Comparative clinical pharmacokinetics of antibody-drug conjugates in first-in-human Phase 1 studies

Abstract

Although there are currently more than 30 antibody-drug conjugates (ADC) in clinical development for the treatment of blood cancers and solid tumors, comparison of their clinical pharmacokinetics (PK) is challenging because of the large number of, and differences between, the targets, ADC constructs, dosing regimens, and patient populations. In this review, we standardized the evaluation, using non-compartmental PK data reported at Cycle 1, i.e., following the first drug administration of what is usually a repeated-dose treatment, in monotherapy. We report ADC clinical PK properties, dosing regimen, determination of doses ranges and associated maximum tolerated doses. We also evaluated the effect of structural characteristics and target types (hematological vs. solid tumors) on PK. In addition, we discuss how integration of PK/pharmacodynamics approaches on top of classical dose escalation in first-in-human studies may improve dosing regimen determination for subsequent phases of clinical development.

Keywords: antibody-drug conjugates; dose selection; dosing regimen; maximum tolerated dose; oncology; pharmacokinetics; phase I.

Figure 1. ADC dose ranges and maximum tolerated doses in first-in-humans studies. Gray symbol: MTD; open symbol: MTD not reached.

Figure 2. ADC dose escalation profiles in first-in-human studies.

Figure 3. Dose-exposure relationship for ADC administered every 3 wk.

Figure 4. Effect of dose on ADC clearance, by target antigen type (HT, hematological tumor; ST, solid tumors. (Boxes indicate maximum tolerated dose in mg/kg)

Figure 5. Unconjugated drug plasma exposure vs. ADC plasma exposure.