CRITERIA TO ASSESS IN-VIVO PERFORMANCE OF SUSTAINED-RELEASE PRODUCTS - APPLICATION TO DILTIAZEM FORMULATIONS

The three classical pharmacokinetic parameters used to assess bioequiv alence, AUC (total area from zerio to infinity), C-max (peak plasma co ncentration), and t(max) (time to reach C-max), are suitable to determ ine the extent and rate of absorption of immediate-release drug produc ts. However, they may fail to evaluate the pharmacokinetic performance , particularly the rate of absorption of sustained-release (SR) formul ations, which yield flat plasma curves with multiple peaks. This paper evaluates the inclusion of the following criteria for bioequivalence assessment of diltiazem SR formulations: MRT (mean residence time), C- max/AUC, peak occupancy time (POT), t(apical) (the arithmetic mean of the times associated with the concentrations within 25% of C-max, C-ap ical) (the arithmetic mean of the concentration within 25% of C-max), percent fluctuation and flatness of the curve as assessed by the coeff icient of variation of the C-ss (steady state concentration) values ob tained during a dosing interval at steady state. The above proposed cr iteria, as well as the classical parameters AUC, C-max and t(max) were utilized in a recent pharmacokinetic study of a new SR product of dil tiazem, Dilapress 240 (formulation A). Formulation A was analyzed foll owing single (240 mg) and multiple (240 mg qd for 6 days) dosing at st eady state (day 6) in comparison to Cardizem CD (formulation B). The b ioavailability of formulation A relative to that of formulation B foll owing single and multiple dosing was 92 +/- 28% and 90 +/- 24%, respec tively. The 90% confidence intervals (CI) over a mean AUC ratio of 89% were 78-101% (single dose, SD) and 77-101% (multiple dose, MD). Follo wing the administration of formulations A and B, identical mean values of the peak plasma concentration were obtained: 84 ng/mL (SD) and 132 ng/ml (MD). The 90% CI over a mean C-max ratio of 100% were 83-115% ( SD) and 86-115% (MD). In the SD study, subject 8 had a relative bioava ilability value of 24%, which deviated by 7.5 standard errors (SE) fro m the mean AUC ratio. Consequently, we repeated the single dose analys is without subject 8. The mean bioavailability data was 97 +/- 37% wit h a 90% CI of 80-114% over a mean AUC ratio of 92%. ANOVA analysis did not show any formulation or period effect in all tested pharmacokinet ic parameters. On the basis of these results, these two formulations w ere judged to be bioequivalent. In contrast to the AUC and C-max ratio , the 90% Cls associated with the ratio of the proposed criteria, with the exception of C-apical, did not fall within the acceptable limits. In the current study, a discrepancy was found between the above pharm acokinetic parameters, which were examined concerning their ability to detect differences in bioequivalence between SR products and the clas sical parameters regularly used for bioequivalence assessment. Althoug h the parameters examined are theoretically more attractive than the s ingle point parameters C-max and t(max) for rate of absorption assessm ent, their utility in bioequivalence evaluation would require further examination.