, and the current prescribing information includes the choice of 240 mg every 2 weeks or 480 mg every 4 weeks, likely at least twice that required for maximal efficacy. 50,148 As noted above, similar opportunities to reduce dose and/or frequency of administration for several other immune checkpoint inhibitors likely exist, 53 and an ongoing randomized trial to evaluate this hypothesis is ongoing. 149 In addition, multiple case reports and small case series, as well as a single-arm phase II trial in Hodgkin lymphoma, provide more justification for a formal evaluation of lower doses of these agents.…”

“…Although a similar analysis has not been performed (to our knowledge) for patent-protected parenteral drugs, there are some important opportunities, best exemplified by the immune checkpoint inhibitors. [49][50][51][52][53][54] Furthermore, because many patients treated with immune checkpoint inhibitors have prolonged progression-free survival (PFS) despite treatment discontinuation (e.g., due to adverse events), [55][56][57][58][59][60] the optimal duration of treatment is unknown. [61][62][63] Strategy to Identify Candidate Drugs for Financially Guided Dosing…”

“…The strategies that have been discussed in the sections above have been addressed comprehensively in several recent reviews. 5,6,48,53,131 In the previous section, ibrutinib was elaborately discussed as an example drug for receptor occupancy-guided dosing, but a few additional examples are worth highlighting in this article to illustrate how the discussed dosing strategies can be applied in clinical practice. It has to be noted, though, that most of the cited studies are early-phase trials and observational studies with relatively small sample sizes that do show equivalent pharmacokinetics but do not demonstrate survival noninferiority.…”