Novel Gastroretentive Controlled Release Formulations for Once-Daily Administration: Assessment of Clinical Feasibility and Formulation Concept for Raltegravir

Background:Raltegravir is an integrase strand transfer inhibitor indicated in combination with other anti-retroviral medicinal products for the treatment of HIV-1 infection, given twice daily. Although a BCS class II compound, raltegravir exhibits low colonic absorption, thus making development of modified release formulations challenging. It was hypothesized that a gastroretentive (GR) formulation would increase trough (C24 h) concentrations of raltegravir, hence being amenable to a once-daily (QD) regimen.Methods:Iterative prototype GR formulations were developed in monolithic, bilayer, and trilayer tablet designs. Four phase I studies in healthy subjects were conducted to provide proof of formulation concept.Results:Raltegravir C24 h was increased by a GR formulation with scintigraphy data supporting gastric retention. Single-dose exposures from a trilayer tablet administered in the morning with a high-fat meal resulted in acceptable C24 h values. However, C24 h values for evening dosing with a high-fa...