Sustained release depot pre-exposure prophylaxis in breast feeding populations

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DESCRIPTION (provided by applicant): The broad long term goal of this project is to prevent mother to child transmission of HIV through breast feeding in resource poor countries. In the developing world, perinatal transmission is greatly reduced through relatively simple expedients such as dosing mother and child around the time of delivery with nevirapine. However breast feeding still accounts for approximately 315,000 cases annually of pediatric AIDS in sub-Saharan Africa. Despite concerns about potential toxicity, a Phase III trial is underway to study daily oral nevirapine to be given to infants in order to reduce this transmission. We have developed a platform technology for the sustained release of a broad range of drugs by subcutaneous / intramuscular injection that can potentially provide 6 weeks of protection from each injection. A program that incorporates these injections could piggyback onto existing accelerated DPT immunization protocols currently in widespread use in Africa. In Phase 1 of this project we accomplished the specific aims proposed: we formulated sustained release suspensions for nevirapine; we tested the in vitro release characteristics of these formulations into buffer; and we determined preliminary in vivo pharmacokinetics and safety of the formulations in rats. Specific aims of this Phase 2 proposal are to: 1, optimize the production parameters of the formulation; 2, manufacture lots for clinical trials under FDA Good Manufacturing Procedures (GMP); 3, perform required animal pharmacokinetic and safety studies in 2 species under Good Laboratory Procedures (GLP); 4, submit a request for an Investigational New Drug Exemption (IND) to the FDA; The successful completion of this project will lead rapidly to the development of an injectable dosage form that could ideally deliver continuous antiviral blood levels through weaning. Completion of these aims will constitute a readily identifiable milestone that will continue in Phase 3, in which we will carry out Phase 1 testing in volunteers and Phase 2 testing in a small population at risk. Ultimately a trial comparing daily oral therapy to the injectable system will prove the potential value of this approach. Each year 315,000 infants in sub-Saharan Africa are infected by HIV though breast milk. Lack of clean water prevents bottle feeding. Daily oral nevirapine administered by mothers to their breast feeding babies is being tested in a Phase III clinical trial but will be resource intensive. The goal of this work is to develop an injectable drug depot formulation for nevirapine that could reduce the infrastructure requirements for an effective prophylaxis program to prevent mother to child HIV transmission in breast feeding populations.