A perspective for biowaivers of human bioequivalence studies on the basis of the combination of the ratio of AUC to the dose and the biopharmaceutics classification system.

The ratio of AUC to the dose (AUC/dose) was previously found as a parameter that predicts a risk of bioinequivalence of oral drug products. On the basis of the combination of this parameter and the biopharmaceutics classification system (BCS), a perspective for biowaivers of human bioequivalence studies is discussed. Databases of bioequivalence studies using immediate-release solid oral dosage forms were disclosed by 6 Japanese generic pharmaceutical companies, and the number of subjects required for demonstrating bioequivalence between generic and reference products was plotted as a function of AUC/dose for each BCS category. A small variation in the number of subjects was constantly observed in bioequivalence studies using dosage forms containing an identical BCS class 1 or class 3 drug, even though formulations of the generic product differ between companies. The variation was extremely enlarged when the drugs were substituted with BCS class 2 drugs. Rate-determining steps in oral absorption of highly water-soluble BCS class 1 and class 3 drugs are independent of formulations when there is no significant difference in the in vitro dissolution profiles between formulations. The small variation observed for both BCS categories indicates that the number of subjects converges into one value for each drug. Our analysis indicates the appropriateness of biowaiver of bioequivalence studies for immediate-release solid oral dosage forms containing not only BCS class 1 drugs but also class 3 drugs.

Reaction of perfluorocyclopentene with various carbon nucleophiles--heteroaromatic lithium reagents, enolate and phosphonium ylide.

The addition of heteroaromatic lithium reagents 2 to a THF solution of perfluorocyclopentene (1) provided preferentially the corresponding monosubstituted products 5, while the addition of 1 to 2 effectively gave the 1,2-disubstituted products 6 in good to excellent yields. The reaction of 1 with sodiomalonate 3 or phosphonium ylide 4 also proceeded smoothly to form the 1,3-disubstituted product 8 or 10 in high yield, respectively.

[Pharmacokinetics of perospirone hydrochloride at an excessive dose and changes in the serum prolactin level].

A 36-year-old female, in whom 8 mg perospirone hydrochloride tablets had been prescribed, took 178 tablets (corresponding to 1,424 mg) as a single dose. After 4.5 hours, she was admitted under a diagnosis of acute drug intoxication. We investigated her clinical course and medical records including the laboratory data, and measured serial changes in the serum levels of perospirone hydrochloride and prolactin by HPLC and ELISA. Concerning the clinical course, the consciousness level on admission was JCS II-10, but normalized 18 hours after dosing. Thereafter, there were no intoxication symptoms or sequelae related to massive administration of this agent, and the patient was discharged 3 days after admission. There were no abnormalities in the laboratory data obtained on admission and 2 days after admission. The serum levels of perospirone hydrochloride were 695 ng/mL 4.5 hours after dosing and approximately 60 ng/mL 18 hours after dosing, when consciousness became clear. The t1/2 beta value was 8 hours, similar to that in healthy adults. Furthermore, the serum level of prolactin 4.5 hours after dosing was 49.5 ng/mL, but returned to the normal range 18 hours after dosing, when consciousness became clear.