Impact of pharmacometric reviews on new drug approval and labeling decisions--a survey of 31 new drug applications submitted between 2005 and 2006.

Exploratory analyses of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression are often referred to as the pharmacometrics (PM) analyses. The objective of the current report is to assess the role of PM, at the Food and Drug Administration (FDA), in drug approval and labeling decisions. We surveyed the impact of PM analyses on New Drug Applications (NDAs) reviewed over 15 months in 2005-2006. The survey focused on both the approval and labeling decisions through four perspectives: clinical pharmacology primary reviewer, their team leader, the clinical team member, and the PM reviewer. A total of 31 NDAs included a PM review component. Review of NDAs involved independent quantitative evaluation by FDA pharmacometricians. PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs. Case studies are presented to demonstrate the applications of PM analysis.

Cubic phase gels as drug delivery systems.

Lipids have been used extensively for drug delivery in various forms such as liposomes, and solid-matrices. The focus of this review is evaluation of liquid crystalline cubic phases, spontaneously formed when amphiphilic lipids are placed in aqueous environment, for drug delivery. Cubic phases have an interesting thermodynamically stable structure consisting of curved bicontinuous lipid bilayer in three dimensions, separating two congruent networks of water channels. The unique structure of cubic phase has been extensively studied using various spectroscopic techniques and their resemblance to biomembranes has prompted many scientists to study behavior of proteins in cubic phases. The ability of cubic phase to incorporate and control release of drugs of varying size and polar characteristics, and biodegradability of lipids make it an interesting drug delivery system for various routes of administration. Cubic phases have been shown to deliver small molecule drugs and large proteins by oral and parenteral routes in addition to local delivery in vaginal and periodontal cavity. A number of different proteins in cubic phase appear to retain their native conformation and bioactivity, and are protected from chemical and physical inactivation perhaps due to the reduced activity of water and biomembrane-like structure of cubic phase. Release of drugs from cubic phase typically show diffusion controlled release from a matrix as indicated by Higuchi's square root of time release kinetics. Incorporation of drug in cubic phase can cause phase transformation to lamellar or reversed hexagonal phase depending on the polarity and concentration of the drug, which may affect the release profile. Biodegradability, phase behavior, ability to deliver drugs of varying sizes and polarity and the ability to enhance the chemical and/or physical stability of incorporated drugs and proteins make the cubic phase gel an excellent candidate for use as a drug delivery matrix. However, shorter release duration and the extremely high viscosity may limit its use to specific applications such as periodontal, mucosal, vaginal and short acting oral and parenteral drug delivery.

pKa of 4MP and chemical equivalence in formulations of free base and salts of 4MP.

Fomepizole (4-Methylpyrazole, 4MP) is used as an antidote for ethylene glycol and methanol poisoning. In France it is administered intravenously as the sulfate or hydrochloride salt formulation and in the United States, as the free base formulation. Since its pKa was unknown, it was unknown if the free base, hydrochloride and sulfate salt formulations of 4MP are chemically equivalent, and if 4MP is in chemically equivalent forms in blood when these base and salt formulations are administered intravenously. Using UV spectrophotometry, the pKa of 4MP was determined to be 2.91 +/- 0.05 (n = 7) at a low concentration of 0.006 M in formate buffers of various pH, and 3.00 +/- 0.16 (n = 7) when high concentration of 4MP (0.06 M) was titrated with HCl at 25 degrees C. The hydrochloride salt formulation (pH 6.64) was ionically and hence chemically equivalent to the free base formulation (pH 7.02), while the sulfate salt formulation, due to its lower pH of 2.33, showed presence of some ionized 4MP indicating chemical inequivalence. In order to determine chemical equivalence upon intravenous administration, these formulations were diluted with phosphate buffer (pH 7.4) with identical ionic strength and buffer capacity as blood. In spite of chemical inequivalence of the sulfate salt formulation, 4MP free base was observed from all three formulations when diluted with physiological buffer suggesting chemical equivalence under physiological conditions due to the strong buffering action of blood.