Abstract
The pharmacokinetics of a liposomal subunit antigen vaccine system composed of the cationic lipid dimethyldioctadecylammonium bromide (DDA) and the immunostimulatory agent trehalose 6,6-dibehenate (TDB) (8:1 molar ratio) combined with the Ag85B-ESAT-6 (H1) antigen were modelled using mouse in-vivo data. Compartment modelling and physiologically based pharmacokinetics (PBPK) were used to predict the administration site (muscle) and target site (lymph) temporal concentration profiles and factors governing these. Initial estimates using compartmental modelling established that quadriceps pharmacokinetics for the liposome demonstrated a long half-life (22.6 days) compared to the associated antigen (2.62 days). A mouse minimal-PBPK model was developed and successfully predicted quadriceps liposome and antigen pharmacokinetics. Predictions for the popliteal lymph node (PLN) aligned well at earlier time-points. A local sensitivity analysis highlighted that the predicted AUCmuscle was sensitive to the antigen degradation constant kdeg (resulting in a 3-log change) more so than the fraction escaping the quadriceps (fe) (resulting in a 10-fold change), and the predicted AUCPLN was highly sensitive to fe. A global sensitivity analysis of the antigen in the muscle demonstrated that model predictions were within the 50th percentile for predictions and showed acceptable fits. To further translate in-vitro data previously generated by our group, the mouse minimal-PBPK model was extrapolated to humans and predictions made for antigen pharmacokinetics in muscle and PLN. Global analysis demonstrated that both kdeg and fe had a minimal impact on the resulting simulations in the muscle but a greater impact in the PLN. In summary, this study has predicted the in-vivo fate of DDA:TDB:H1 in humans and demonstrated the roles that formulation degradation and fraction escaping the depot site can play upon the overall depot effect within the site of administration.
Highlights
The liposomal system composed of the cationic lipid dimethyldioctadecylammonium (DDA)and the immunomodulating glycolipid trehalose dibehenate (TDB) is a two-component adjuvant system known as CAF01
Pharmaceutics 2017, 9, 57 with the immunostimulation provided by TDB; TDB is a synthetic analog of trehalose 6-6-dimycolate, an immunostimulatory component of Mycobacterium tuberculosis, a mincle-recognised ligand and its adjuvant effect in vivo is MyD88 dependent [4]
When considering the biodistribution of these cationic liposomal adjuvants after immunisation, research from our group has shown that DDA:TDB liposomes are retained at the injection site and that these vesicles promote the retention of antigen at the site of injection, promoting co-delivery of both liposomal adjuvant and antigen to appropriate antigen-presenting cells [5]
Summary
The liposomal system composed of the cationic lipid dimethyldioctadecylammonium (DDA)and the immunomodulating glycolipid trehalose dibehenate (TDB) is a two-component adjuvant system known as CAF01. Korsholm et al (2007) described that one of the key mechanisms behind this immunomodulatory effect results from the cationic charge of the vesicles, which electrostatically binds and enhances antigen uptake by antigen-presenting cells via actin-dependent endocytosis [3]. It has been shown that DDA:TDB vesicles from ~200 to 1500 nm have similar clearance kinetics from the injection site This suggests that with these cationic systems, size reduction does not modify clearance kinetics [8].
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