内源性药物碘制剂的生物等效性研究

目的：以卵磷脂络合碘的人体生物等效性研究为例,探讨内源性药物的生物等效性研究方法。方法：对内源性及其他来源（饮食性）的碘进行控制。24名健康受试者进行双周期、双交叉、单剂量口服9片卵磷脂络合碘试验品和参比品,采用砷铈催化分光光度法测定血、尿中碘的浓度,用DAS2.1.1软件计算药动学参数,并进行生物等效性检验。结果：试验品与参比品的血碘平均净浓度增加值分别为16.8%和19.0%,尿碘回收率分别为84.5%和83.3%。计算同一周期的尿碘净排泄量,用尿碘累积净排泄量（Ae0-t）、最大净排泄速率（Rmax）进行生物等效性分析。本实验研究表明卵磷脂络合碘受试制剂与参比制剂具有生物等效性。结论：具有生物自稳定机制的内源性药物的生物等效性研究,实验设计更加复杂,各种内外因素对结果影响较大,需要尿药浓度结合背景扣除。     

Enantiomers of benzothiadiazine diuretics by direct chromatographic resolution of the racemic drugs

A number of racemic benzothiadiazine diuretics and two carbonyl analogue drugs were resolved into their optical isomers by liquid chromatography on chiral polyacrylamides 1. Enantiomeric resolution, which was, in some cases, almost complete, depended considerably on the substitution of the heterocyclic moiety of the drug molecules. Synthesis of the new adsorbent lb is described. The enantiomers of the benzothiadiazines penflutizide (2a) and bendroflumethiazide (2b) in high optical purity, as well as enriched (+)-buthiazide (2j) were obtained by repeated chromatography on a semipreparative scale. Chiroptical data, optical purity employing the chromatographic method, and first-order racemization kinetics as a function of pH in aqueous solutions were determined.     

Bioequivalence and intrasubject variability.

Bioequivalence of the two formulations refers to the equivalence of the marginal distributions of the two formulations. Under normal assumptions, this would require the equivalence of both average and intrasubject variability of bioavailability. A procedure is introduced for the equivalence in intrasubject variability for bioavailability/bioequivalence studies with the standard two-by-two crossover design. It is shown that the confidence interval approach is operationally identical to the hypothesis testing in assessment of equivalence of intrasubject variability. A hypothetical data set from a two-by-two crossover bioequivalence study illustrates the procedure.     

Bioequivalence review for drug interchangeability.

To monitor the performance of the approved generic copies of a brand-name drug, we propose some methods in assessing bioequivalence among generic copies and the brand-name drug, and among generic copies themselves, using data from several bioequivalence studies adopting the standard 2 x 2 crossover design without carryover effects. We propose a meta-analysis method that increases statistical power when the between-subject variability is not large. A nonmeta-analysis is also considered. A numerical example of applying both methods is presented for illustration.     

Bioequivalence

The bioequivalence of two formulations of the same drug may be determined by evaluating the similarity of their respective plasma concentration curves. The similarity of two plasma concentration functions can be measured by an index called the bioequivalence index. This paper shows how such an index may be defined and calculated.     

Gender differences in labetalol kinetics: importance of determining stereoisomer kinetics for racemic drugs

STUDY OBJECTIVE: To evaluate the impact of gender on labetalol kinetics. DESIGN: Part of a randomized, crossover study. SETTING: Academic medical center. PATIENTS: Nineteen hypertensive patients (14 men, 5 women; 6 blacks, 13 whites). INTERVENTIONS: Participants had labetalol dosages titrated to a specific antihypertensive response, then underwent ambulatory blood pressure monitoring (ABPM) and a pharmacokinetic study. Labetalol plasma concentrations were measured by high-performance liquid chromatography (HPLC) and labetalol stereoisomer ratios were determined in a single plasma sample by chiral HPLC, both with fluorescence detection. MEASUREMENTS AND MAIN RESULTS: Labetalol concentrations were 80% higher in women (area under the concentration-time curve [AUC]/dose x 1000: 6.79 +/- 2.11 in women vs 3.82 +/- 1.37 hr/L in men, p<0.05), yet both genders had a similar antihypertensive response by 24-hour ABPM. Dose-corrected AUC (AUC/dose x 1000) for labetalol's stereoisomers in women and men, respectively, were S,R-labetalol 7.55 +/- 1.47 and 4.83 +/- 1.54 hr/L (p<0.05), S,S-labetalol 8.23 +/- 2.93 and 4.65 +/- 1.78 hr/L (p<0.05), R,S-labetalol 6.99 +/- 3.30 and 4.25 +/- 2.35 hr/L (p=0.11), and R,R-labetalol 3.91 +/- 2.57 and 3.55 +/- 3.08 hr/L (NS). CONCLUSION: The higher labetalol concentration in women than in men was explained largely by differences in inactive and alpha1-blocking stereoisomers. However, concentrations were similar between genders for the beta-blocking stereoisomer (R,R-labetalol), possibly explaining the similarity in antihypertensive response to the drug. This study highlights the importance of determining stereoisomer kinetics for agents administered as racemates, particularly when relating concentrations to pharmacologic response.     

