Mother-to-child transmission (MTCT) of HIV-1 remains a global health problem. The World Health Organization (WHO recommendations advise the administration of a once-daily, oral, prophylactic regimen of the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) from birth until four to six weeks of age for infants born to HIV-infected mothers in regions without access to safe and nutritionally adequate alternatives to breast milk. A critical factor driving the successful implementation of the WHO guidelines involves sustaining high adherence to frequent dosing. With these challenges in mind, we have developed the first injectable, sustained release NVP formulations with the goal of providing, for six weeks or longer, preventative plasma drug levels from a single subcutaneous administration at birth. The long-acting NVP consists of large (> 50 μm), monodisperse NVP particles coated with biocompatible polymers that control the drug release kinetics. Two lead formulations exhibiting burst-free, sustained release kinetics for up to 75 days in vitro were developed. Subsequent in vivo studies in rats demonstrated no toxicity related to the formulations. Rat plasma NVP concentrations were above the analytical assay’s limit of quantification for up to 28 days. Pharmacokinetic analysis of the rat plasma NVP concentration-time data allowed absorption rate constants to be calculated. These data then were used to simulate infant NVP exposure from a single injected dose (< 200 mg) of our long-acting formulations, demonstrating preliminary feasibility of the technology to maintain safe, preventative NVP plasma levels (0.2-3.0 μg mL-1) for six weeks, or longer.
Author(s): John Cortez, Rafaela Quintero, John Moss, Martin Beliveau, Thomas Smith, Marc Baumb