The simulations with the extended model closely resemble in vivo pharmacokinetics, and the model is a valuable tool for data interpretation and predictions.

Objectives: To establish the first plasma and cerebrospinal fluid (CSF) oxycodone population pharmacokinetic (PopPK) model after epidural (EPI) and intravenous (IV) oxycodone administration. Methods: The study was conducted with 30 female subjects undergoing elective gynecological surgery with epidural analgesia. A parallel single dose of EPI oxycodone with IV placebo (EPI group; n = 18) or IV oxycodone with EPI placebo (IV group; n = 12) was administered. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for CSF sampling at L3/4. Plasma and CSF for oxycodone analysis were frequently collected. A PopPK model was built using the NONMEM software package. Results: Plasma and CSF oxycodone concentrations were evaluated using separate central plasma and CSF compartments and separate peripheral plasma and CSF compartments. Epidural space served as a depot compartment with transfer to both the plasma and CSF central compartments. The population parameters for plasma clearance and apparent distribution volumes for central and peripheral compartments for plasma and CSF were 37.4 L/h, 90.2 L, 68.9 L, 0.035 L (fixed based on literature), and 0.039 L, respectively. Conclusion: A PopPK model was developed and found to precisely and accurately describe oxycodone time-concentration data in plasma and CSF.

Purpose To estimate the diffusion coefficients of an IgG antibody (150 kDa) and its antigen-binding fragment (Fab; 50 kDa) in the neural retina (Dret) and the combined retinal pigment epithelium-choroid (DRPE-cho) with a 3-dimensional (3D) ocular pharmacokinetic (PK) model of the rabbit eye. Methods Vitreous, retina, and aqueous humor concentrations of IgG and Fab after intravitreal injection in rabbits were taken from Gadkar et al. (2015). A least-squares method was used to estimate Dret and DRPE-cho with the 3D finite element model where mass transport was defined with diffusion and convection. Different intraocular pressures (IOP), initial distribution volumes (Vinit), and neural retina/vitreous partition coefficients (Kret/vit) were tested. Sensitivity analysis was performed for the final model. Results With the final IgG model (IOP 10.1 Torr, Vinit 400 μl, Kret/vit 0.5), the estimated Dret and DRPE-cho were 36.8 × 10−9 cm2s−1 and 4.11 × 10−9 cm2s−1, respectively, and 76% of the dose was eliminated via the anterior chamber. Modeling of Fab revealed that a physiological model parameter “aqueous humor formation rate” sets constraints that need to be considered in the parameter estimation. Conclusions This study extends the use of 3D ocular PK models for parameter estimation using simultaneously macromolecule concentrations in three ocular tissues.

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