Model-based optimal dosing regimen for recombinant hepatitis B human immunoglobulin (GC1102) in Chronic Hepatitis B Patients
Do Hoon Keum (1,2), Byung Hak Jin (1), Yesong Shin (3), Choon Ok Kim (1), Min Soo Park (1,2,4) and Dongwoo Chae (1,3)
(1) Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (2) Department of Pharmaceutical Medicine and Regulatory Sciences, College of Medicine and Pharmacy, Yonsei University, Incheon, South Korea (3) Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea (4) Department of Pediatrics, Yonsei University College of Medicine, Seoul, South Korea
Objectives:
To propose a model-based optimal dosing regimen of recombinant hepatitis B human immunoglobulin based on phase 1 clinical data of GC1102.
Methods:
In a prospective, open-label, phase 1 clinical trial performed at Severance Hospital in Seoul, Korea, pharmacokinetic (PK) (GC1102 concentration) and pharmacodynamics (PD) data (HBsAg titer) were collected from patients with chronic hepatitis B who received intravenous single ascending doses and multiple ascending doses of GC1102.
In Part A of the clinical trial, six subjects were given single intravenous doses of GC1102 at different levels: 80000 IU, 120000 IU, 180000 IU, and 240000 IU, respectively.
Part B involved administering the same doses used in Part A to six subjects weekly for four weeks. The M3 method was used to handle the significant fraction of BQL (below the limit of quantification) concentrations, and a Target-Mediated Drug Disposition Model (TMDD) was used to fit the data. RStudio Version 1.4.1106 was used for data preprocessing and exploration, while NONMEM (version 7.4, ICON Development Solutions) was used for modeling and simulation.
Results:
As a preliminary modeling step, a simple one-compartment PK model was fitted to the data and was found to describe the typical pharmacokinetics of GC1102 well. The estimated clearances were found to be significantly correlated with baseline HBsAg levels (p=4.66e-05). Based on this evidence, a Target-Mediated Drug Disposition (TMDD) model of GC1102 was developed under the Quasi-Steady State (QSS) assumption.
The estimation revealed higher target-mediated clearance of HBsAg (k_int=0.0072/hr) than its free form (k_deg=0.0031/hr). Pre-treatment HBsAg was 277.2 IU/mL, and K_ss was 184 IU/mL.
Simulations indicated rapid HBsAg reduction even at the lowest GC1102 dose, but suppression duration increased with higher doses. Pre-treatment HBsAg level inversely correlated with suppression duration, implying dose adjustment based on HBsAg levels is necessary. In addition, the Target-Mediated Drug Disposition (TMDD) model was integrated with HBV viral dynamics in order to better understand this complex disease.
Conclusions:
The TMDD model accurately described the time courses of GC1102 and HBsAg in single- and multiple-dose studies, with doses ranging from 80,000 IU to 240,000 IU. Our simulations showed that higher doses of GC1102 resulted in a more significant reduction in HBsAg titer shortly before administration, suggesting a personalized dosing regimen based on pre-treatment HBsAg levels.
References:
[1] World Health Organization (WHO). (2022). Hepatitis B. Fact Sheet
[2] Revill, P., Testoni, B., Locarnini, S., & Zoulim, F. (2019). Global strategies are required to cure and eliminate HBV infection. Nature Reviews Gastroenterology & Hepatology, 16(4), 244-258.
[3] Prifti, G. M., Moianos, D., Giannakopoulou, E., Pardali, V., Tavis, J. E., & Zoidis, G. (2021). Recent Advances in Hepatitis B Treatment. Pharmaceuticals, 14(5), 417.