The quantification of enzyme activity in the patient treated with enzyme replacement therapy (ERT) has been suggested as a tool for dosage individualization, so we conducted a study to evaluate the relationship between glucocerebrosidase activity and clinical response in patients with Gaucher disease type I (GD1) to ERT. The study included patients diagnosed with GD1, who were being treated with ERT, and healthy individuals. Markers based on glucocerebrosidase activity measurement in patients' leucocytes were studied: enzyme activity at 15 min. post-infusion (Act ) reflects the amount of enzyme that is distributed in the body post-ERT infusion, and accumulated glucocerebrosidase activity during ERT infusion (Act ) indicates the total drug exposure during infusion. The clinical response was evaluated based on criteria established by Pastores et al. and Gaucher Severity Score Index. Statistical analysis included ROC analysis and area under the curve test. Act and Act were found to be moderate predictive markers of an optimal clinical response (area under the ROC of Act was 0.733 and Act was 0.817). Act showed statistical significance in its discriminative capacity (p < 0.05) for obtaining an optimal response to ERT. The cut-off point was 58% (RR = 1.800; 95% CI: 1.003-3.229; p < 0.05). Moreover, Act showed a significant and inverse correlation with the Gaucher Severity Score Index, and Act and Act presented a significant correlation with residual enzyme activity at diagnosis. Markers based on glucocerebrosidase activity have a good correlation with clinical response to ERT. Therefore, it could provide supporting clinical data for dose management in GD1 patients.
The aims of this study are (i) to develop a population pharmacokinetic model of enzyme activity in Gaucher-type 1 (GD1) patients after intravenous administration of enzyme replacement therapy (ERT), and (ii) to establish an exposure-efficacy relationship for bone marrow infiltration to propose dose adjustments according to patient covariate values.Methods: A prospective follow-up, semi-experimental multi-centre study was conducted in four hospitals to evaluate the pharmacokinetics, efficacy and safety of ERT in GD1 patients. Twenty-five individuals with 266 glucocerebrosidase (GCase) observations in plasma and leukocytes and 14 individuals with 68 Spanish magnetic resonance imaging (S-MRI) observations were enrolled. Results: A two concatenated compartment model with zero-order endogenous production and first-order distribution (CL 1 = 3.85 Â 10 À1 L/d) and elimination (CL 2 = 1.25 L/d) allowed GCase observations in plasma and leukocytes to be described, respectively. An exponential time dependency (k T = 6.14 Â 10 À1 d À1 ) effect on CL 1 was incorporated. The final exposure-efficacy model was a longitudinal logistic regression model with a first-order Markov element. An E max function (EC 50 = 15.73 U/L and E max = 2.33) linked steady-state concentrations of GCase in leukocytes to the probability of transition across the different S-MRI stages. Conclusion: A population pharmacokinetic model successfully characterized the leukocyte activity-time profiles of GCase following intravenous administration of ERT in GD1 patients together with an exposure-efficacy relationship in bone marrow using Markovian elements. The information obtained from this study could be of high clinical relevance in individualization of ERT in GD1 patients, as this could lead to anticipative decision-making regarding clinical response in bone and optimal dosing strategy.The authors confirm that the Principal Investigator for this paper is Elena Gras-Colomer and that she had direct clinical responsibility for patients.
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