Bioequivalence of a generic metformin tablet preparation.

OBJECTIVE: The bioavailability of a generic preparation of metformin (Diabetmin from Hovid Sdn Bhd) was evaluated in comparison with a proprietary product (Glucophage from Lipha Pharma Ltd., UK). PATIENTS AND METHODS: Twenty-four healthy male volunteers participated in the study conducted according to a two-way crossover design. The bioavailability was compared using the parameters total area under the plasma concentration-time curve (AUC0-infinity), peak plasma concentration (Cmax and time to reach peak plasma concentration (Tmax). RESULTS: No statistically significant difference was observed between the values of the two products in all three parameters. Moreover, the 90% confidence interval for the ratio of the logarithmic-transformed AUC0-infinity and Cmax values of Diabetmin over those of Glucophage was found to lie between 0.94-1.03 and 0.94-1.06, respectively, being within the acceptable bioequivalence limit of 0.80-1.25. CONCLUSION: These findings indicate that the two preparations are comparable in the extent and rate of absorption. In addition, elimination rate constant (k(e)) and apparent volume of distribution (Vd) were calculated. There was no statistically significant difference between the values of the two preparations in the k(e) and Vd. Moreover, the values are comparable to those reported in the literature.     

Bioequivalence of rifampicin when administered as a fixed-dose combined formulation of four drugs versus separate formulations

A bioequivalence study of the antitubercular drug rifampicin in a four-drug combination (rifampicin, isoniazid, pyrazinamide and ethambutol) and separate formulations of the drugs at the same dose levels was carried out in a group of 22 healthy male volunteers. The investigation was designed as an open crossover study. The drugs were administered once in individual formulations and once in a fixed-dose combination. The WHO-approved protocol was followed according to which six blood samples were collected over a period of 8 h for each volunteer and each experimental session. Pooled urine samples were also collected during the study. Rifampicin and desacetyl rifampicin concentrations in both plasma and urine samples were assessed. Various pharmacokinetic parameters such as AUC0-8 h, Cmax and Tmax were calculated for both rifampicin and desacetyl rifampicin. The results indicated that combined (the four-drug combination) and separate formulations are bioequivalent for rifampicin.     

Bioequivalence of Topical Dermatological Dosage Forms-Methods of Evaluation of Bioequivalence

Pharmaceutical Research -     

Characterization of racemic species of chiral drugs using thermal analysis, thermodynamic calculation, and structural studies

The identification of the racemic species, as a racemic compound, a racemic conglomerate, or a racemic solid solution (pseudoracemate), is crucial for rationalizing the potential for resolution of racemates by crystallization. The melting points and enthalpies of fusion of a number of chiral drugs and their salts were measured by differential scanning calorimetry. Based on a thermodynamic cycle involving the solid and liquid phases of the enantiomers and racemic species, the enthalpy, entropy and Gibbs free energy of the racemic species were derived from the thermal data. The Gibbs free energy of formation, is always negative for a racemic compound, if it can exist, and the contribution from the entropy of mixing in the liquid state to the free energy of formation is the driving force for the process. For a racemic conglomerate, the entropy of mixing in the liquid state is close to the ideal value of R ln 2 (1.38 cal.mol-1. K-1). Pseudoracemates behave differently from the other two types of racemic species. When the melting points of the racemic species is about 30 K below that of the homochiral species, is approximately zero, indicating that the racemic compound and racemic conglomerate possess similar relative stabilities. The powder X-ray diffraction patterns and 13C solid-state nuclear magnetic resonance spectra are valuable for revealing structural differences between a racemic compound and a racemic conglomerate. Thermodynamic prediction, thermal analysis, and structural study are in excellent agreement for identifying the nature of the racemic species.     

Optimization strategies for HPLC enantioseparation of racemic drugs using polysaccharides and macrocyclic glycopeptide antibiotic chiral stationary phases

The chiral resolution by high performance liquid chromatography (HPLC) is controlled by a number of parameters. The optimization of HPLC parameters is an important issue in chiral resolution. This review discusses the optimization of HPLC conditions for the chiral resolution of racemic drugs on polysaccharides and macrocyclic glycopeptide antibiotic chiral stationary phases (CSPs). The most important parameters discussed are composition of mobile phase, pH of mobile phase, flow rate, temperature and effect of other parameters.     

