Rodrigo Cristofoletti

Assessment of Bioequivalence of Weak Base Formulations Under Various Dosing Conditions Using Physiologically Based Pharmacokinetic Simulations in Virtual Populations. Case Examples: Ketoconazole and Posaconazole

Postabsorptive factors which can affect systemic drug exposure are assumed to be dependent on the active pharmaceutical ingredient (API), and thus independent of formulation. In contrast, preabsorptive factors, for example, hypochlorhydria, might affect systemic exposure in both an API and a formulation-dependent way. The aim of this study was to evaluate whether the oral absorption of 2 poorly soluble, weakly basic APIs, ketoconazole (KETO) and posaconazole (POSA), would be equally sensitive to changes in dissolution rate under the following dosing conditions-coadministration with water, with food, with carbonated drinks, and in drug-induced hypochlorhydria. The systems-components of validated absorption and PBPK models for KETO and POSA were modified to simulate the above-mentioned clinical scenarios. Virtual bioequivalence studies were then carried out to investigate whether formulation effects on the plasma profile vary with the dosing conditions. The slow precipitation of KETO upon reaching the upper part of the small intestine renders its absorption more sensitive to the completeness of gastric dissolution and thus to the gastric environment than POSA, which is subject to extensive precipitation in response to a pH shift. The virtual bioequivalence studies showed that hypothetical test and reference formulations containing KETO would be bioequivalent only if the microenvironment in the stomach enables complete gastric dissolution. We conclude that physiologically based pharmacokinetic modeling and simulation has excellent potential to address issues close to bedside such as optimizing dosing conditions. By studying virtual populations adapted to various clinical situations, clinical strategies to reduce therapeutic failures can be identified.

Exploratory Investigation of the Limiting Steps of Oral Absorption of Fluconazole and Ketoconazole in Children Using an In Silico Pediatric Absorption Model

Due to the higher total clearance of certain drugs in children than in adults, it is recommended that, in such cases, higher relative doses on a milligram/kilogram basis should be administered to children in order to achieve similar systemic exposure to adults. This is the case for fluconazole and ketoconazole. Even though the lower absorptive surface area and smaller volumes of intestinal fluids in children does not affect fluconazole absorption, cumulative fraction absorbed of ketoconazole seems to be dose dependent. A dose of 200 mg of ketoconazole, which belongs to the class 2a of the Developability Classification System (DCS) in adults, seems to be higher than the maximum absorbable dose in children, and ketoconazole absorption is expected to be solubility limited (i.e., DCS class 2b) in this population, indicating a DCS class migration. Therefore, extrapolating DCS and DCS drug classification from adults to pediatric groups does not seem to be straightforward and the development of specific pediatric classification systems should be a high priority.

Matching phosphate and maleate buffer systems for dissolution of weak acids: Equivalence in terms of buffer capacity of bulk solution or surface pH? ☆

The development of in vitro dissolution tests able to anticipate the in vivo fate of drug products has challenged pharmaceutical scientists over time, especially in the case of ionizable compounds. In the seminal model proposed by Mooney et al. thirty-five years ago, the pH at the solid-liquid interface (pH0) was identified as a key parameter in predicting dissolution rate. In the current work it is demonstrated that the in vitro dissolution of the weak acid ibuprofen in maleate and phosphate buffer systems is a function of the pH0, which in turn is affected by properties of the drug and the medium. The reported pH0 for ibuprofen dissolution in bicarbonate buffer, the predominant buffer species in the human small intestine under fasting conditions, can be achieved by reducing the phosphate buffer concentration to 5.0mM or the maleate buffer concentration to 2.2mM. Using this approach to identify the appropriate buffer/buffer capacity combination for in vitro experiments in FaSSIF-type media, it would be possible to increase the physiological relevance of this important biopharmaceutics tool. However, the necessity of monitoring and adjusting the bulk pH during the experiments carried out in 5.0mM phosphate or 2.2mM maleate buffers must also be taken into consideration.

Risk assessment for extending the Biopharmaceutics Classification System-based biowaiver of immediate release dosage forms of fluconazole in adults to the paediatric population

The paediatric population undergoes developmental changes in gastric pH, gastric emptying, intestinal transit time, membrane permeability, protein binding, body water, distribution and metabolism. It is widely recognised that changes in these parameters may result in an alteration of the plasma profile and thus in key bioequivalence parameters such as Cmax (maximum plasma concentration of drug) and area under the plasma concentration vs time profile curve. The aim of this work is to assess the risk of extending the biowaiver for immediate release dosage formulations of fluconazole from the adult to the paediatric population.

Integrating biopharmaceutics risk assessment and in vivo absorption model in formulation development of BCS class I drug using the QbD approach

Abstract Objective: Clinically relevant critical quality attributes (CQA’s) were identified for the development of generic drug products containing fluconazole and potential design spaces relevant to the clinical application of the drug candidate was explored. Significance: A simplified scoring system for the biopharmaceutics risk assessment roadmap (BioRAM) is proposed to guide product development. Methods: Factorial design of experiments was employed to study the effect of formulation and process variables on CQA’s. The in vivo model was developed for predicting the fraction of drug absorbed and to identify the effect of formulation components on drug absorption. Results: BioRAM yielded low scores for fluconazole absorption with respect to severity (risks of sub and supra-bioavailable drug products), probability of incidence of bioinequivalent results and capacity of detection. The results demonstrated that dissolution was highly influenced by the active pharmaceutical ingredient (API) polymorphism and the ratio of diluents. Process variables (mixing time, lubricant concentration, lubrication time and filling speed) did not impact the clinical outcome of the formulation with respect to dissolution and content uniformity. Conclusions: Understanding the clinical implications of the adopted formulation approach led to the construction of purposeful design space and control strategy.

FaSSIF-V3, but not compendial media, appropriately detects differences in the peak and extent of exposure between reference and test formulations of ibuprofen.

BACKGROUND The predictive capacity of in vitro dissolution tests using 50mM phosphate buffer at pH 6.8 to anticipate in vivo bioequivalence outcomes for highly permeable and poorly soluble weak acids has been questioned. In previous work, it was shown that using a lower buffer capacity could correctly distinguish the in vivo behavior of products containing ibuprofen free acid and those containing its salts. AIM To assess whether adjustments in the composition of the medium, including matching the phosphate buffer concentration to the reported pH0 of dissolving ibuprofen free acid in bicarbonate buffer, as well as in the stirring rate, could detect differences in the extent and peak of exposure between reference and test formulations. RESULTS Using the recently revised fasted state simulated intestinal fluid (FaSSIF-V3) with reduced phosphate buffer concentration (5mM), it was possible to predict in vivo differences in peak and extent of exposure between test and reference formulations of ibuprofen. CONCLUSION For ibuprofen products, a modified Biopharmaceutics Classification System (BCS) based biowaiver dissolution test may be a way forward to approve generic products without having to perform pharmacokinetic studies. More studies with other BCS Class 2 weakly acidic compounds would be necessary to assess whether this approach could be applied more generally.

Past, Present, and Future of Bioequivalence: Improving Assessment and Extrapolation of Therapeutic Equivalence for Oral Drug Products

The growth in the utilization of systems thinking principles has created a paradigm shift in the regulatory sciences and drug product development. Instead of relying extensively on end product testing and one-size-fits-all regulatory criteria, this new paradigm has focused on building quality into the product by design and fostering the development of product-specific, clinically relevant specifications. In this context, this commentary describes the evolution of bioequivalence regulations up to the current day and discusses the potential of applying a Bayesian-like approach, considering all relevant prior knowledge, to guide regulatory bioequivalence decisions in a patient-centric environment.