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Patient acceptance of pediatric formulations is critical to compliance and consequently therapeutic outcomes; thus, having anThe discriminating potential of the method was examined using tribology profiles (coefficient of friction (COF) vs. sliding speed) for commercially available products and products made for this study with widely varying sweetness, thickness, and grittiness; these formulations were used to judge the sensitivity of the method. Samples were measured using 3M Transpore™ surgical tape to simulate the tongue surface, steel half ring geometry, constant gap setting, target axial force of 2 N in a 600 s exponential ramp for rotation speed.The COF ranged from 0.1 to 0.6. For the speeds studied, the high viscosity commercial suspension ibuprofen drops and acetaminophen suspension show a classic Stribeck curve with an increasing COF at the higher rotation speeds, which indicates these formulations entered the hydrodynamic lubrication phase, while the lower viscosity suspensions only reached the mixed lubrication phase.The contribution of particles affects the COF in a dynamic tribologic pattern compared to products that are categorized as either low gritty or high viscosity. These results are important as they provide a potentially rapid

Furosemide is a widely used diuretic for treating excessive fluid accumulation caused by disease conditions like heart failure and liver cirrhosis. Furosemide tablet formulation exhibits variable pharmacokinetics (PK) with bioavailability ranging from 10 to almost 100%. To explain the variable absorption, we integrated the physicochemical, in vitro dissolution, permeability, distribution, and the elimination parameters of furosemide in a physiologically-based pharmacokinetic (PBPK) model. Although the intravenous PBPK model reasonably described the observed in vivo PK data, the reported low passive permeability failed to capture the observed data after oral administration. To mechanistically justify this discrepancy, we hypothesized that transporter-mediated uptake contributes to the oral absorption of furosemide in conjunction with passive permeability. Our in vitro results confirmed that furosemide is a substrate of intestinal breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), and organic anion transporting polypeptide 2B1 (OATP2B1), but it is not a substrate of P-glycoprotein (P-gp) and MRP2. We then estimated the net transporter-mediated intestinal uptake and integrated it into the PBPK model under both fasting and fed conditions. Our in vitro data and PBPK model suggest that the absorption of furosemide is permeability-limited, and OATP2B1 and MRP4 are important for its permeability across intestinal membrane. Further, as furosemide has been proposed as a probe substrate of renal organic anion transporters (OATs) for assessing clinical drug-drug interactions (DDIs) during drug development, the confounding effects of intestinal transporters identified in this study on furosemide PK should be considered in the clinical transporter DDI studies.

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.

The focus on drug delivery for the pediatric population has been steadily increasing in the last decades. In terms of developing in vitro models simulating characteristics of the targeted pediatric population, with the purpose of predicting drug product performance after oral administration, it is important to simulate the gastro-intestinal conditions and processes the drug will encounter upon oral administration. When a drug is administered in the fed state, which is commonly the case for neonates, as they are typically fed every 3 h, the digestion of the milk will affect the composition of the fluid available for drug dissolution/solubilization. Therefore, in order to predict the solubilized amount of drug available for absorption, an in vitro model simulating digestion in the gastro-intestinal tract should be utilized. In order to simulate the digestion process and the drug solubilization taking place in vivo, the following aspects should be considered; physiologically relevant media, media volume, use of physiological enzymes in proper amounts, as well as correct pH and addition of relevant co-factors, e.g., bile salts and co-enzymes. Furthermore, physiological transit times and appropriate mixing should be considered and mimicked as close as possible. This paper presents a literature review on physiological factors relevant for digestion and drug solubilization in neonates. Based on the available literature data, a novel in vitro digestion model simulating digestion and drug solubilization in the neonate and young infant pediatric population (2 months old and younger) was designed.

