2015 - Hersonissos, Crete - Greece

PAGE 2015: Drug/Disease modelling
Natalie  Filmann

Modeling the PK/PD of hepatitis B immunoglobulin after hepatitis B induced liver transplantation by an extended Target Mediated Drug Disposition Model

N Filmann (1), J Rosenau (2), MP Manns (3), H Wedemeyer (3), E Herrmann (1)

(1) Goethe University Frankfurt, Germany, (2) University of Kentucky Hospital, (3) Medical School Hannover

Objectives: Although hepatitis B immune globuline (HBIg) administration in combination with hepatitis B virus (HBV) polymerase inhibitors is the standard of care for prophylaxis of reinfection after liver transplantation (LTX) for HBV–related liver disease in many transplant centers worldwide, no rational basis for individualized HBIg doses schedules exists until today.
The objective of the present study is the analysis of the virus kinetics after HBV-induced LTX and pharmacokinetics (PK) of HBIg after LTX.

Methods: To analyze the HBsAg- and HDV RNA kinetics and the anti-HBs PK after liver transplantation, we developed and evaluated virus kinetics models based on existing models for chronic HBV or chronic HBV/HDV [1, 2, 3] and the general Target Mediated Drug Disposition Model (TMDD-Model) of [4]. The TMDD-Model is used for the analysis of the pharmacokinetics and pharmacodynamics (PK/PD) of drugs where a significant proportion relative to dose is bound with high affinity to the pharmacological target, such that this is reflected in the PK of the drug. Model parameters were estimated by non-linear fitting of individual patient data (serial quantifications of 67 patients of anti-HBs, HBsAg, and -if present- HDV RNA).

Results: The application of the general TMDD-model led to systematic deviations between data and fits, especially, because a decreasing effect after repeated HBIg doses could not be modeled adequately. Our extension of the TMDD-model proposed here therefore also takes account of the binding of anti-HBs and HBsAg antigens to anti-HBs-HBsAg-immune complexes and the ratio of antigens and antibodies.

Our findings confirm a strong correlation between HBsAg- and HDV decline, anti-HBs increase and HBIG dosing schemes, which was already described by [5]. Global sensitivity analysis indicates that, besides the volume of distribution and baseline HBsAg-levels, the elimination of immune complexes has large influence on the PK/PD, too.
Different therapy regimes were analyzed by means of simulations. The simulation results indicate that treatment classification according to baseline HBsAg-levels is reasonable with regard to minimization of the HBIg doses and concurrent HBsAg elimination.

Conclusion: We propose an approach to model the PK/PD of HBIg after HBV-induced LTX by an extension of the general TMDD model. The modeling results form a basis for treatment individualization.

[1] M. A. Nowak, S. Bonhoeffer, A. M. Hill, R. Boehme, H. C. Thomas and H. McDade. Viral dynamics in hepatitis B virus infection. Proceedings of the National Academy of Sciences, 93:4398–402, 1996.
[2] S. A. Gourley, Y. Kuang and J. D. Nagy. Dynamics of a delay differential equation model of hepatitis B virus infection. Journal of Biological Dynamics, 2:140–53, 2008.
[3] B. C. de Sousa and C. Cunha. Development of mathematical models for the analysis of hepatitis delta virus viral dynamics. PLoS ONE, 5:e12512, 2010.
[4] D. E.Mager and W. J. Jusko. General pharmacokinetic model for drugs exhibiting target mediated drug disposition. Journal of Pharmacokinetics and Pharmacodynamics, 28: 507–32, 2001.
[5] J. Rosenau, T. Kreutz, M. Kujawa, M. Bahr, K. Rifai, N. Hooman, A. Finger, G. Michel, B. Nashan, E. R. Kuse, J. Klempnauer, H. L. Tillmann and M. P. Manns. HBsAg level at time of liver transplantation determines HBsAg decrease and anti-HBs increase and affects HBV DNA decrease during early immunoglobulin administration. Journal of Hepatology, 46:635–44, 2007.

Reference: PAGE 24 (2015) Abstr 3454 [www.page-meeting.org/?abstract=3454]
Oral: Drug/Disease modelling