Felix Stader1, Cong Liu1, Adriana Zyla1, Abdallah Derbalah1, Armin Sepp1
1Certara Predictive Technologies
Introduction Hepatic impairment (HI) is a common comorbidity in cancer patients [1]. Monoclonal antibodies (mAbs) are frequently used in cancer treatment; however, the impact of HI on the pharmacokinetics (PK) of mAbs is not well characterized. Alirocumab and evolocumab are two PCSK9 antagonists for which dedicated clinical studies in patients with mild and moderate HI were conducted. Both mAbs show a decrease in drug exposure up to 43%, which could be the result of elevated serum IgG [2, 3], which itself can be explained by higher de novo IgG synthesis [4]. Objectives The impact of elevated IgG concentration on alirocumab and evolocumab PK in patients with HI was investigated by a physiologically based pharmacokinetic (PBPK) model. Methods The whole-body PBPK model for mAbs, implemented in the Simcyp Simulator V24®, was used [5]. A literature search was conducted with the keywords “IgG” and “liver cirrhosis” to investigate the serum IgG concentration with severity of HI, classified by the Child-Pugh score. Alirocumab and evolocumab were used to evaluate the PBPK model performance against clinically observed data [2, 3]. Both drugs were administered subcutaneously. The demographics and the baseline circulating target concentration, measured in the clinical study, were used to generate a virtual population in 20 different trials. Simulations with the HI populations implemented in the Simcyp Simulator® were done with the control and the increased serum IgG levels. The predictions of the plasma concentration-time profile, the peak concentration (Cmax), and the area under the curve extrapolated to infinity (AUCinf) were compared against the clinically observed data. The ratio of HI to healthy controls was calculated. Results Serum IgG levels in liver cirrhosis were reported in six studies, ranging from 8.6 to 40.0 g/L [4, 6-10], which means a higher maximum value compared with the normal range of IgG serum concentration (8 to 18 g/L). The calculated fold increase in IgG concentration was 1.4, 1.5 and 2.0 in mild, moderate, and severe HI. The clinically observed concentration-time profiles of both mAbs were predicted within the 95% confidence interval for healthy controls, mild and moderate HI. PK parameters were predicted within 2.0-fold of observed data. Predicted alirocumab exposure decreased by 16% (pred:obs 1.02) and 22 % (pred:obs: 0.80) in mild and moderate HI when control IgG values were used in the simulations. If plasma IgG levels were increased, the predicted decline in drug exposure was 39% (pred:obs 0.73) and 47% (pred:obs: 0.55) in mild and moderate HI. The predicted drug exposure of evolocumab decreased by 15% (pred:obs: 0.93) and 17% (pred:obs 0.68) when control IgG levels were used and by 34% (pred:obs 1.19) and 40% (pred:obs: 0.94) with increased IgG plasma concentration in mild and moderate HI, respectively. Conclusion The study demonstrated that the PBPK approach can be successfully used to simulate the PK of mAbs in HI. IgG has high variability, and some patients might have elevated IgG levels that impact the PK as shown for evolocumab. Thus, sensitivity analysis is recommended with control IgG, mean elevated IgG and the maximum of measured IgG concentration to predict the worst-case scenario. However, other factors such as alterations of FcRn abundance or changes in the lymphatic system might also play a role.
1. Krens SD, et al., Lancet Oncol., 2019. 20(4): p. e200. 2. US Food and Drug Administration. Plaluent – Clinical Pharmacology Review. 2014; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125559Orig1s000ClinPharmR.pdf. 3. Gibbs JP, et al., J Clin Pharmacol., 2017. 57(4): p. 513. 4. Tanaka S, et al., Hepatogastroenterology, 2007. 54(80): p. 2301. 5. Huang W, et al., Front Pharmacol., 2022. 13: p. 974423. 6. Westergaard H, et al., Scand J Gastroenterol, 1972. 7(7): p. 623. 7. Mutchnick M, et al., Clin Exp Immunolo, 1981. 43(2): p. 370. 8. Feng Z-J, et al., World J Gastroenterol., 1997. 3(1): p. 22. 9. Zhang K, et al., World J Clin Cases, 2022. 10(36): p. 13208. 10. Zheng W, et al., Exp Ther Med, 2021. 21(1): p. 1.
Reference: PAGE 33 (2025) Abstr 11684 [www.page-meeting.org/?abstract=11684]
Poster: Clinical Applications