Elena Gras-Colomer1,2,3 Javier MartÃnez-Moreno1, VÃctor Mangas-Sanjuán3,4, Mónica Climente-Martà 1,3, Matilde Merino-Sanjuan 3,4
1 Department of Pharmacy, University Hospital Doctor Peset of Valencia, Spain. 2 Foundation for the Promotion of Health and Biomedical Research of Valencia (FISABIO), Valencia, Spain. 3 Department of Pharmacy Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Valencia, Spain. 4 Interuniversity Institute of Recognition Research Molecular and Technological Development
Objectives: The aim of this study is (i) to develop a population pharmacokinetic model of enzyme activity in Gaucher disease type I (GD1) patients after intravenous (IV) administration of enzyme replacement therapy (ERT) and, (ii) to establish an exposure-efficacy relationship for a categorical outcome in order to propose dose adjustments according to patient covariate values
Methods: A prospective follow-up, semi-experimental 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. 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, with grades 1, 2 and 3, based on the number of infiltrated Gaucher cells. GBA1 in leukocytes and monocytes were described with compartmental models parameterized in apparent volumes of distribution, and first-order distribution and elimination clearances. A zero-order synthesis (k0) of GBA was also considered in order to physiologically describe the endogenous production of GBA in humans. Between subject variability (IIV) on pharmacokinetic (PK) model parameters was modeled exponentially, and residual variability was described with an additive model on the logarithmic scale. The covariate analysis was carried out by the stepwise covariate modelling (SCM). The significance of potential covariates was systematically evaluated in a stepwise forward selection (∆OFV <3.84 points, p<0.05) one at a time. Model evaluation was performed through prediction-corrected visual predictive checks and bootstrap analysis. 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.
Results: A total number of 18 individuals with 180 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 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[1], 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: In conclusion, a population pharmacokinetic model has been developed and successfully qualified to explain the leukokycte and monocyte GBA1-time profiles following intravenous administration of ERT in GD1 patients. A 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. The information obtained from this study could be of high clinical relevance in ERT individualization in GD1 patients as it can lead to anticipate these decisions regarding clinical response and optimal dosing strategy.
References:
[1] 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 28 (2019) Abstr 8896 [www.page-meeting.org/?abstract=8896]
Poster: Drug/Disease Modelling - Endocrine