BIOEQUIVALENCE OF A HIGHLY VARIABLE DRUG - AN EXPERIENCE WITH NADOLOL

Purpose. To assess the bioequivalence of nadolol 40mg and 160mg tablet s (Zenith-Goldline Pharmaceuticals) using Corgard(R) 40mg and 160mg ta blets (Bristol-Meyers Squibb) as reference products, to estimate the e ffect of food in the gastrointestinal tract on nadolol bioavailability , and to evaluate the effectiveness of standard pharmacokinetic metric s AUC(t), AUC(infinity), and C-max in bioequivalence determinations. M ethods. Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conduct ed to establish bioequivalence of the 40mg tablet in terms of C-max. R esults. Fasted and food-effect studies of the 160mg tablet clearly est ablished bioequivalence and revealed an unexpected reduction in nadolo l bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUC(t) and AUC(infinity). However, C-max criteria proved extremely di fficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable. number of subjects. Conclusions. Final results clearly established bioequivalence of both strengths and characterized an unex pected food effect which did not appear to be formulation-related. How ever, the C-max of nadolol is only slightly sensitive to absorption ra te and the relatively large variability of C-max reduces its effective ness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.