To cope with the problems of increasing demand for medicines and to help reduce the costs of imported finished pharmaceutical products, a number of developing countries including Thailand have set up several strategies, one of which is to promote the local manufacture and usage of quality generic drugs. For any generic products to be approved by the regulatory authority, scientific evidence about the product safety and efficacy must be demonstrated [10
]. In this article, we reported the outcome of the first randomized crossover study in Thailand, which compared the clinical efficacy of a locally manufactured generic 10 mg simvastatin tablets with that of original, imported product (10 mg Zocor©
tablets) in 43 healthy Thai volunteers with hypercholesterolemia.
In general, study to establish bioequivalence between the original and the generic products involves measurements of the drug level or active metabolite(s) in the blood, which is based on a pharmacokinetic approach. However, measurements of plasma simvastatin concentration proved to be more difficult because the drug is in an inactive lactone form which is preferentially taken up by the liver, the target site of action. Simvastatin has a high liver uptake after gastrointestinal absorption, with hepatic extraction ratio greater than 90%. Less than 5% of the simvastatin dose was reported to reach the systemic circulation in healthy human volunteers [11
]. Thus, most of the drug will accumulate in the liver, where it is metabolized to several active compounds, the major one of which is simvastatin acid. The active metabolites will act by inhibiting hepatic enzyme HMG-CoA reductase, thereby interfering with the synthesis of endogenous cholesterol in the liver. Apparently, accurate determination of extremely low concentrations of simvastatin metabolite(s) in the blood could be very difficult to achieve. And even if it is possible, it may not represent the actual amount of drug accumulating in the target organ and thus, it may not provide good correlation to the drug therapeutic result.
In this case, indirect study by measurements of its pharmacodynamic or therapeutic effect can provide a good resolution [12
]. A study design based on a clinical approach was utilized here to compare the safety and efficacy of a generic simvastatin with that of the original product. Similar to the general bioequivalence study based on plasma drug concentration measurements, studies employing a clinical/pharmacodynamic approach can provide useful information on the quality of the locally made products so as to assure both the physicians and the patients that the products can produce equivalent therapeutic outcome.
However, there are a number of variables to be concerned in this type of study. Differences in the individual subjects' physiology, age, sex, lifestyle, diet and exercise control, as well as compliance, can lead to great variation in the therapeutic response. Control of these factors is very important. Thus, strict inclusion and exclusion criteria have been observed throughout this study. Closed monitoring of the patient compliance was also carried out by direct interview of the individual subjects as well as by checking the amount of the capsules remaining after each visit. To further control the variation, the number of subjects was carefully calculated to account for the increased variability associated with the dynamic nature of the study [13
]. A conventional bioequivalence study using a crossover design with plasma drug concentration measurement will usually requires 12–24 subjects. In our study, however, the number of subjects was calculated to have sufficient power to detect at least 10% difference in the primary outcome (blood LDL-cholesterol level). By using the above condition and the standard deviation from the previous clinical trial [16
], the value of 17 subjects was obtained. The total number of subjects in this study was 43, which was acceptable for statistical analysis (even in the case of several dropouts) based on the hypothesis that both drugs provided no difference in the primary therapeutic outcome [16
According to the result of this study conducted in Thai hypercholesterolemic subjects without other related diseases (DM, CAD, etc.), there was no statistical significant difference between the two products with regards to changes in blood LDL-cholesterol either at 8 weeks or 16 weeks (P > 0.05). The result indicated that the two products were equivalent in terms of efficacy. Also, other blood chemistry parameters were found to be similar such as the triglyceride level and hepatic enzyme activities.
Apart from direct evaluation of the therapeutic result, another advantage of the clinical study over the conventional bioequivalence test is the ability to compare the drug unwanted side effects. The side effects reported here (dizziness and nausea) may or may not relate to the drug. Some reported drug side effects in clinical trials may also originate from the placebo known as the placebo effects. However, it is also possible that the side effects may be due to the presence of impurities or the inclusion of inappropriate " inert" excipients in the drug formula. In this study, the incidence of the side effect was mild. Only two subjects in the second group reported symptoms of dizziness and/or nausea and voluntarily withdrew from the study. A few other subjects in both groups reported the same symptoms but remained in the study until completion. In general, the subjects appeared to have good tolerance for both products and the frequency of side effect was similar. The rest of the dropouts were due to non-compliance (failure to adhere to the administration routine).