Ibuprofen disposition in obese individuals.
ABSTRACT Eleven obese subjects (weight 114 +/- 11 kg, mean +/- SE) and 11 age-matched subjects with normal body weight (61 +/- 3 kg) were given 600 mg of ibuprofen orally after an overnight fast. Peak ibuprofen concentration was significantly decreased in obese subjects (P less than 0.02), although the time from administration to peak concentration was not different. Ibuprofen volume of distribution was increased in obese subjects, and this increased distribution correlated positively with body weight (r = 0.82; P less than 0.001). Volume of distribution corrected for body weight was decreased in obese subjects, and this decrease correlated negatively with body weight. Ibuprofen clearance was also increased in obese subjects; the increase correlated positively with body weight (r = 0.81; P less than 0.001). Since the independent variables, volume of distribution and clearance, were increased in parallel in the obese subjects, the dependent variable, elimination half-life, was unchanged. Using mean values of distribution calculated from the 2 groups, ibuprofen distribution into body weight in excess of ideal body weight was found to be approximately 0.44 times as extensive as the distribution into ideal body weight. Furthermore, ibuprofen clearance increased in parallel with the volume of distribution and total body weight. Clinically, these data indicate that in obese patients, the ibuprofen dose may be increased without changing the dose interval, in order to achieve necessary plasma concentrations.
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ABSTRACT: Analgesics are the most commonly consumed over-the- counter preparations in the United States. They are used in the treatment of various pain syndromes and other medical conditions. Although analgesics are generally perceived to be safe agents, serious toxicity may occur in the setting of acute overdose, chronic abuse, or overuse. The indications for therapeutic drug monitoring in patients using these medications appropriately is as yet not well defined. The emphasis of this discussion, therefore, is on recommendations for monitoring in situations where toxicity is suspected. Preanalytical, analytical, and practice issues including drug interac- tions, frequency of monitoring, pertinent ancillary tests, reporting, and special patient groups at risk for toxicity are reviewed. Recent information from a major manu- facturer of evacuated tubes arguing against the use of gel tubes for blood collection for drug monitoring is included. Colorimetric/enzymatic/immunoassays for the routine/stat monitoring of acetaminophen and salicylate and diflunisal cross-reactivity with most of the currently used salicylate assays are presented. Achiral and chiral chromatographic assays and newly introduced columns such as restricted access media and/or automated chro- matographic systems are reviewed for the analysis of ibuprofen, naproxen, and the recently introduced tram- adol. Finally, concepts regarding future directions in- cluding drug chirality and chiral analysis are presented. Analgesic drugs comprise the largest category of pharma- ceutical agents consumed by individuals in the United States. The number of over-the-counter formulations available to the consumer is staggering. Acetaminophen alone is estimated to be present in .200 brand name,01/1998;
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ABSTRACT: The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS class III and BCS class II have been proposed, in particular, BCS class II weak acids. However, a discrepancy between the in vivo BE results and in vitro dissolution results for BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH of 6.0. Further the experimental dissolution of ibuprofen tablets in a low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol l (-1) /pH) was dramatically reduced compared with the dissolution in SIF (the average buffer capacity 12.6 mmol l (-1) /pH). Thus these predictions for the oral absorption of BCS class II acids indicate that the absorption patterns depend largely on the intestinal pH and buffer strength and must be considered carefully for a bioequivalence test. Simulation software may be a very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. Copyright © 2012 John Wiley & Sons, Ltd.Biopharmaceutics & Drug Disposition 07/2012; 33(7):366-77. · 2.18 Impact Factor
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ABSTRACT: The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include sub-specification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a Sub-classification extension of the original BCS Classification. This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology (). Such a dissolution methodology can be used by development scientists to assess the likelihood of a formulation and dosage form functioning as desired in humans, can be optimized along with parallel human pharmacokinetic studies to set a dissolution methodology for Quality by Design (QbD) and in vitro-in vivo correlations (IVIVC) and ultimately can be used as a basis for a dissolution standard that will ensure continued in vivo product performance.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 01/2014; · 2.61 Impact Factor