Figures 5C and 5Dshow that the
C max was slightly underpredicted by the model. We considered two more types of models to improve the
C max prediction. The drug has to cross the sclera and the choroid-RPE to reach the retina after periocular administration. In this process, there is a possibility that some of the drug is eliminated by the episcleral and choroidal circulation and lymphatics. Hence, instead of using a hybrid rate constant for absorption (which combines absorption in sclera, choroid, and retina) an inclusion of a transfer compartment that could be either the choroid or a combination of the sclera-choroid-RPE may lead to a better fit. Further, since the drug can be eliminated from the sclera-choroid-RPE (transfer compartment/choroidal compartment), we used a third parallel elimination pathway from the choroid. The structural model is shown in
Figure 5E . When the data were fit to this revised model, an excellent data-fit was obtained (
R 2: 0.92; AIC: 218.4). All the time points were well fit by this model. Further, this model predicted the
C max better than the previous models. There was good correlation between the observed and the model-predicted data. We included a distribution compartment for the choroidal compartment, to evaluate whether this would further improve the goodness of fit. However, no further improvement was achieved by inclusion of this compartment (data not shown). Thus, the model in
Figure 5Ewas initially selected as the model to describe retinal pharmacokinetics after periocular administration. The elimination from the retina could be due to retinal blood flow or metabolism of the drug in the retina. There is not much evidence that a significant drug metabolism can take place in the neural retina. The RPE has metabolic activity, but we have included the RPE as a part of the transfer compartment, as the retinal concentrations measured in the studies are concentrations in the neural retina. Also, the blood flow to the choroid is significantly greater than the blood flow to the retina in many species including the rat, rabbit, cat, and the dog.
42 43 44 45 In addition, the choroidal vessels are leakier and the choroidal vessels perform much of the retinal perfusion in mammals. It has been demonstrated by cryotherapy that choroidal blood flow does not play a significant role in the removal of triamcinolone acetonide after periocular administration.
14 It has been argued that cryotherapy does not cause damage to the episcleral and conjunctival circulation but does affect the choroidal circulation. However, no actual measurements have been made of the choroidal and conjunctival blood flow with and without the cryotherapy. Also, only one time point was evaluated, and no statistical comparisons were performed. It is possible that the drug is eliminated via the choroid even when given intravitreously.
46 47 Several previous modeling attempts have used the choroid as a perfect sink and have good fit between the model-predicted and observed data for intravitreous kinetics.
48 49 50 51 Hence, we evaluated an additional model that did not have elimination from the retina. We assumed that the drug is distributed from the choroidal compartment (transfer compartment) into the retina but is eliminated primarily through the choroidal compartment and the periocular tissue. The fits to the revised model are shown in
Figure 5F . The difference between
Figures 5E and 5Fis the presence or absence of the retinal elimination pathway, respectively. The model in
Figure 5E(
R 2: 0.92; AIC: 218.4) with an elimination pathway in the retina results in a better fit than the model in
Figure 5F(
R 2: 0.89; AIC: 228). There are species differences in the retinal circulation, with humans and rodents having a holangiotic retina and rabbits having a merangiotic retina.
52 53 The model in
Figure 5Fwithout the retinal elimination pathway may be more representative of the rabbit physiology. Based on the statistical goodness-of-fit criteria model described in
Figure 5Ewas selected as the finalized model to describe retinal pharmacokinetics after periocular administration in the rat model.