Background: Profound changes in the development and the maturation of neonates' organs and organ systems over variable periods of time potentially place neonates at increased risk and/or at different risks compared with adults or older children on exposure to pharmaceutical agents. Most studies of drugs in neonates focus on pharmacokinetic and pharmacodynamic end points and include insufficient numbers of patients to permit evaluation of safety. Only one fourth to one third of approved drugs have received adequate pediatric study to permit labeling for treatment of all appropriate pediatric populations. Objective: The initial goal of the Newborn Drug Prioritization Group was to develop a reproducible, objective process for evaluating drugs most in need of study in the neonatal population based on a universally acceptable priority ranking. The criteria would be applicable across therapeutic classes and would identify those drugs for which immediate study was most needed. Methods: Because the therapeutic requirements of the neonate are unique in comparison to older infants and children, the National Institute of Child Health and Human Development and the US Food and Drug Administration (FDA) developed the Newborn Drug Development Initiative to address the limited study of off-patent drugs in newborns. In March 2003, they convened a meeting of pediatric pharmacologists and pediatric specialists from the FDA, the American Academy of Pediatrics, the National Institutes of Health, and academic institutions to discuss how to increase the study of drugs for the newborn. One of the working groups was charged to develop generic criteria for overall prioritization of drugs for study in newborns. Because resources are limited, and not all drugs identified by the 4 clinically focused working groups can receive study at the same time, a process for priority ranking is necessary. Results: The panel identified 4 general categories containing different numbers of criteria as important for ranking drugs for priority investigation: (1) the disease and indication, including elements such as the potential for adverse outcomes, frequency in newborns, and level of evidence for treatment of newborns; (2) drug characteristics, including elements such as duration of dosing, lack of age-appropriate formulation, clinically relevant drug-drug and drug-disease interactions, and drug disposition in newborns; (3) feasibility and methodology for newborn studies, including both analytical considerations and clinical end points; and (4) the ethical basis for study, including elements to address benefit or harm due to exposure to the study drug, study methodology, and benefit of the new treatment relative to established standard therapy. Based on these categories, a list of criteria to warrant study of a drug in newborns was developed. Conclusion: A process for judicious use of limited resources to rectify these deficiencies remains an urgent public health need.

Objectives 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. Methods Using solubility, dissolution kinetics, gastrointestinal (GI) parameters and disposition parameters, a PBPK model for furosemide was developed with STELLA software. Solubility and dissolution profiles for both formulations were evaluated in biorelevant and compendial media. The simulated plasma profiles were compared with in-vivo profiles using point estimates of area under plasma concentration-time curve, maximal concentration after the dose and time to maximal concentration after the dose. Key findings Simulated plasma profiles of both furosemide IR tablets and MR capsules were similar to the observed in-vivo profile in terms of PK parameters. Sensitivity analysis of the IR tablet model indicated that both the gastric emptying and absorption rate have an influence on the plasma profile. For the MR capsules, the sensitivity analysis suggested that the release rate in the small intestine, gastric emptying and the absorption rate all have an influence on the plasma profile. Conclusions A predictive model to describe both IR and MR dosage forms containing furosemide was attained. Because sensitivity analysis of the model is able to identify key factors influencing the plasma profile, this in-vitro–in-silico–in-vivo approach could be a useful tool for facilitating formulation development of drug products.

The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate "learning and confirming" studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile.

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.

A four-way cross-over study was performed to assess the temporal effect of food on the rate and extent of tacrine (Cognex, THA) absorption after drug administration to healthy, older volunteers. Each volunteer received four single 40-mg THA doses at 1-week intervals. Doses were administered after an 8-hour overnight fast, 1 hour before a standard breakfast, 15 minutes after beginning a standard breakfast, and 2 hours after completion of a standard breakfast. Gastrointestinal side effects were most frequently reported after drug administration to fasted subjects. Mean Cmax and AUC(0-infinity) values after THA administration during breakfast (9.9 ng/mL and 70.2 ng.hr/mL) and 2 hours after breakfast (11.6 ng/mL and 74.2 ng.hour-1.mL-1) were significantly lower than values determined after administration of THA to fasting subjects (15.8 ng/mL, and 91.8 ng.hour-1.mL-1). Little effect was evident when THA was administered 1 hour before breakfast.

