Gastric-State-Controlled Bioequivalence Studies

Fasting and then drinking 200 mL water one hour before taking antibiotic tablets may reduce variability caused by the gastric system.
Oct 01, 2004


Table 1. Pharmacokinetic Means (SEM) and T-test of AUC0-t and Cmax
Bioequivalence is the absence of a significant difference in the rate and extent of drug absorption of a test product when compared to a reference product.1 Bioequivalence is assessed using statistical analysis of pharmacokinetic measures, such as area under the curve (AUC). Researchers calculate 90% confidence intervals for the ratio of the averages (population geometric means) of the data points for the test and reference products. It is well known that establishing bioequivalence is difficult for drugs with high inter-subject variability or strong dependence on the physiological state of the gut, especially pH and motility. This applies to many of the class I drugs, which are highly soluble and permeable, according to the newest biopharmaceuticals classification system.2 Clavulanic acid and amoxicillin are classic examples.

Amoxicillin is a beta-lactam antibiotic with a wide antibacterial spectrum. Clavulanic acid has comparatively low antibacterial activity but irreversibly inhibits a broad spectrum of beta-lactamase enzymes. The elimination half-lives of amoxicillin and clavulanic acid are 1 to 1.5 h, with peak plasma levels after 1 to 2.5 h following oral administration.3 Our data suggest that the inter-subject variability in the pharmacokinetic parameters of clavulanic acid is 25 to 50%. Therefore, a minimum set of 24 subjects is needed for a bioequivalance study with 80% statistical power to detect a 20% mean difference with 95% confidence. (The power of a statistical test is the probability of correctly rejecting the null hypothesis.)


Figure 1. Mean (±SD) for Amoxicillin Serum Concentrations (µg/mL) After 250 mg Oral Dose
We believe we are the first to investigate the role of gastric state on these important and costly studies conducted in humans. We compared two independent bioequivalence studies of an amoxicillin-clavulanic acid combination to examine the effect of controlling gastric state on bioequivalence.

MATERIALS AND METHODS We tested amoxicillin-clavulanic acid combination tablets (from the same lots bought on the Jordanian market) against GlaxoSmithKline's Augmentin, the reference drug. All reagents were obtained from Sigma Chemical Company, USA. Both test and reference products met in vitro USP compendial standards.


Table 2. Analysis of the Test-to-Reference Ratios of AUC0-t and Cmax
We investigated two outcomes: the bio-equivalence of the test and reference tablets and the impact of gastric state on bioequivalence. A total of 24 healthy, male subjects gave written informed consent to participate in the study, which was approved by the Institutional Review Board of the study site, Istiklal Hospital in Amman, Jordan. Subjects were judged healthy based on medical history, physical examination, complete blood count, and serum chemistry. In addition, all subjects were medication-free, including over-the-counter drugs, for seven days prior to the study day. However, as one subject was dropped due to vomiting, 23 subjects completed the trial and formed the basis for our analysis.