Predicting Pharmacokinetics of Multisource Acyclovir Oral Products Through Physiologically Based Biopharmaceutics Modeling.

Highly variable disposition after oral ingestion of acyclovir has been reported, although little is known regarding the underlying mechanisms. Different studies using the same reference product (Zovirax ®) showed that Cmax and AUC were respectively 44 and 35% lower in Saudi Arabians than Europeans, consistent with higher frequencies of reduced-activity polymorphs of the organic cation transporter (OCT1) in Europeans. In this study, the contribution of physiology (i.e., OCT1 activity) to the oral disposition of acyclovir immediate release (IR) tablets was hypothesized to be greater than dissolution. The potential role of OCT1 was studied in a validated physiologically-based biopharmaceutics model (PBBM), while dissolution of two Chilean generics (with demonstrated bioequivalence) and the reference product was assessed in vitro. The PBBM suggested that OCT1 activity could partially explain population-related pharmacokinetic differences. Further, dissolution of generics was slower than the regulatory criterion for BCS III IR products. Remarkably, virtual bioequivalence (incorporating in vitro dissolution into the PBBM) correctly and robustly predicted the bioequivalence of these products, showcasing its value in support of failed BCS biowaivers. These findings suggest that very-rapid dissolution for acyclovir IR products may not be critical for BCS biowaiver. They also endorse the relevance of cross-over designs in bioequivalence trials.