Quantitative assessment of the exposure–efficacy relationship of glucocerebrosidase using Markovian elements in Gaucher patients treated with enzyme replacement therapy

Aims 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 (CL1 = 3.85 × 10−1 L/d) and elimination (CL2 = 1.25 L/d) allowed GCase observations in plasma and leukocytes to be described, respectively. An exponential time dependency (kT = 6.14 × 10−1 d−1) effect on CL1 was incorporated. The final exposure–efficacy model was a longitudinal logistic regression model with a first‐order Markov element. An Emax function (EC50 = 15.73 U/L and Emax = 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.