Streamlining Food Effect Assessment - Are Repeated Food Effect Studies Needed? An IQ Analysis.

Current regulatory guidelines on drug-food interactions recommend an early assessment of food effect to inform clinical dosing instructions, as well as a pivotal food effect study on the to-be-marketed formulation if different from that used in earlier trials. Study waivers are currently only granted for BCS class 1 drugs. Thus, repeated food effect studies are prevalent in clinical development, with the initial evaluation conducted as early as the first-in-human studies. Information on repeated food effect studies is not common in the public domain. The goal of the work presented in this manuscript from the Food Effect PBPK IQ Working Group was to compile a dataset on these studies across pharmaceutical companies and provide recommendations on their conduct. Based on 54 studies collected, we report that most of the repeat food effect studies do not result in meaningful differences in the assessment of the food effect. Seldom changes observed were more than twofold. There was no clear relationship between the change in food effect and the formulation change, indicating that in most cases, once a compound is formulated appropriately within a specific formulation technology, the food effect is primarily driven by inherent compound properties. Representative examples of PBPK models demonstrate that following appropriate validation of the model with the initial food effect study, the models can be applied to future formulations. We recommend that repeat food effect studies should be approached on a case-by-case basis taking into account the totality of the evidence including the use of PBPK modeling.

Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging.

Basmisanil, is a lipophilic drug substance, exhibiting poor solubility and good permeability (BCS class 2). A validated physiologically based biopharmaceutics model (PBBM) has been previously described for tablets dosed in the fed state. The PBBM captured the less than proportional increases in exposure at higher doses well and indicated that absorption was dissolution rate-limited below 200 mg while solubility was limiting for higher doses. In this study, a model for dosing in the fasted state is described and is verified for simulation of the food effect where exposures were ~1.5 fold higher when a 660 mg tablet was given with food. The model is then applied to simulate the food effect for a granules formulation given at a lower dose (120 mg). The food effect at the lower dose was reasonably simulated with a ratio of simulated/observed food effect of 1.35 for Cmax and 0.83 for AUC. Sensitivity analysis was carried out for uncertain model parameters to confirm that the model could predict the magnitude of the positive food effect with moderate to high confidence. This study suggests that a verified PBBM can provide a useful alternative to a repeat food effect study when formulation changes are minor. However, there is need for further evaluation of the approach and a definition of what formulation changes are minor in this context. In addition, this work highlights some uncertainties in the handling of solubility in PBBM, in particular around temperature dependency of solubility and the parameterization of bile salt solubilization using measurements in biorelevant media.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron.

Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver. Ondansetron, a 5HT3 receptor antagonist, is used at doses ranging from 4 mg to 24 mg in the management of nausea and vomiting associated with chemotherapy, radiotherapy, and postoperative treatment. It is a weak base and thus exhibits pH-dependent solubility. However, it is able to meet the criteria of "high solubility" as well as "high permeability" and can therefore be classified as a BCS class I drug. Furthermore, ondansetron hydrochloride 8 mg IR tablets (Zofran® 8 mg) and multiples thereof (16 mg = Zofran® 8 mg × 2 tablets and 24 mg = Zofran® 8 mg × 3 tablets) meet the criteria of "rapidly dissolving" in dissolution testing. Ondansetron hydrochloride has a wide therapeutic window and is well-tolerated after oral administration. Based on its favorable physicochemical properties, pharmacokinetic data and the minimal risks associated with an incorrect bioequivalence decision, the BCS-based biowaiver procedure can be recommended for ondansetron hydrochloride dihydrate IR tablets.

Lipid Architectonics for Superior Oral Bioavailability of Nelfinavir Mesylate: Comparative in vitro and in vivo Assessment.

Nelfinavir mesylate (NFV), a human immunodeficiency virus (HIV) protease inhibitor, is an integral component of highly active anti retro viral therapy (HAART) for management of AIDS. NFV possesses pH-dependent solubility and has low and variable bioavailability hampering its use in therapeutics. Lipid-based particulates have shown to improve solubility of poorly water soluble drugs and oral absorption, thereby aiding in improved bioavailability. The current study compares potential of vesicular and solid lipid nanocarriers of NFV with drug nanocrystallites and microvesicular systems like cochleates in improving bioavailability of NFV. The paper outlines investigation of systems using in vitro models like in vitro lipolysis, in vitro release, and permeation through cell lines to predict the in vivo potential of nanocarriers. Finally, in vivo pharmacokinetic study is reported which provided proof of concept in sync with results from in vitro studies. Graphical Abstract ᅟ.

Pulmonary delivery of synergistic combination of fluoroquinolone antibiotic complemented with proteolytic enzyme: A novel antimicrobial and antibiofilm strategy.

Bacterial resistance remains a major hindrance in treatment with antimicrobial agents. Therefore, we assessed the improved antimicrobial and antibiofilm activity of Levofloxacin (LFX) and Serratiopeptidase (SRP) combinations in in vitro microbiological studies. Further, pharmacodynamic and pharmacokinetic studies of liposomal LFX in combination with SRP (LFX liposome-SRP) were performed in S. aureus infected rats. LFX at sub-MIC with SRP eradicated >90% of the preformed biofilm. The entrapment efficiency of LFX in liposome was >80% and the co-spray dried product had MMAD <5 µm. We observed high LFX concentration in the lung (3.39 µg/ml over 3 h) and AUC/MIC ≥100. In a pharmacodynamic study, untreated infected rat lungs demonstrated higher mRNA expression for inflammatory markers, cytokine levels and microbial load compared to control. Conversely, LFX liposome-SRP significantly abated these adverse repercussions. Histological findings were also in agreement with these observations. Furthermore, our findings corroborate exhibited improved antibiofilm and antimicrobial efficacy of LFX liposome-SRP in treating S. aureus infection.