The pharmacokinetics of cephalexin and cefadroxil were compared following single 500 mg oral doses to 12 healthy male volunteers. Doses were administered after an overnight fast according to a crossover design. Plasma and urinary levels of both compounds were determined by HPLC procedures. Cephalexin was absorbed rapidly, achieving a mean peak plasma level of 17.5 micrograms ml-1 at 1 h, compared to 16 micrograms ml-1 at 1.8 h for cefadroxil. Elimination half-lives of cephalexin and cefadroxil were 0.7 and 1.1 h, respectively. The area under the cefadroxil plasma curve was significantly larger than that for cephalexin. However, after allowing for differences in elimination rate constants and assuming equal distribution volumes, plasma data indicated the compounds were equally well absorbed. Only 70 per cent of cefadroxil was recovered in urine compared to 87 per cent of cephalexin during the 12 h following drug administration. The therapeutic significance of the different pharmacokinetic characteristics of cephalexin and cefadroxil, if any, may be a function also of their pharmacologic activity and/or the sensitivity of the target organism.

The bioavailability of hydrochlorothiazide was determined following single oral 25-, 50-, 100-, and 200-mg tablet and suspension doses in 12 healthy male volunteers. Plasma and urine levels of hydrochlorothiazide were determined by HPLC. Plasma levels of hydrochlorothiazide were satisfactorily described by a triexponential function. Mean peak plasma levels, Cmax (127-135, 270-280, and 437-490 ng/mL from the 25-, 50-, and 100-mg doses, respectively) were dose proportional, as were areas under plasma profiles, AUC0----36. Mean percentage recovery of unchanged hydrochlorothiazide in 48-h urine samples accounted for 50-59, 54-55, 60-63, and 54-57% of the 25-, 50-, 100-, and 200-mg doses, respectively. There were no significant differences among these values. Correlation coefficients between 48-h urinary recovery of hydrochlorothiazide and the plasma values (Cmax and AUC0----36) for the 25-, 50-, and 100-mg doses were 0.73 and 0.84. There were no differences in the net increases in electrolyte excretion among the treatments during the 0-12-h postdose period. The systematic availability of hydrochlorothiazide, unlike that of chlorothiazide, is dose proportional in the therapeutic range.

The pharmacokinetics of probenecid were examined following single 0.5-, 1.0-, and 2.0-g oral doses to healthy male volunteers. Doses were administered following overnight fast, according to a randomized design. Plasma levels of probenecid were determined by high-pressure liquid chromatography (HPLC), using sulfamethazine as the internal standard. Mean peak probenecid levels of 35.3, 69.6, and 148.6 micrograms/ml were obtained at 3-4 hr following the 0.5-, 1.0-, and 2.0-g doses, respectively. Probenecid levels from the 0.5- and 1.0-g doses declined in apparent monoexponential fashion, with mean elimination half-lives of 4.2 and 4.9 hr. Interpretation of the 2.0-g data by a kinetic model incorporating first-order elimination resulted in a plasma drug half-life of 8.5 hr. When first-order elimination was replaced by a Michaelis-Menten-type function, the mean value of the resulting Vm/Km ratios was 0.20, equivalent to a plasma drug half-life [0.693/(Vm/Km)] of 3.8 hr. Plasma probenecid curves from all three dosages were successfully fitted to the saturable elimination model using nonlinear regression and numerical integration routines. The results suggest that probenecid elimination may be saturable at therapeutic dose levels.

The steady-state multiple-dose pharmacokinetics of tacrine were evaluated in twelve patients (mean age = 77 years) with Alzheimer’s Disease. Each patient sequentially received nine doses of 10, 20 and 30 mg of tacrine every 6 hours. Plasma tacrine concentrations were measured using a specific, validated HPLC method. Mean maximum plasma concentrations (Cmax) were 5.09, 20.7, and 33.9 @ml following the 10, 20 and 30 mg tacrine doses, respectively. Corresponding values for area under the curve (AUC) were 19.8, 83.7 and 141 ng/hr/ml. Dose normalized Cmax and AUC values determined following administration of 20 and 30 mg doses of tacrine were significantly greater (p < .05) than those after 10 mg of tacrine. Tacrine elimination half-life was approximately 3.4 hours at all dose levels. Dose-dependent increases in Cmax and extent of tacrine systemic bioavailability observed in patients with Alzheimer’s Disease were similar to those reported previously in healthy young volunteers. Saturable first-pass hepatic metabolism may be responsible for dose-dependent tacrine kinetics.