Elena Gras-Colomer (1,2), M Amparo Martinez-Gomez (1), Marina Saez-Bello (1), Virginia Merino-Sanjuan (3,4), Mónica Climente-Martà (1), Matilde Merino-Sanjuan (3,4), VÃctor Mangas-Sanjuán (3,4)
(1) Department of Pharmacy, University Hospital Doctor Peset of Valencia, Spain. (2) Department of Pharmacy, Hospital of Manises, Valencia, Spain. (3) Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Valencia, Spain. (4) Interuniversity Institute of Recognition Research Molecular and Technological Development
Objectives: Gaucher disease (GD) is a rare, recessively inherited lysosomal storage disorder caused by deficiency of a lysosomal enzyme, glucocerebrosidase (GBA1), which leads to insufficient elimination of cellular glucosylceramide[1] and its subsequent storage in cell lysosomes from the monocyte-macrophage system [2]. Pathologic accumulation of glucosylceramide (or other substrates, such as glucosylsphingosine) in the lysosomes of tissue macrophages (Gaucher cells), results in splenomegaly, hepatomegaly and multiple forms of skeletal disease[3]. The aim of this study is (i) to quantitatively characterize the relationship between efficacy markers and treatment exposure and, (ii) to determine the conditions for the optimal selection of the dosage regimen.
Methods: A prospective follow-up, observational multicentre study was conducted in four public hospitals from June 2010 to December 2017. Continuous glucocerebrosidase activity (GBA1) observations were collected 10 and 75 minutes pre- and post-administration, respectively, during therapeutic drug monitoring (TDM) up to one year after the patient’s enrolment. GBA1 observations in leukocyte and monocyte were available for the analysis. Two different analytical procedures (Fluorescence and ultraviolet) were used, which measured GBA1,2,3 and GBA1, respectively. The efficacy dataset consisted of categorical data of infiltration of Gaucher cells in the bone marrow collected every 12 months during seven years of treatment based on the number of infiltrated Gaucher cells, where several different indexes were evaluated (SMRI, Zimran and GausSI scales). Logistic regression models using a discrete-time Markov model (DTMM) was performed. The efficacy data were treated as ordered categorical data, and through a fist-order Markov element. Several exposure metrics were evaluated (Cmin, Css, and AUC), which were predicted based on the population PK model, coinciding with the days on which the PD samples were obtained. A simulation-based analysis was carried out to assess how different experimental conditions may affect parameter estimation, and subsequently dose selection.
Results: A total number of 25 individuals with 266 GBA1 in leucocytes and monocytes observations were included in the PK analysis. The base population PK model contains a two concatenated compartments to describe GBA1 observations in leucocytes and monocytes, respectively. The structural model assumes a zero-order endogenous production of GBA1 to describe a constant synthesis of the endogenous enzyme. A first-order distribution of GBA1 from leucocytes into monocytes and a first-order elimination process of GBA1 from monocytes properly modelled GBA1 profiles. An exponential time-dependency effect on CL1 statistically improved the description of the data (p<0.01), demonstrating a roughly 10% decrease over time in CL1 after 3 months of enzyme replacement therapy (ERT). A total of 14 individuals with 68 observations of efficacy after ERT administration were included for the analysis during 7 cycles of treatment. Pharmacodynamics (PD) measurements of 4 patients from the PK study could not be collected. The final exposure-efficacy model was a longitudinal logistic regression model with a first-order Markov element[4], where the probability of improving efficacy outcome raised from 7% (grade 3 to 2) and 16% (grade 2 to 1) to 20% and 38%, respectively. An Emax model (1.24 U/kg) best described the dose effect with exponential IIV (129%) included on EC50 parameter. Inclusion of averaged steady-state concentrations in plasma or monocyte provided slightly worse results in terms of OFV and model stability.
Conclusions: The dose-efficacy relationship, measured as infiltrated Gaucher cells in bone marrow scale adequately predicts the pharmacodynamic outcome along treatment cycles using a first-order Markov dependency.
References:
[1] Grabowski, G.A., Gaucher disease. Enzymology, genetics, and treatment. Adv Hum Genet, 1993. 21: p. 377-441.
[2] Pastores, G.M., et al., Therapeutic goals in the treatment of Gaucher disease. Semin Hematol, 2004. 41(4 Suppl 5): p. 4-14.
[3] Mistry, P.K., et al., Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease. Proc Natl Acad Sci U S A, 2014. 111(13): p. 4934-9.
[4] Niebecker R., Maas H., Staab A., Freiwald M., Karlsson MO. Modelling exposure-drive adverse event time courses in oncology exemplified by afatinib. CPT: PSP. 2019.
Reference: PAGE () Abstr 9317 [www.page-meeting.org/?abstract=9317]
Poster: Drug/Disease Modelling - Other Topics