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Improving Pediatric Dosing Through Pediatric Initiatives: What We Have Learned

OBJECTIVE. The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling. METHODS. We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing. RESULTS. The first 108 drugs with new or revised pediatric labeling changes had dosing changes or pharmacokinetic information (n = 23), new safety information (n = 34), information concerning lack of efficacy (n = 19), new pediatric formulations (n = 12), and extended age limits (n = 77). A product might have had ≥1 labeling change. We selected specific examples (n = 16) that illustrate significant differences in pediatric pharmacokinetics. CONCLUSIONS. Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.

Preparation of an amorphous sodium furosemide salt improves solubility and dissolution rate and leads to a faster Tmax after oral dosing to rats.

Amorphous forms of furosemide sodium salt and furosemide free acid were prepared by spray drying. For the preparation of the amorphous free acid, methanol was utilised as the solvent, whereas the amorphous sodium salt was formed from a sodium hydroxide-containing aqueous solvent in equimolar amounts of NaOH and furosemide. Information about the structural differences between the two amorphous forms was obtained by Fourier Transform Infrared Spectroscopy (FTIR), and glass transition temperature (Tg) was determined using Differential Scanning Calorimetry (DSC). The stability and devitrification tendency of the two amorphous forms were investigated by X-ray Powder Diffraction (XRPD). The apparent solubility of the two amorphous forms and the crystalline free acid form of furosemide in various gastric and intestinal stimulated media was determined. Moreover, the dissolution characteristics of the two amorphous forms and of crystalline free acid were investigated. FTIR confirmed molecular differences between the amorphous free acid and salt. The amorphous salt showed a Tg of 101.2 °C, whereas the Tg for the amorphous free acid was found to be 61.8 °C. The amorphous free acid was physically stable for 4 days at 22 °C and 33% relative humidity (RH), while the amorphous salt exhibited physical stability for 291 days at the same storage conditions. When storing the amorphous forms at 40 °C and 75% RH both forms converted to crystalline forms after 2 days. The apparent solubility of the amorphous salt form was higher than that of both amorphous and crystalline free acid in all media studied. All three forms of furosemide exhibited a greater solubility in the presence of biorelevant media as compared to buffer, however, an overall trend for a further increase in solubility in relation to an increase in media surfactant concentration was not seen. The amorphous salt demonstrated an 8- and 20-fold higher intrinsic dissolution rate (IDR) when compared to amorphous and crystalline free acid, respectively. The promising properties of the amorphous salt in vitro were further evaluated in an in vivo study, where solid dosage forms of the amorphous salt, amorphous and crystalline free acid and a solution of furosemide were administered orally to rats. The amorphous salt exhibited a significantly faster Tmax compared to the solution and amorphous and crystalline free acid. Cmax for the solution was significantly higher compared to the three furosemide forms. No significant difference was found in AUC and absolute bioavailability for the solution, crystalline free acid and the two amorphous forms of furosemide. It can be concluded that the higher IDR and higher apparent solubility of the amorphous salt resulted in a faster Tmax compared to the amorphous and crystalline free acid.

Meeting report: applied biopharmaceutics and quality by design for dissolution/release specification setting: product quality for patient benefit.

A biopharmaceutics and Quality by Design (QbD) conference was held on June 10–12, 2009 in Rockville, Maryland, USA to provide a forum and identify approaches for enhancing product quality for patient benefit. Presentations concerned the current biopharmaceutical toolbox (i.e., in vitro, in silico, pre-clinical, in vivo, and statistical approaches), as well as case studies, and reflections on new paradigms. Plenary and breakout session discussions evaluated the current state and envisioned a future state that more effectively integrates QbD and biopharmaceutics. Breakout groups discussed the following four topics: Integrating Biopharmaceutical Assessment into the QbD Paradigm, Predictive Statistical Tools, Predictive Mechanistic Tools, and Predictive Analytical Tools. Nine priority areas, further described in this report, were identified for advancing integration of biopharmaceutics and support a more fundamentally based, integrated approach to setting product dissolution/release acceptance criteria. Collaboration among a broad range of disciplines and fostering a knowledge sharing environment that places the patients needs as the focus of drug development, consistent with science- and risk-based spirit of QbD, were identified as key components of the path forward.

Utilizing in vitro and PBPK tools to link ADME characteristics to plasma profiles: Case example nifedipine immediate release formulation

