On top of that, a distinct-time Markov model desired proper anticipate of exposure–effectiveness dating having fun with S-MRI measure when you look at the limbs
The covariates tested in the base population PK model for their effects on CLstep step step 1 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 matter research modeling
Shape 4 portrays the brand new VPC of your own effectiveness levels, and this found an effective concordance ranging from noticed and design-forecast transitions with a small overprediction about odds of values step one. There can be a small underprediction of probability of level 2. Dining table cuatro contains the fresh and you may individual predict transition chances collectively that have a simulation-founded investigation away from applied dosage membership (ten, 31 and 60 You/kg) all of the 14 days.
4 DISCUSION
An inhabitants PK design could have been efficiently created to define additionally the fresh new chemical activity inside the plasma and you can leukocytes into the GD1 people managed that have ERT playing with observations from the computing 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). (more…)