Heeyoung Kim(1,2) and Dongwoo Chae (1,2)
(1) Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea (2)Brain Korea 21 Four Project for Medical Science, Yonsei University, Seoul, Korea.
Introduction: Hepatitis B is an infectious disease caused by hepatitis B virus (HBV) that affects the liver. 15% to 40% of untreated chronic hepatitis B patients progress to cirrhosis, ultimately leading to liver failure and liver cancer [1]. So far, 7 antiviral treatments are approved for the treatment of chronic hepatitis B. Pegylated alpha-2a and pegylated alpha-2b are interferons that activate immunomodulatory and antiviral proteins. Lamivudine, Adefovir, entecavir, tenofovir disoproxil and tenofovir alafenamide are nucleos(t)ide analogues that inhibit HBV polymerase [2]. Among these, nucleos(t)ide analogues are the current first-line therapy. As cure rate is low, most patients require therapy for an indefinite period [1], and attempts to develop new type of treatment are ongoing. GC1102(recombinant hepatitis B human immunoglobulin) is a biopharmaceutical in development for the treatment of chronic hepatitis B. Currently HBIG (hepatitis B human immunoglobulin) is being used for postexposure prophylaxis and prevention of HBV recurrence after liver transplantation. GC1102, which has high affinity to HBsAg, aims for a complete cure of chronic hepatitis B, expanding the present indications of HBIG.
Objectives: Propose a model-based optimal dosing regimen of recombinant hepatitis B human immunoglobulin based on a phase 1 clinical data of GC1102.
Methods: PK (GC1102 concentration) and PD data (HBsAg titer) were collected from a prospective, open label, phase 1 clinical trial performed in Severance hospital, Seoul, Korea. Intravenous single ascending dose and multiple ascending dose were given to patients with chronic hepatitis B. In Part A, single intravenous doses of 80000 IU, 1200000 IU, 180000 IU, and 240000 IU of GC1102 were given to 6 subjects respectively. In Part B, the same doses used in Part A were given weekly for 4 weeks to 6 subjects respectively. M3 method was used to deal with the significant fraction of BQL (below the limit of quantification) concentrations. Target mediated drug disposition model(TMDD) was used to fit the data. For data preprocessing and exploration, RStudio Version 1.4.1106 was used. For modeling and simulation, NONMEM (version7.4, ICON Development Solutions) was used.
Results: As a preliminary modeling step, a simple 1-compartment PK model was fitted to data and was found to well describe the typical pharmacokinetics of GC1102. Correlations between the individual estimates of clearance and baseline HBsAg level were highly significant (p=4.66e-05). Based on this evidence, we proceeded with developing a TMDD model of GC1102 under the quasi-state state (QSS) assumption. The estimation result suggested a significantly larger target-mediated clearance of HBsAg ( =0.0072/hr) relative to that in its free form ( =0.0031/hr). The typical pre-treatment HBsAg level and were 277.2 IU/mL and 184 IU/mL, respectively. Simulations based on the final model showed that HBsAg level promptly decreased to BQL level even at the lowest of doses, but the duration of HBsAg suppression correlated with the dose of GC1102. On the other hand, the level of pre-treatment HBsAg inversely correlated with the duration of HBsAg suppression, suggesting the need to tailor the dose in accordance with HBsAg levels.
Conclusions: TMDD model well described time courses of GC1102 and HBsAg in both single- and multiple-dose studies, covering doses from 80,000 IU to 240,000 IU. Using simulations, we applied PKPD parameters that we estimated from the final model to hypothetical human subjects with baseline HBsAg titer 200, 400, 600 and 800 IU/ml. GC1102 doses from 80000 IU to 240000 IU were administered weekly for 5 weeks to each subject. The simulation results suggested that a higher dose of GC1102 led to a longer period of HBsAg suppression. We proposed a personalized dosing regimen based on different individual pre-treatment HBsAg levels. As a further study, we plan to couple our TMDD model with HBV viral dynamics.
References:
[1] Tang, Lydia SY, et al. “Chronic hepatitis B infection: a review.” Jama 319.17 (2018): 1802-1813.
[2] AASLD 2018 Hepatitis B Guidance
Reference: PAGE 30 (2022) Abstr 9958 [www.page-meeting.org/?abstract=9958]
Poster: Clinical Applications