The pharmacokinetics (PK) of the anti-CD20 monoclonal antibody obinutuzumab was assessed after single intravenous dosing to cynomolgus monkeys. In addition, the pharmacokinetic-pharmacodynamic (PKPD) relationship for B-cell depletion was characterized. The PKPD model was used to estimate the B-cell repopulation during the recovery phase of chronic toxicology studies, thereby supporting the study design, in particular planning the recovery phase duration. Marked immunogenicity against obinutuzumab was observed approximately 10 days after single dose, leading to an up to ∼30-fold increase in obinutuzumab clearance in the affected monkeys. Despite this accelerated clearance, the PK could be characterized, either by disregarding the clearance in noncompartmental PK analysis or by capturing it explicitly as an additional time-dependent clearance process in compartmental modeling. This latter step was crucial to model the PKPD of B-cells as an indirect response to obinutuzumab exposure, showing that-without immune response-the limiting factor is obinutuzumab elimination with concentrations below 0.02 μg/mL required for initiation of B-cell recovery. Overall, the results demonstrate that despite a marked anti-drug antibody response in the nonclinical animal species, the PK and PKPD of obinutuzumab could be characterized successfully by appropriately addressing the immune-modulated clearance pathway in data analysis and modeling.
Keywords: B-cell; PKPD modeling; cynomolgus monkey; immunogenicity; monoclonal antibodies; obinutuzumab; pharmacokinetics.
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