Advances and challenges in PBPK modeling--Analysis of factors contributing to the oral absorption of atazanavir, a poorly soluble weak base.

Many active pharmaceutical ingredients (APIs) exhibit a highly variable pharmacokinetic (PK) profile. This behavior may be attributable to pre-absorptive, absorptive and/or post-absorptive factors. Pre-absorptive factors are those related to dosage form disintegration, drug dissolution, supersaturation, precipitation and gastric emptying. Absorptive factors are involved with drug absorption and efflux mechanisms, while drug distribution and clearance are post-absorptive factors. This study aimed to investigate the relative influence of the aforementioned parameters on the pharmacokinetic profile of atazanavir, a poorly soluble weakly basic compound with highly variable pharmacokinetics. The pre-absorptive behavior of the drug was examined by applying biorelevant in vitro tests to reflect upper gastrointestinal behavior in the fasted and fed states. The in vitro results were implemented, along with permeability and post-absorptive data obtained from the literature, into physiologically based pharmacokinetic (PBPK) models. Sensitivity analysis of the resulting plasma profiles revealed that the pharmacokinetic profile of atazanavir is affected by an array of factors rather than one standout factor. According to the in silico model, pre-absorptive and absorptive factors had less impact on atazanavir bioavailability compared to post-absorptive parameters, although active drug efflux and extraction appear to account for the sub-proportional pharmacokinetic response to lower atazanavir doses in the fasted state. From the PBPK models it was concluded that further enhancement of the formulation would bring little improvement in the pharmacokinetic response to atazanavir. This approach may prove useful in assessing the potential benefits of formulation enhancement of other existing drug products on the market.

Prediction of oral absorption of cinnarizine--a highly supersaturating poorly soluble weak base with borderline permeability.

Two important driving forces for oral absorption of active pharmaceutical ingredients are drug dissolution and permeability in the gastrointestinal tract. Poorly soluble weak bases typically exhibit high solubility under fasted gastric conditions. However, the solubility of such drugs usually decreases drastically in the fasted small intestine, constraining drug absorption. Since there is a discrepancy in solubility between the fasted state stomach and intestine, it is crucial to examine the influence of dissolution, supersaturation and precipitation on the oral absorption of poorly soluble weak bases during and after fasted state gastric emptying. Cinnarizine is a poorly soluble weak base with borderline permeability, exhibiting supersaturation and precipitation under simulated fasted state gastric emptying conditions. Interestingly, supersaturation and precipitation of cinnarizine under fed state conditions is not expected to occur, since the drug shows good solubility in fed state biorelevant media and exhibits a positive food effect in pharmacokinetic studies. The present work is aimed at investigating the dissolution, supersaturation and precipitation behavior of marketed cinnarizine tablets under fasted and fed state conditions using biorelevant dissolution and transfer methods. In order to predict the in vivo performance of these cinnarizine formulations, the in vitro results were then coupled with different physiologically based pharmacokinetic (PBPK) models, which considered either only dissolution or a combination of dissolution, supersaturation and precipitation kinetics. The results of the in silico predictions were then compared with in vivo observations. The study revealed that under fasting conditions, plasma profiles could be accurately predicted only when supersaturation and precipitation as well as dissolution were taken into account. It was concluded that for poorly soluble weak bases with moderate permeability, supersaturation and precipitation during fasted state gastric emptying may have an essential influence on oral drug absorption and thus on in vivo drug performance.

Evaluation of activity-based costing versus resource-based relative value costing.

Activity-based costing (ABC) and relative value units costing (RVU) are two approaches that a practice manager can use to determine the cost of physician services. Each costing approach has features that provide distinction as well as differentiation in the cost estimates that are estimated. This paper will provide cost estimates under each approach along with cost estimates under a hybrid approach that merges features from each costing approach known as the ABC-RVU costing technique. A comparison of the results will be provided.