As a scientist at Certara and proud Dad to my three kids, pediatric drug development is a topic that is near to my heart. Clearly, children are not just “small adults.” They require special consideration for their distinct physiology during drug development. Likewise, for ethical reasons, it is important to minimize children’s exposure to experimental therapeutics. Modeling and simulation is an important tool that helps maximize knowledge of drug safety and efficacy in pediatric indications. In this blog post, I’ll discuss how we worked with a sponsor to characterize the pharmacokinetics of a novel long-lasting antiretroviral to help prevent mother-to-child transmission (MTCT) of HIV.
Mother-to-child transmission of HIV remains a global health problem
MTCT of HIV can occur during pregnancy, birth, or lactation. According to the World Health Organization (WHO), without intervention, the rate of MTCT ranges from 15-45%. MTCT is the most common cause of HIV infection in children.
Antiretroviral prophylaxis can drastically reduce MTCT to less than 5%. The most widely used protocol calls for giving the mother a single-dose of the non-nucleoside reverse transcriptase inhibitor, nevirapine (NVP), at the onset of labor and then, giving the infant a single dose shortly after birth.
Breast is best, but what if mom is HIV+?
While this protocol reduces MTCT by almost half, there is still a significant risk of MTCT in breastfeeding infants during the first six weeks of life. Thus, the U.S. Centers for Disease Control and Prevention (CDC) recommends that HIV+ mothers do not breastfeed their babies, and use formula instead. Formula feeding is not feasible for most HIV+ mothers in developing countries due to both the cost of formula and a lack of safe drinking water with which to prepare formula. The WHO recommends that babies born to HIV+ mothers, who lack safe alternatives, receive daily oral NVP until four to six weeks of age to prevent MTCT from breastfeeding.
Unfortunately, the success of this recommendation is highly dependent on close adherence to the daily dosing protocol. Previous research shows that it is very difficult for patients to maintain compliance with frequent dosing for long durations. To address these challenges, a sponsor sought to develop the first injectable, sustained-release NVP formulation that would provide, for six weeks or longer, protective plasma drug levels from a single administration to babies at birth.
A new formulation for long-acting NVP from a single dose
Long-acting NVP consists of large, monodisperse NVP particles coated with biocompatible polymers that control drug release kinetics. In vitro assays suggested that these formulations could exhibit burst-free, sustained release of NVP for up to 75 days. Studies in rats showed no toxicity related to the NVP formulation. I used Phoenix NLME to characterize the pharmacokinetics of sustained-release NVP in rats. Then, I used this data to simulate infant NVP exposure from a single injected dose of the long-acting NVP formulation. These data demonstrate preliminary feasibility for this technique to maintain safe, effective NVP plasma levels for six weeks or longer.
Implications for preventing HIV MTCT in breastfeeding infants
Based on these results, the sponsor applied for and received orphan drug designation from the FDA for NVP in preventing pediatric HIV infection. I am excited about the potential of this treatment to save the lives of some of the littlest patients in regions of the world most affected by the HIV epidemic.
This work was recently published in the journal, Antimicrobial Agents and Chemotherapy, as “Pharmacokinetics of Injectable, Long-Acting Nevirapine for HIV Prophylaxis in Breastfeeding Infants.” I hope that you’ll read it and let me know what you think in the comments section.
All information presented derive from public source materials.
To learn more about how Phoenix NLME can be a powerful, easy-to-use tool for population PK modeling, watch our webinar “Population Analysis of Complex Multidimensional Responses Using Phoenix NLME.”