One of the most prominent food-drug interactions is the inhibition of intestinal cytochrome P450 (CYP) 3A enzymes by grapefruit juice ingredients, and, as many drugs are metabolized via CYP 3A, this interaction can be of clinical importance. Calcium channel-blocking agents of the dihydropyridine type, such as felodipine and nifedipine, are subject to extensive intestinal first pass metabolism via CYP 3A, thus resulting in significantly enhanced in vivo exposure of the drug when administered together with grapefruit juice. Physiologically based pharmacokinetic (PBPK) modeling was used to simulate pharmacokinetics of a nifedipine immediate release formulation following concomitant grapefruit juice ingestion, that is, after inhibition of small intestinal CYP 3A enzymes. For this purpose, detailed data about CYP 3A levels were collected from the literature and implemented into commercial PBPK software. As literature reports show that grapefruit juice (i) leads to a marked delay in gastric emptying, and (ii) rapidly lowers the levels of intestinal CYP 3A enzymes, inhibition of intestinal first pass metabolism following ingestion of grapefruit juice was simulated by altering the intestinal CYP 3A enzyme levels and simultaneously decelerating the gastric emptying rate. To estimate the in vivo dispersion and dissolution behavior of the formulation, dissolution tests in several media simulating both the fasted and fed state stomach and small intestine were conducted, and the results from the in vitro dissolution tests were used as input function to describe the in vivo dissolution of the drug. Plasma concentration-time profiles of the nifedipine immediate release formulation both with and without simultaneous CYP 3A inhibition were simulated, and the results were compared with data gathered from the literature. Using this approach, nifedipine plasma profiles could be simulated well both with and without enzyme inhibition. A reduction in small intestinal CYP 3A levels by 60% was found to yield the best results, with simulated nifedipine concentration-time profiles within 20% of the in vivo observed results. By additionally varying the dissolution input of the PBPK model, a link between the dissolution characteristics of the formulation and its in vivo performance could be established.

Real-time dissolution behavior of furosemide in biorelevant media as determined by UV imaging

The potential of UV imaging as a new small scale flow-through dissolution testing platform and its ability to incorporate biorelevant media was tested. Furosemide was utilized as a model poorly soluble drug, and dissolution media simulating conditions in the small intestine (5/1.25 mM and 40/10 mM bile salt/phospholipid, pH 6.5) together with corresponding blank buffer were employed. Dissolution rates as a function of flow rate (0.2–1.0 mL/min) were determined directly from UV images, and by analysis of collected effluent using UV spectrophotometry. A good agreement in dissolution rates was observed, however repeatability of data based on measurement of collected effluent was superior to that obtained by UV imaging in the utilized prototypic flow cell. Both methods indicated that biorelevant media did not markedly increase the dissolution rate of furosemide as compared to buffer. Qualitatively, UV images indicated that uncontrolled swelling/precipitation of furosemide on the compact surface was occurring in some samples. In situ Raman spectroscopy together with X-ray diffraction analysis confirmed that the observations were not due to a solid form transformation of furosemide. The presented results highlight the complementary features of the utilized techniques and, in particular, the detailed information related to dissolution behavior which can be achieved by UV imaging.

Advancing Product Quality: a Summary of the Second FDA/PQRI Conference

Lawrence X. Yu, Ilgaz Akseli, Barbara Allen, Gregory Amidon, Tara Gooen Bizjak, Ashley Boam, Margaret Caulk, David Doleski, Joseph Famulare, Adam C. Fisher1, Scott Furness, Brian Hasselbalch, Henry Havel, Stephen W. Hoag, Robert Iser, Bruce D. Johnson, Robert Ju, Paula Katz, Emanuela Lacana, Sau L. Lee, Richard Lostritto, Grace McNally, Mehul Mehta, Ganapathy Mohan, Moheb Nasr, Roger Nosal, Mary Oates, Thomas O’Connor, Jim Polli, G.K. Raju, Mahesh Ramanadham, Giuseppe Randazzo, Susan Rosencrance, Anna Schwendeman, Arzu Selen, Paul Seo, Vinod Shah, Ramesh Sood, Michael P. Thien, Tony Tong, Bernhardt L. Trout, Katherine Tyner, Siva Vaithiyalingam, Martin VanTrieste, Fionnuala Walsh3, Russell Wesdyk1, Janet Woodcock1, Geoffrey Wu, Larisa Wu, Louis Yu, Diane Zezza

Prediction of in-vivo pharmacokinetic profile for immediate and modified release oral dosage forms of furosemide using an in-vitro-in-silico-in-vivo approach.

To develop a physiologically based pharmacokinetic (PBPK) model for furosemide immediate release (IR) tablets and modified release (MR) capsules by coupling biorelevant dissolution testing results with pharmacokinetic (PK) and physiologic parameters, and to investigate the key factors influencing furosemide absorption using simulation approaches and the PBPK model.

Studying furosemide solubilization using an in vitro model simulating gastrointestinal digestion and drug solubilization in neonates and young infants

Objective: The aim of the present study was to study the oral performance of furosemide in neonates and young infants using a newly developed in vitro model simulating digestion and drug solubilization in the gastrointestinal (GI) tract of the human neonate and young infant population (age 0–2 months). Methods: The utilized in vitro model was designed to mimic the digestion and drug solubilization processes occurring in the stomach, and the small intestine of the neonate and young infant population, using physiologically relevant media, volumes and digestive enzymes. Overall the experimental model setup was based on the dynamic in vitro lipolysis model previously described by Fernandez et al. (2009). The amount of furosemide solubilized in the aqueous phase during a digestion study was used as an estimate for the amount of drug available for absorption in vivo. By varying different factors in the model setup, e.g. presence of food (food‐effect), effect of digestion (tested with and without addition of digestive enzymes), and properties of the dosage form, it was possible to estimate the importance of these factors in vivo. Key findings and conclusions: The present in vitro data suggest that the oral performance of furosemide in neonates and young infants will be increased by the presence of food (frequent feedings) due to increased drug solubilization, however, not influenced by the GI digestion of this food. The properties of the dosage form (immediate release tablets) did not affect the drug solubilization as compared to administration of the pure drug powder. Graphical abstract Figure. No caption available.