(W1030-10-67) Pharmacokinetics of Biologics in Obese Rats

Purpose: The prevalence of obesity is rapidly increasing. Current knowledge regarding appropriate dosing strategies for protein therapeutics and monoclonal antibodies treatments in patients with obesity is very limited. In this study, we compared the pharmacokinetics of nivolumab and recombinant human erythropoietin between lean and obese rats.

Methods: Male Long-Evans rats were randomized to receive either Teklad high-fat diets (HFD; Custom Diet TD.06414) or Teklad regular diets (2014S) from the age of 3 weeks. Total body weight (TBW) and body composition were monitored weekly. At the age of 18 weeks, the rats were dosed intravenously with nivolumab (1 mg/kg or 8 mg/kg) or recombinant human erythropoietin (1000 IU/kg) and the blood samples were collected from the saphenous veins. Serum samples were analyzed by enzyme-linked immunosorbent assay (ELISA). Pharmacokinetics parameters were calculated using noncompartmental approach using Phoenix WinNonLin (Certara, NJ) and compared using t-tests.

Results: Total body weight was 433 ± 43 g and fat mass was 63 ± 26 g of obese group; total body weight was 281 ± 32 g and fat mass was 18 ± 5 g of lean group at the time of dosing, indicating obesity was developed successfully using high-fat diet. As shown in Figure 1, no significant differences were found in the pharmacokinetics profiles of either nivolumab or recombinant human erythropoietin between lean and obese groups. As shown in Table 1 and 2, no statistical differences were found in pharmacokinetics parameters between lean and obese groups either.

Conclusion: We have previously demonstrated significant differences in pharmacokinetics of human IgG in obese Zucker rats in comparison to lean Zucker rats after intravenous and subcutaneous administration. However, there was no observable difference in pharmacokinetics of nivolumab and recombinant human erythropoietin between lean and obese rats. Therefore, additional studies with other biologics are urgently needed in both preclinical and clinical settings.

References: Mechanisms of Obesity-Induced Changes in Pharmacokinetics of IgG in Rats. Xizhe Gao, Yi-Hua Sheng, Sijia Yu, Jiadong Li, Raymond Rosa, Simone Girgis, Tiffany Guo, Luigi Brunetti and Leonid Kagan. Pharm Res. 2023 Mar 22;1-16.

Figure 1. Observed pharmacokinetics profiles for intravenous nivolumab and recombinant human erythropoietin.

Table 1. Pharmacokinetics parameters for intravenous nivolumab calculated by NCA. AUC, area under the curve; CL, clearance; Vss, volume of distribution at steady state; T1/2, half-life.

Table 2. Pharmacokinetics parameters for intravenous erythropoietin calculated by NCA. AUC, area under the curve; CL, clearance; Vss, volume of distribution at steady state; T1/2, half-life.