What is the importance of monitoring free and total pharmacokinetics (PK) in humans for bispecific antibodies?

Monitoring Free and Total Pharmacokinetics in Humans for Bispecific Antibodies

For bispecific antibodies, monitoring both free and total pharmacokinetics is essential for accurate assessment of target engagement, efficacy prediction, and optimal dosing strategies due to their complex binding characteristics and target-mediated drug disposition.

Key Considerations for Bispecific Antibody PK Assessment

Importance of Free vs. Total PK Measurements

• Free drug concentration at the site of action drives pharmacological effects, making free drug measurements critical for bispecific antibodies that target extracellular antigens 1
• Unlike small molecules where plasma protein binding studies are routinely needed, for antibody therapeutics including bispecifics, free drug is typically directly measured as the second part of the free drug hypothesis does not apply 1
• Target-mediated drug disposition (TMDD) significantly affects bispecific antibody clearance, especially at lower doses, necessitating mechanistic PK models that incorporate both free and total measurements 2

Unique Challenges in Bispecific Antibody PK Assessment

• Bispecific antibodies require characterization of multiple functional domains and consideration of potential interference by antitherapeutic antibodies against each domain 3
• Multiple bioanalytical methods may be needed to answer critical questions for each phase of drug development for molecules with multiple binding domains 3
• Understanding the relative affinities to each target is crucial for determining mechanism of action and efficacy of bispecific antibodies 4

Sampling Strategy and Timepoints

Optimal Sampling Approach

• A staggered sampling approach that captures binding kinetics of both receptors is recommended, as they may differ significantly 5
• Precise recording of drug administration and sampling times is essential to ensure accurate PK modeling 5
• Sampling schedules should be designed to capture the full duration of receptor occupancy, particularly for irreversibly binding compounds 5

Laboratory Measurements and Reporting

• Use appropriate laboratory tests for measuring bispecific antibody concentrations and report measurements in standardized units 1
• Include preinfusion samples when the patient receives treatment in the clinic to establish baseline levels 1
• Report activity levels below the limit of quantification (BLQ) rather than discarding this information, as ignoring BLQ data may bias individual estimates 1

PK/PD Modeling Approach

Model Development

• Integrated PK/PD models that incorporate binding characteristics of both receptors and downstream signaling effects are recommended 5
• Population pharmacokinetic (PopPK) modeling should be used to account for variability in receptor expression and binding across patients 5
• PBPK modeling can guide and support bispecific antibody development, from target evaluation and drug optimization to therapeutic dose selection 6

Clinical Implementation

• Include pharmacodynamic biomarkers in Phase I trials to confirm target engagement predictions from preclinical models 5
• Consider using surrogate tissues (e.g., PBMCs) for initial receptor occupancy measurements, but validate correlation with target tissue 5
• Implement broader eligibility criteria to ensure the trial population resembles the real-world population in whom the drug will ultimately be used 5

Physiological Limitations and Considerations

Tissue Distribution Factors

• Only about 0.1-1% of the dosed bispecific antibody is likely to reach solid tumors, while the rest ends up in healthy tissues due to target-mediated internalization and nonspecific uptake 6
• Dual-positive tumor cell targeting specificity with bispecific antibodies is likely to be higher at lower drug concentrations and doses 6
• Normal physiological characteristics like organ volumes, blood flow rates, lymphatic circulation, and rates of extravasation substantially limit the tissue-targeting accuracy of bispecific antibodies 6

Special Patient Populations

• For patients receiving bispecific antibody therapy for multiple myeloma, monitoring for hypogammaglobulinemia is important as it may affect drug clearance and increase infection risk 1
• Consider the impact of prior treatments (e.g., CAR T-cell therapy, chemotherapy, proteasome inhibitors) on the PK profile of bispecific antibodies 1

Practical Implementation

Assay Design Principles

• Ensure the assay can detect allosteric interactions between the two binding sites that may affect drug binding kinetics 5
• Incorporate measurements of receptor occupancy as a key pharmacodynamic endpoint, particularly for irreversibly binding compounds 5
• Establish the physical association of both receptors in native tissue through appropriate technologies to confirm their interaction patterns 5

Potential Pitfalls and Limitations

• Differences in species biology may lead to differences in receptor expression, binding kinetics, and downstream signaling between preclinical models and humans 5
• Consider the possibility of synergistic or overlapping toxicities when targeting multiple receptors simultaneously 5
• Account for potential PK interactions between the two binding sites that may affect exposure-response relationships 5, 7