Elucidating the Critical Role of Excipients in Gastric Emptying and Oral Absorption of a Rapidly Eliminated BCS I Drug: Implications from Zidovudine Bioequivalence

Background/Objectives:Despite the presumption of bioequivalence for BCS Class I drugs due to their high solubility and permeability, recent evidence indicates that those with rapid systemic elimination exhibit heightened vulnerability toCmaxnon-equivalence, primarily attributable to intrasubject variability in gastrointestinal transit and absorption kinetics. It is well known that gastric emptying is a significant physiological-dependent factor. But, does the formulation affect gastric emptying?Methods:Using zidovudine as a model drug, formulations containing sodium carboxymethyl starch (CMS-Na), pregelatinized starch, hydroxypropyl methylcellulose (HPMC), and lactose were investigated for their effects on gastric emptying kinetics, and the impact of excipient-mediated gastric emptying prolongation on pharmacokinetic parameters was also evaluated.Results:Relative to AZT alone (Cmax= 13,350 ng/mL; gastric %ID = 11.3%), co-administration with CMS-Na, pregelatinized starch, or HPMC significantly prolonged gastric retention (%ID: 23.4%, 30.5%, and 40.8% at 22.5 min) and reducedCmaxin rats by 47.8%, 34.4%, and 35.1%, respectively, with no effect on intestinal permeability. Viscosity positively correlated with gastric emptying delay.Conclusions:Our rat findings provide new possible mechanistic evidence that certain viscosity-modifying excipients can delay gastric emptying and reduceCmaxof zidovudine, a rapidly eliminated BCS Class I drug, with potential implications for biowaiver risk assessment. Gastric emptying is not only a physiological-dependent variation but also, in cases where common excipients may significantly delay gastric emptying, a formulation-dependent rate-limiting step. For such drugs, excipient-induced gastric emptying delay poses an underappreciated risk to the biowaiver approach, necessitating more prudent regulatory assessment that encompasses the dynamic interplay among sequential rate processes governing drug disposition.