盐酸氟桂利嗪两种制剂的生物等效性

目的评价2种盐酸氟桂利嗪制剂人体生物等效性。方法用双周期交叉实验设计,采用液相色谱-质谱-质谱联用法测定了20名健康男性受试者口服盐酸氟桂利嗪口腔崩解片和盐酸氟桂利嗪胶囊后血浆中氟桂利嗪的浓度,绘制了血药质量浓度-时间曲线并计算药动学参数。结果20名受试者口服含盐酸氟桂利嗪20 mg的受试制剂和参比制剂后血浆中氟桂利嗪的tmax分别为(2.7±0.6)和(2.5±0.6)h,ρmax分别为(55.85±20.66)和(56.74±21.40)μg.L-1,t1/2分别为(6.70±2.46)和(6.89±1.98)h,用梯形法计算,AUC0-t分别为(419.0±126.7)和(428.1±175.2)μg.h.L-1,AUC0-∞分别为(465.3±147.8)和(477.0±202.3)μg.h.L-1。以AUC0-t计算,盐酸氟桂利嗪口腔崩解片的相对生物利用度平均为(104.6±22.0)%。结论盐酸氟桂利嗪两制剂生物等效。     

Comparative effects of felodipine,nitrendipine and nifedipine in healthy subjects: concentration-effect relationships of racemic drugs and enantiomers

Summary The effects of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all 20 mg solution p.o.) on non-invasively measured blood pressure and heart rate were investigated in a randomised, double-blind, cross-over study in 12 normotensive, young, healthy males. Compared to baseline values, heart rate increased more after rac-felodipine treatment (+47% at maximum) than rac-nitrendipine (+40%) and nifedipine (+38%); only small and variable changes in blood pressure were observed with any of the drugs. The baseline-corrected area under the heart rate-time curve up to 4 h after the administration of rac-felodipine was 197% and 180% larger than after nifedipine and rac-nitrendipine treatment, respectively. The effects on heart rate could be fitted individually to a sigmoidal E_max-model without hysteresis for all drugs under investigation. The relative potencies of the unbound drugs for their indirect effects on heart rate were 1:7:43 for nifedipine, rac-nitrendipine and rac-felodipine, respectively. The active (S)-enantiomers of felodipine and nitrendipine appeared to be 9-and 60-times as potent as nifedipine in this respect, assuming no (inter)activity of the (R)-enantiomers. Individual and mean changes in blood pressure were small, they were not related to plasma concentrations, and did not differ between treatments.Pharmacokinetic data obtained in this study are reported in the accompanying paper     

Bioequivalence testing of a new tablet formulation of generic fluoxetine.

The pharmacokinetics and relative bioavailability of fluoxetine capsules (reference) and tablets (test) were compared in 24 healthy subjects of both sexes after a single 20 mg oral dose of fluoxetine (as a hydrochloride salt). A randomized, crossover design with a 2-week wash-out period between each dose was applied. Serum samples, obtained before dosing and at various appropriate time points up to 192 hours, were analyzed for fluoxetine and norfluoxetine content by a simple, accurate and precise HPLC method. ANOVA, power analysis, 90% confidence intervals (CI), and two one-sided tests were used for the statistical analysis of pharmacokinetic parameters. The tolerability of the preparations was good. The respective point estimates of the ratios of the geometric means of log-Cmax and log-AUC(0-infinity) of fluoxetine were 0.912 and 0.935 with 90% of 0.838-0.992 and 0.857-1.020. The corresponding point estimates of norfluoxetine were 0.952 (90% CI = 0.843-1.075) and 0.904 (90% CI = 0.807-1.013), respectively. Since both 90% CI for the AUC(0-infinity). and Cmax geometric mean ratios of fluoxetine and norfluoxetine were included in the 80% to 125% interval proposed by the FDA the test drug (fluoxetine tablets) was considered bioequivalent to the reference one (Prozac capsules) according both to the rate and extent of absorption.     

外消旋药喇叭酸甲酯的制备

目的制备外消旋药喇叭酸甲酯。方法以廉价易得的1,10-癸二醇为原料,经单苄醚化、溴代、格氏反应、乙酰化、氢解脱苄、Jone’s氧化和甲酯化等7步反应,制得外消旋药喇叭酸甲酯。结果以总收率7.2%合成了目标化合物,并经1HNMR1、3CNMR和MS确证其结构。结论所用方法成本低廉,反应条件温和,适于外消旋药喇叭酸甲酯的大量合成。