The impact of neglecting nonlinear plasma-protein binding on disopyramide bioavailability studies

Disopyramide has nonlinear protein binding and thus the relationship between the extent of its bioavailability and AUC, the area under the plasma concentration-time curve, is nonlinear and absorption rate-dependent. The unbound species follows linear pharmacokinetics. A solution of disopyramide, the innovator's product, and two generic formulations were found to be statistically indistinguishable in their bioavailability of disopyramide, whether comparison was based upon AUC or area under the plasma unbound concentration-time curve (AUCu). The AUC and AUCu gave similar results because of truly similar bioavailability, coupled with sufficiently similar release rates, among the four preparations chosen for study. The concentration dependence of disopyramide protein binding and the time course of unbound plasma concentrations were fit by models which then allowed prediction of AUC under various biopharmaceutical scenarios. Nonlinear binding of disopyramide to plasma proteins renders AUC an insensitive parameter for the discrimination of products with different extents of bioavailability; immediate-release products allowing bioavailabilities of 75 or 125% relative to the solution can generate AUCs 86 and 112%, respectively, of that from the solution. Nonlinear binding, furthermore, leads to a tendency for AUC to overestimate the bioavailability of slower release products in single-dose studies; if AUC were the index of bioavailability, products permitting the same bioavailability as the solution but releasing over 12 hr could appear to allow 114% relative bioavailability. Moreover, in some situations the bias arising from the insensitivity of AUC to product differences can be reinforced by the dependence of AUC on release rate; an apparent relative bioavailability of 80% can be achieved by a 12-hr release product allowing a true relative bioavailability of a mere 58%. While multiple-dose studies appear largely to avoid the tendency to overestimate low bioavailability in slow-release products, in these studies AUC appears to be even more insensitive in resolving discrepancies between products. Assay technology now available makes AUCu a feasible and more reliable index of bioavailability than AUC when plasma protein binding of drugs is nonlinear.