Oral pharmacokinetics of the anti-HIV efavirenz encapsulated within polymeric micelles

Aiming to improve the pediatric pharmacotherapy of the human immunodeficiency virus (HIV) infection, our group has recently developed a concentrated formulation of the first-line antiretroviral efavirenz by means of encapsulation within polymeric micelles. The aqueous solubility of the drug was increased more than 8400 times (up to 34 mg/mL) and preliminary preclinical data suggested the significantly greater oral bioavailability with respect to an extemporaneous suspension and an oleous solution (similar to the only “commercially available” pediatric formulation). As the preamble to a bioequivalence trial to evaluate the micellar system in adult healthy volunteers, the present work investigated the effect of parameters such as dose per body weight and drug concentration on the oral pharmacokinetics of the drug. The non-linear pharmacokinetics of the drug was confirmed for all the formulations. Despite the drug concentration and dose, micelles consistently resulted in significantly greater absorption rates, PK parameters increasing up to 3-fold. For example, Cmax values increased from 687, 1789 and 2657 ng/mL for the oily system to 1145, 2856 and 7056 ng/mL for the micellar one, for EFV doses between 20 and 80 mg/kg. Data clearly showed that the smaller the micellar size, the higher the bioavailability attained. The effect of micellar size was also assessed. In addition, a comparison between in vitro dissolution rates of EFV for the different micelles and AUC values suggested that micelles releasing faster in vitro lead to a less pronounced absorption in vivo. These findings would suggest the involvement of additional absorption mechanisms.