III-053 Agustos Cetin Ozbey

PBPK modeling based clinical dose adaptation in liver cirrhosis patients for seven CYP and UGT enzyme substrates

Agustos C. Ozbey (1, 2), Pieter Annaert (1), Stephen Fowler (1), Neil Parrott (1), Kenichi Umehara (1), Stephan Krähenbühl (3, 4, 5), Georgina Meneses-Lorente (1)

(1) Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland, (2) Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49-box 921, 3000, Leuven, Belgium, (3) Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland, (4) Department of Clinical Research, University of Basel, Switzerland, (5) Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Switzerland

Introduction:

In patients with impaired liver function, understanding the pharmacokinetics (PK) is crucial for effective and safe medication management. Liver cirrhosis results in multiple physiological changes mainly due to liver dysfunction and portal hypertension, and can significantly alter drug systemic clearance and exposure, posing challenges for appropriate dosing strategies [1-3]. Determining appropriate dosing for liver cirrhosis is complex due to the absence of a single reliable marker [1].

In this scenario, physiologically-based pharmacokinetic (PBPK) modeling emerges as a powerful tool, harnessing its ability to integrate mechanistic insights into the combination of pathophysiological changes and pharmacological properties of the drugs. This integration enables anticipation of the impact of liver cirrhosis, aiding in clinical dosage adjustments [4].

 Objectives:

The present project aims to assess the predictive capability of PBPK-based simulations for the effects of liver cirrhosis on the metabolism of various substrates of cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. Additionally, the project will propose strategies for utilizing PBPK-based simulations to suggest dose adjustments tailored to cirrhotic patients.

 Method:

Clinical data were obtained from two different sources.

  • Clinical study conducted by Duthaler et al. [5], where 12 control patients and 36 patients with different Child-Pugh (CP) stages of liver cirrhosis were orally administered single doses of: caffeine (10 mg), efavirenz (50 mg), flurbiprofen (12.5 mg), omeprazole (10 mg), metoprolol (12.5 mg) and midazolam (2 mg). Blood samples were obtained until 24 hours after administration.
  • Clinical trial results, where 8 healthy individuals and 38 patients with different CP stages of liver cirrhosis were orally administered a single dose of entrectinib (100 mg). Blood samples were collected until 95 hours after administration.

 For each compound, PBPK models were developed in Simcyp™. Each model was verified in non-cirrhotic (control) subjects before being extrapolated to the hepatically impaired population [6]. Predicted and observed plasma concentration-time profiles and AUC calculated with trapezoidal method were compared with a twofold acceptance criterion to evaluate the capacity of PBPK modeling to capture the changes in exposure of drugs due to liver cirrhosis. The ratio of AUCcirrhotic/AUCcontrol was used to calculate a dose adjustment. Additional PBPK-based simulations were performed with the adjusted dose levels to evaluate the predicted AUC of each compound. PBPK projected dose adjustments were further compared to the dosing adjustment recommendations taken from the drug labels.

 Results:

PBPK models were successfully able to predict the PK profiles of all 7 compounds with more than 80% of observed concentration points within 5th-95th percentiles of predictions. Similarly, predicted AUC were within two-fold of observed values, except for entrectinib AUC, which was overpredicted in moderate and severe cirrhotic patients, omeprazolol AUC, which was overprediced in mild cirrhotic patients, and flurbiprofen AUC, which was underestimated in severe cirrhotic patients. For entrectinib, PBPK-based simulations corroborated clinical observations in that exposure was not significantly affected in hepatically impaired patients, implying no dose corrections were required.

For the six compounds of the Basel Cocktail, AUCs predicted with the adjusted doses in patients with liver cirrhosis resulted in AUCs comparable to those measured in control subjects.

 Conclusion:

This study unveils findings from two clinical trials involving the administration of seven drugs to both control subjects and individuals with liver cirrhosis. PBPK-based simulations were utilized to predict alterations in drug exposure resulting from pathophysiological alterations induced by liver cirrhosis. We confirmed the capacity of PBPK modeling to accurately capture exposure changes attributable to liver cirrhosis.  Furthermore, predicted AUC were used to propose a dose adjustment and improve the clinical efficiency of the caffeine, efavirenz, flurbiprofen, omeprazole, metoprolol, and midazolam.

References:

  1. Delco, F.; Tchambaz, L.; Schlienger, R.; Drewe, J.; Krahenbuhl, S. Dose adjustment in patients with liver disease. Drug Saf 2005, 28, 529-545.
  2. Franz, C.C.; Hildbrand, C.; Born, C.; Egger, S.; Rätz Bravo, A.E.; Krähenbühl, S. Dose adjustment in patients with liver cirrhosis: Impact on adverse drug reactions and hospitalizations. European journal of clinical pharmacology 2013, 69, 1565-1573.
  3. Morgan, D.J.; McLean, A.J. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update. Clin Pharmacokinet 1995, 29, 370-391.
  4. Ozbey, A.C.; Fowler, S.; Leys, K.; Annaert, P.; Umehara, K.; Parrott, N. Pbpk modelling for drugs cleared by non-cyp enzymes: State-of-the-art and future perspectives. Drug Metab Dispos 2023.
  5. Duthaler, U.; Bachmann, F.; Suenderhauf, C.; Grandinetti, T.; Pfefferkorn, F.; Haschke, M.; Hruz, P.; Bouitbir, J.; Krahenbuhl, S. Liver cirrhosis affects the pharmacokinetics of the six substrates of the basel phenotyping cocktail differently. Clin Pharmacokinet 2022, 61, 1039-1055.
  6. Ozbey, A.C.; Bachmann, F.; Duthaler, U.; Annaert, P.; Fowler, S.; Umehara, K.; Parrott, N.; Krähenbühl, S. Dose adjustment in patients with liver cirrhosis – comparison of two different modeling approaches. Clin Pharmacol Ther 2023, 113, 1346-1358

Reference: PAGE 32 (2024) Abstr 10990 [www.page-meeting.org/?abstract=10990]

Poster: Drug/Disease Modelling - Absorption & PBPK

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