100: Sex-Related Differences in the Pharmacokinetics of Therapeutic Proteins

Statement of Purpose, Innovation or Hypothesis: Pharmacotherapy has witnessed a significant shift towards therapeutic proteins (TPs), with a wide array of protein-based treatments having gained approval for clinical use. Despite the increasing prominence of TPs, there remains a gap in understanding potential sex-specific differences in their pharmacokinetics (PK). This brief review aims to explore the existing literature on sex-specific disparities in the PK of TPs.

Description of Methods & Materials: We constructed a dataset containing TPs currently approved for use in the US market. Our data sources comprised publicly available information from the drug approval packages at the FDA website, published scientific articles, conference abstracts, and other relevant sources. The results obtained from our analysis were categorized into four groups: 1.) "Different", TPs where PK differences were explicitly mentioned for any of the PK parameters in the available literature and if sex emerged as a significant covariate for any PK parameter in a population pharmacokinetic (PPK) analysis. These PK differences persisted after adjusting for the body weight differences, which is considered a potential confounding factor.; 2.) "Not Different", TPs where no PK differences were reported, or if sex was not deemed a significant covariate for any PK parameter in a PPK analysis; 3.) "Not available" this group includes situations where data regarding sex-related differences in PK were absent; 4.) "Not applicable" this category was utilized when PK data were exclusively available within specific patient populations, rendering the assessment of sex-related differences impractical or irrelevant.

Data & Results: Our analysis revealed that 65% (176/274) of all reviewed TPs, reported sex-related information about PK. Among these, 74% (126/176) showed “No Differences”, while approximately 26% (51/176) exhibited variations in one or more PK parameters (“Different”). Generally, males demonstrated higher volumes of distribution (Vd) and clearances, with differences typically falling within the range of 10% to 30%. Notably, for 3 TPs, the differences were more pronounced: clearances were 39%, 33%, 49% lower in females compared to males for rituximab, infliximab and elranatamab respectively. Exceptions were observed where Vd was higher in females (e.g., palifermin, peginterferon beta-1a), and exposures and clearances were higher in females (e.g., lonapegsomatropin, palifermin, peginterferon alfa-2b, pegvisomant, golimumab, secukinumab). However, none of these differences were deemed clinically significant, as the proposed doses for males and females remained unchanged. About 28% (76/274) of the TPs lacked data on sex-related differences (“Not Available) in PK, and 8% of them were not evaluated due to their association with sex-specific diseases (“Not applicable”).

Interpretation, Conclusion or Significance: Sex-related differences in the Vd of TPs and clearance may arise from variations in the proportions of muscular and adipose tissue between males and females. Typically, females exhibit lower body weight and body surface area, leading to smaller organ sizes, reduced blood flow, and differences in extracellular fluid volume. Additionally, females tend to have a higher percentage of body fat and differences in the lymphatic system. Nonetheless, certain classes of TPs, such as mAbs targeting B cells and growth factors, exhibit consistent sex-related differences in volumes of distribution and clearance potentially due to variations in target expression levels, Fc receptor biology, or hormonal influences.

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