Evaluating Predictive Methods & Product Performance in Healthy Adults for Pediatric Patients, A Case Study: Furosemide

Low solubility drugs are common in the pharmacopeia and it has been estimated that more than 40% of new chemical entities developed by the pharmaceutical industry are practically insoluble in water. Exploratory in vitro studies by the CDER have recently demonstrated that the solubility, and thus potentially the bioavailability, of poorly soluble drugs may be highly enhanced when administered with milk (Parmalat™ Whole Milk) or baby formula (Similac Pro-Advance™).

While the reasons for variable bioavailability of furosemide are not well characterized, the effect of gastric pH, food and dosing liquids are commonly observed on the absorption of BCS Class IV drugs. Absorption variability is much greater in children due to developmental changes in factors such as gastric fluid, blood flow to the intestine, bile acid composition/secretion, intestinal surface area and drug metabolizing enzyme and transporter abundance. Therefore, it is critical to determine the physio-chemical physiological interactions for furosemide that can explain inter-subject and inter-dosing variability. An integrated in vitro, in silico and in vivo pharmacology approach to study the effect of dosing liquids on PK and PD of furosemide is novel. Quantitative understanding of factors affecting furosemide absorption will first be evaluated using in vitro tests such as solubility, dissolution and protein binding with the dosing liquids. The physiochemical information relevant to drug absorption and elimination will be curated from the literature to build the PBPK model. Such in vitro- in vivo extrapolation (IVIVE) linked PBPK modeling approach is crucial to better characterize furosemide's variable bioavailability. Another novel aspect of this study is that we will include renal metabolism of furosemide in the PBPK modeling. While plasma concentration will be critical in determining rate and extent of furosemide absorption, the renal elimination is the primary contributor to the PD response of furosemide as delivery of drug to the luminal surface of the renal tubule is required. PBPK modeling allows extrapolation of model to special population. For example, once the model is optimized and validated to predict effect of dosing liquids on adult PK of furosemide from in vitro data, this approach can be further extrapolated to children using pediatric gut physiological parameters. This novel approach will allow prediction of furosemide PK and PD in children without conducting a clinical study in this difficult to study population.