Andrews AFB, MD, United States
Andrews AFB, MD, United States

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Bai J.P.F.,Office of Generic Drugs | Bai J.P.F.,U.S. Food and Drug Administration | Hausman E.,Office of Pharmacovigilance and Epidemiology | Lionberger R.,Office of Generic Drugs | Zhang X.,Office of Generic Drugs
Molecular Pharmaceutics | Year: 2012

Prolonged use of proton pump inhibitors has reportedly caused rare clinically symptomatic hypomagnesemia. A review of the literature suggests PPI drugs may impair intestinal magnesium absorption. With the goal of preventing PPI-induced hypomagnesemia, an oral absorption-centric model was developed by referencing literature data. Our modeling with human data reveals that magnesium absorption is substantial in the distal intestine. We then perform simulations by referring to the reported reduction in mid to distal intestinal pH caused by one week of oral esomeprazole, and to reported reduction of the divalent cation-sensitive current when the carboxyl side chains of glutamic and aspartic residues in the binding channels of TRPM6/TRPM7 were neutralized. Our simulations reveal that short-term PPI therapy may cause a very small reduction (5%) in the serum magnesium level, which is qualitatively consistent with the reported 1% reduction in magnesium absorption following 1 week of omeprazole in humans. Simulations provide insight into the benefit of frequent but small dose of magnesium supplementation in maintaining the serum magnesium level when magnesium deficiency occurs. © This article not subject to U.S. Copyright. Published 2012 by the American Chemical Society.

Ziolkowska N.E.,Technical University of Lodz | Ziolkowska N.E.,U.S. National Institutes of Health | Bujacz A.,Technical University of Lodz | Randad R.S.,Office of Generic Drugs | And 4 more authors.
Chemical Biology and Drug Design | Year: 2012

Four novel linear non-peptidic HIV-1 protease inhibitors derived from 2,5-diamino-1,6-diphenyl-3-hexanol were synthesized and characterized. All of them exhibit tight binding to HIV-1 protease, with inhibition constants K i in the range 20pm-5nm. The investigated inhibitors were crystallized, and their crystal structures were determined by X-ray diffraction. In all cases, the conformations found in the crystalline state differ significantly from the conformations obtained by computational docking of the inhibitor in the binding cleft of native HIV-1 protease. Owing to the prevalence of hydrophobic substituents in all these inhibitors, the conformational mobility in water solution is restricted to their compact forms. The spectrum of low-energy conformations in solution dramatically changes during the formation of inhibitor crystals (phenyl ring stacking as a leading motif) or during the formation of a complex with HIV-1 protease (elongated conformation suitable to fit the enzyme pockets as a factor responsible for tight binding). High conformational flexibility and low conformational stress in the molecules of these inhibitors most likely increase their biological activity in comparison with more rigid compounds. © 2012 John Wiley & Sons A/S.

Roudier B.,CITES | Roudier B.,University of Auvergne | Davit B.M.,Office of Generic Drugs | Davit B.M.,Merck And Co. | And 2 more authors.
Pharmaceutical Research | Year: 2014

Purpose In vitro in vivo correlation (IVIVC) is a biopharmaceutical tool recommended for use in formulation development. When validated, IVIVC can be used to set dissolution limits and, based on the dissolution limits, as a surrogate for an in vivo study. The purpose of this paper is to study the various methods used to fix dissolution limits. Methods Fixing dissolution limits is not a straightforward process; various approaches exist. The classical ±10% of dissolution limits was compared to the recommended ±10% of Cmax and AUC and to an innovative back calculation of the 90% CI. Based on simulated values the influence of the calculation method as well as of the variability of the results and pharmacokinetic processes was investigated. Results Depending upon the method, the results are different and their comparison leads to possible rules. It appears that the usage of a back calculation of a 90% CI is an accurate and advantageous method when intra-individual variability associated with the drug is low. Those findings are in accordance with the current practice of IVIVC, which is not recommended for highly variable drugs. Conclusions The approach of using a 90% CI allows the intra-subject variability to be taken into account and fixes limits that ensure a greater chance to show acceptable BE, in case of reasonable intra-subject variability, leading to setting broader in vitro dissolution limits compared to classical solutions. © 2014 Springer Science+Business Media New York (outside the USA).

PubMed | Office of Pharmaceutical Quality and Office of Generic Drugs
Type: Journal Article | Journal: The AAPS journal | Year: 2015

Various drug delivery approaches can be used to maximize therapeutic efficacy and minimize side effects, by impacting absorption, distribution, metabolism, and elimination (ADME) of a drug compound. For those drugs with poor water solubility or low permeability, techniques such as amorphous solid dispersion, liposomes, and complexations have been used to improve their oral bioavailability. Modified release (MR) formulations have been widely used to improve patient compliance, as well as to reduce side effects, especially for those drugs with short half-lives or narrow therapeutic windows. More than ten drugs using sterile long-acting release (LAR) formulations with clear clinical benefit have been successfully marketed. Furthermore, drug delivery systems have been used in delaying drug clearance processes. Additionally, modifying the in vivo drug distribution using targeted delivery systems has significantly improved oncology treatments. All the drug delivery approaches have their advantages and limitations. For both brand and generic drugs, the achievement of consistent quality and therapeutic performance using drug delivery systems can also pose serious challenges in developing a drug for the market, which requires close collaboration among industry, academia, and regulatory agencies. With the advent of personalized medicines, there will be great opportunities and challenges in utilizing drug delivery systems to provide better products and services for patients.

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