The objective of this study was to assess the contribution of the lymphatics to the absorption and systemic pharmacokinetic profiles of 29 compounds administered by oral administration, and to apply a pharmacokinetic model to describe the lymphatic absorption process
Based on a literature review, a total of 29 drugs (Acyclovir, Amiodarone, Amphotericin B, BCY, BET, Bexarotene, Cannabidiol, CyclosporinA Dexanabinol, DP-VPA, Etizolam, Halofantrine, Ibuprofen, Indomethacin, Itraconazole, Lapatinib, Loratadine, Lumefantrine, Nicardipine, Ontazolast, Phenytoin, Probucol, PRS-211,220, RAC, Retinoic acid, Seocalcitol, SN38-unde20, Tetrahydrocannabinol, Vitamin D3) including a test systema that simulate an oral administration environment and maximize lymph absorption were selected.
Animal data that reflect lymph circulation are also obtained after a review of studies on each drug. Rat in vivo pharmacokinetic results (time-concentration profiles) of individual drugs were converted into Excel data using the Plot Digitizer program and applied to semi-physiological based pharmacokinetic modeling for describing lymphatic circulation.
When calculating the predicted chylomicron binding rate (%) of each drug, the physicochemical properties were substituted with the drug's own values, and each coefficient was reflected as the value derived from the development and validation of the in-silico model. The finally derived chylomicron binding rate (%) for each drug showed various distributions ranging from 0.00% to 98.31%.
Modeling for each drug was performed using non linear mixed effect modeling software (NONMEM, version 7.4). And PK parameters were estimated by first-order conditional estimation method with the interaction option (FOCE + I). The residual error model was evaluated to be additive. Model evaluation was performed through the method of goodness of fit plot and visual predictive check(n=1,000).
The parameters derived from the final semi-PBPK model were correlated with the predicted result of the drug's chylomicron binding rate (%). And this study is significant in the expansion of the drug range of existing studies as part of the establishment and commercialization of a pharmacokinetic model that reflects lymphatic circulation.