Review of global regulations concerning biowaivers for immediate release solid oral dosage forms.

The regulations with respect to biowaivers for immediate release (IR) solid oral dosage forms in the USA, the EU, Japan and from the World Health Organization (WHO) are summarized and compared. Two case studies are presented, one from our own files and one from the open literature, showing the similarities and the differences among the qualification requirements of the four systems. The regulatory experience gained up to now is reviewed and expected future trends are discussed.

Role of the development scientist in compound lead selection and optimization.

The R&D process for bringing drugs from discovery laboratories to the marketplace is undergoing rapid change, as enabled by new technologies and as demanded by the global pharmaceutical business environment. One consequence of the accelerated R&D paradigm is a blurring of the traditional discovery-development interface, which in turn impacts the traditional roles of discovery and development scientists. R&D organizations must find ways to screen out rapidly compounds that have relatively poor probability of successful registration. Quality of development candidates can be favorably influenced by early consideration of "developability" criteria along with receptor-based potency and specificity. Computational approaches and/or high-throughput experimental determinations will be used increasingly to profile compound characteristics which influence "developability." If such criteria are considered at the time of lead selection and optimization, the compound attrition rate during later development should be decreased from the historical norm. This article discusses the emerging role of development scientists during small-molecule lead selection and optimization. The changing role of development scientists also has implications for graduate curricula in the pharmaceutical sciences.

Analysis of theoretical behavior of a proposed zero-order drug delivery system.

An analysis of the theoretical behavior of a proposed zero-order drug delivery system is presented. Equations describing drug release with time are developed using a physically realistic model. The theory agrees well with experimental data and indicates that drug release from the device is nearly, although not rigorously, zero order.

Degradation kinetics and mechanism of N6-[(dimethylamino)methylene]mitomycin C in aqueous solutions.

The degradation of N6-[(dimethylamino)methylene]mitomycin C, a semisynthetic analogue of mitomycin C, was studied in aqueous solution. The compound degraded rapidly and followed pseudo-first-order kinetics in both acidic (pH less than 5) and basic pH greater than or equal to 9) media. In the near-neutral pH region, however, biphasic kinetics were observed. At the pH of maximum stability (6.5), 10% activity was lost after approximately 6 h at 22 degrees C. Citrate and phosphate species were catalytic at pH 6.5. Spectrophotometric and HPLC methods were used to elucidate the degradation mechanism at pH 7-9. Under these conditions, equilibrium addition of one water molecule into the amidine side chain occurred, followed by parallel formation of mitomycin C and N6-(formyl)mitomycin C. The latter compound subsequently hydrolyzed to mitomycin C.

In vivo evaluation of the absorption and gastrointestinal transit of avitriptan in fed and fasted subjects using gamma scintigraphy.

The study was conducted to assess the bioavailability of avitriptan after a standard high fat meal, in relation to gastrointestinal transit. Six healthy male subjects were enrolled in a four-period study with a partial replicate design where each was administered 150-mg avitriptan capsule (i) after an overnight fast, (ii) 5 min after a standard high-fat breakfast, and (iii) 4 hr after a standard high fat breakfast. The treatment administered in Period 3 was repeated in Period 4 to assess intrasubject variations in pharmacokinetics and gastrointestinal (GI) transit. Avitriptan capsules were specially formulated with nonradioactive samarium chloride hexahydrate which was neutron-activated to gamma-emitting samarium before dosing. Serial blood samples were collected for analysis of avitriptan up to 24-hr postdose, and serial scintigraphic images were obtained to assess the plasma concentration-time profile in relation to the GI transit of the avitriptan capsule contents. Bioavailability of avitriptan was reduced when administered in the fed condition but only the decrease in AUC(INF) was statistically significant. Tmax was significantly delayed between the fed conditions and the fasted condition. Qualitative appearance of plasma concentration-time profiles for avitriptan could be related to the manner in which the drug emptied from the stomach. It was also apparent that avitriptan exerted a secondary pharmacologic effect that temporarily suspended gastric emptying in the fasted treatment. Thus, when gastric emptying was interrupted and then resumed, the net result was a double peak in some of the individual plasma concentration profiles. Scintigraphic analysis also demonstrated that upon emptying from the stomach, avitriptan was rapidly absorbed from the upper small intestine. In the fed state, gastric emptying was slow and continuous resulting in extended absorption and a lower occurrence of double peaks. Qualitatively, the intrasubject variability in Cmax and AUC could be explained by the intrasubject variability in gastric emptying in both fasted and fed conditions.