Simultaneously, a distinct-date Markov design welcome proper forecast of your visibility–efficacy matchmaking having fun with S-MRI size in the bone
The covariates tested in the base population PK model for their effects on CLstep one and CLdos were sex, race, Zdiag, age, weight and ActD. According to the results of the SCM methodology, none of the studied covariates provided a significant improvement in the overall fit.
3.2 Effectiveness number analysis model
Shape cuatro depicts brand new VPC of your own efficacy grade, which revealed an excellent concordance anywhere between noticed and you will design-predict transitions that have a overprediction in the likelihood of values step 1. There clearly was a small underprediction of the probability of levels 2. Table cuatro has the fresh and you may private forecast change probabilities with each other which have a simulation-depending data off administered dosage membership (10, 30 and you can 60 U/kg) every 2 weeks.
4 DISCUSION
A population PK design could have been effortlessly created to define likewise new enzyme hobby inside plasma and you may leukocytes into the GD1 clients managed having ERT playing with observations from the measuring lysosomal and you can low-lysosomal glucocerebrosidase.
Previous phase I/II clinical trials after ERT administration used plasma observations to characterize the pharmacokinetics of GCase. 35, 36 In this work, enzymatic activity in leukocytes was selected in order to develop the exposure–response model because the monocyte/macrophage system is the target in GD1 and plasma enzymatic activity has shown higher IIV than the leukocyte enzymatic activity, possibly due to pharmacokinetic-related factors of the administered enzyme (short t1/2 in plasma). The therapeutic enzyme is designed to be internalized by monocyte/macrophage through receptor-mediated endocytosis via mannose receptors. 37 Therefore, the leukocyte enzymatic activity is considered the PK endpoint to predict the individual enzymatic 
activity. 19 Furthermore, GCase activity was measured in peripheral leukocytes because blood monocytes are a type of leukocyte and previous studies have shown GCase activity in monocytes represents 96% of total leukocyte approximately. 38
The enzyme quantification was performed through the catalytic power, which is focused on enzymatic activity rather than enzyme concentration. 39 This analytical method by HPLC has been proposed as the gold-standard methodology for enzyme quantification, 40, 41 and has been used in most of the enzyme pharmacokinetic studies. 36, 42-44 The specificity of the analytical method for GBA1 20, 36 or GCase, which includes endogenous synthesis of GBA1, GBA2 and GBA3 and exogenous uptake of rGBA1 from ERT administration, has been reported in several publications. 30 In this study, the measurement of GCase activity was selected for the exposure–efficacy model instead of GBA1. The rationale behind this is that, despite it being traditionally considered the sole enzyme responsible for the elimination of glucosylceramide, the latter is also the substrate of an alternative pathway. This is favoured in cases of GBA1 deficiency, in which an acid ceramidase transforms it into glucosylsphingosine and subsequently diffuses into fluids. 45 In the cytoplasm, glucosylsphingosine is metabolized by a GBA2, producing sphingosine that could be toxic, particularly to the bones. Besides, the accumulation of glucosylsphingosine may cause neuronal dysfunction and neurological symptoms, eventually leading to death. 46, 47 Moreover, a feedback in GBA1 levels involving GBA2 has been described as a molecular mechanism in GD. 48 Therefore, the relevant implication of GBA2 in GD justified selection of GCase activity.
Non-linear mixed effects modelling (NLME) has been widely applied in recent years in TDM, characterizing quantitatively the typical time-course profile and the different sources of variability observed in the target population in order to improve clinical outcome, particularly relevant for rare diseases, where sparse sampling and low numbers of patients are expected. 35, 49-53 The observed enzymatic activity data were adequately described by a two concatenated PK model with a zero-order rate constant describing the basal amount of GBA1, and a first-order distribution and first-order elimination processes from leukocytes. Plasma and leukocyte GBA1 half-lives were 0.48 and 3.42 hours, respectively, which are in agreement with previous estimations of GBA1 in plasma. 35, 36 A GCase half-life of 8.6 hours has been described using a population PK/PD model in blood monocytes. 22 Previous studies in rats indicate that after ERT administration, 54, 55 enzyme activity decreases rapidly in plasma, since it is bound by the mannose-6-phosphate receptors of the monocyte–macrophage system with a biphasic decay with short t1/2 of 45 minutes in serum. 56 Additionally, this rapid decrease of GBA1 could be explained by regular proteolytic breakdown in lysosomes. 56, 57 Then, GBA1 is distributed to target organs such as liver, spleen and bone marrow. 55, 58, 59 The low predicted apparent volume of distribution in plasma and leukocytes (1.10 ? 10 ?2 L and 2.57 ? 10 ?1 L) could reflect a high distribution into target organs, where leukocytes are transformed into tissue macrophages. The volume of distribution of peptides is usually small and limited to the extracellular space, 60 which is in accordance with the current results.
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