Physiologically Based Biopharmaceutics Modeling of Regional and Colon Absorption in Dogs

Abstract

Colon absorption is a key determinant for the successful development of modified-release (MR) formulations, and the risk that colon absorption may limit the in vivo performance of an MR product can be assessed early by various in vitro tests or by preclinical in vivo regional absorption studies in dogs. Mechanistic physiologically based biopharmaceutics modeling (PBBM) is becoming increasingly accepted to predict in vivo performance and guide formulation development; however, no evaluation of the ability to predict colon absorption has been performed. The purpose of this study was to investigate if regional and colon absorption of drugs in dogs could be predicted with sufficient accuracy using PBBM to enable the replacement of in vivo dog studies in the early assessment of colon absorption limitation risks. This was done by predicting the regional and colon absorption and plasma exposure of 14 drugs after administration to the dog colon according to an a priori approach using the in silico absorption models GI-Sim and GastroPlus. Predictive performance was primarily assessed by comparing observed and predicted plasma concentration–time profiles, AUC 0- t , and the relative bioavailability in the colon ( F rel,colon ) as compared to an oral/duodenal reference. Trends in dependency of prediction performance on predicted fraction absorbed, permeability, and solubility/dissolution rate were also investigated. For GI-Sim, the absolute average fold error (AAFE) values for AUC 0- t and F rel,colon were within a 2-fold prediction error for both solutions (1.88 and 1.51, respectively) and suspensions (1.58 and 1.99, respectively). For GastroPlus, the AAFE values for AUC 0- t and F rel,colon were outside the set 2-fold prediction error limit for accurate predictions for both solutions (3.63 and 2.98, respectively) and suspensions (2.94 and 2.09, respectively). No trends for over- or underprediction were observed for GI-Sim, whereas GastroPlus showed a slight trend for underprediction of both AUC 0- t and F rel,colon for compounds with low permeability. In addition, regional differences in the plasma profiles were qualitatively predicted in the majority of cases for both software. Despite the differences in prediction performance, both models can be considered to predict regional differences in absorption as well as AUC 0- t and F rel,colon with acceptable accuracy in an early development setting. The results of this study indicate that it is acceptable to replace in vivo regional absorption studies in dogs with the evaluated models as a method for the early assessment of the risk for colon absorption limitation of MR drug product candidates.

Usefulness of the Beagle Model in the Evaluation of Paracetamol and Ibuprofen Exposure after Oral Administration to Pediatric Populations: An Exploratory Study

“…A further uncertainty pertaining to the regional absorption/permeability in the virtual canine physiology could be the utilization of the Opt LogD SA/v6.1 model to estimate ASF. The method selection for scaling of regional permeability in the virtual ACAT physiologies should be decided with caution for the specific model drugs and adjusted if further scientific evidence is available for specific cases. , In the pediatric models, , sensitivity toward the reduced permeability model was demonstrated for lower permeability resulting in delayed absorption under fasted-state conditions. The potentially higher permeability in dogs (and lack of model sensitivity to permeability changes) could pose a challenge for translating or identifying the rate-limiting absorption process in the preclinical species vs humans.…”

“…For both model drugs, performed PSA for the beagle model indicated limited sensitivity to changes in drug and/or physiology-related parameters, including the uncertainty pertaining to utilizing the in-built 3-fold higher permeability for dogs vs humans. Compared to humans, passive permeability in dogs has been demonstrated to be higher, especially for drugs/compounds which are predominantly absorbed via the paracellular route; ,− the high permeability utilized in the canine models for paracetamol and ibuprofen led to a lack of preclinical model sensitivity regarding this parameter. Conversely, the transcellular absorption pathway is expected to be similar for humans and dogs, which is in line with the reported similar effective permeability in both species for two highly permeable drugs .…”

Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics

“…As key ADME parameters can be adjusted, PBPK models can accurately predict how physiological variability affects pharmacokinetics in different patient groups [260]. Research utilising the common PBPK software GI-Sim and GastroPlus has shown that both tools could predict the colonic absorption of 14 drugs, with performances acceptably high as to promote their replacement of in vivo regional absorption in dogs during preclinical drug development [261]. Advantages of MM include the ability to work with both small and large datasets, uncover how variables mechanistically interact within a model, and importantly, understand the mathematical basis on which predictions are made.…”

Impact of gastrointestinal differences in veterinary species on the oral drug solubility, in vivo dissolution, and formulation of veterinary therapeutics

“…Because solubilization must occur within a much shorter timeframe in dogs [ 7 , 91 ] and cats (see above), compounds exhibiting poor oral solubility may fail to attain the bioavailability needed to achieve therapeutic plasma drug concentrations. In these situations, it may be appropriate to administer the therapeutic moiety in a more readily soluble salt form [ 6 ] or as a prodrug.…”