Pharmacokinetics of Injectable, Long-Acting Nevirapine for HIV Prophylaxis in Breastfeeding Infants

Abstract

c 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 4 to 6 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 the frequent dosing. With these challenges in mind, we have developed the first injectable, sustained-release NVP formulations with the goal of providing, for 6 weeks or longer, preventative plasma drug levels from a single subcutaneous administration at birth. The long-acting NVP consists of large (>50 m), 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 longacting formulations, demonstrating preliminary feasibility of the technology to maintain safe, preventative NVP plasma levels (0.2 to 3.0 g ml ؊1 ) for 6 weeks or longer.

Creation of a long-acting nanoformulated dolutegravir

“…Nanoparticle based systems are readily taken up by cells and disseminated into tissues to form drug depots at these sites for subsequent slow release 20 . Other controlled release injection site drug depot formulations include microparticle carrier systems 21 , 22 . However, microparticles tend to aggregate limiting their usage due to lack of particle homogeneity, leading to injection site reactions 23 .…”

Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis

“…We have recently reported on a novel approach to achieve parenteral sustained-release ARV delivery based on large (Ͼ50 m), monodisperse drug particles coated with biocompatible polymers that control the compound's release kinetics (21) and have used it to develop long-acting injectable formulations of the NNRTI nevirapine (LA-NVP). Pharmacokinetic (PK) modeling showed that LA-NVP holds promise as a prophylactic in mother-to-child transmission of HIV-1, providing 6 weeks of protective plasma drug levels in the HIV-1-negative infant from a single subcutane-ous injection at birth (21).…”

“…Pharmacokinetic (PK) modeling showed that LA-NVP holds promise as a prophylactic in mother-to-child transmission of HIV-1, providing 6 weeks of protective plasma drug levels in the HIV-1-negative infant from a single subcutane-ous injection at birth (21). Unfortunately, preliminary studies using large TAF crystals coated with the blocking polymer poly(D,Llactic acid) did not sufficiently slow the in vitro release rate for a viable sustained-release candidate in HIV-1 PrEP, where a dosing interval of 1 month or longer typically is required.…”

The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia

“…As a proof-of-concept, it has been shown that flagellin of which the hypervariable region is removed can be used to activate TLR5 without triggering an inflammation reaction [ 66 ]. This was further applied in a murine infection model, and evidence for therapeutic synergy between antibiotics and flagellin in the context of pneumonia was obtained [ 67 , 68 , 69 ]. Based on these data, FAIR continues to generate PK, PD, and toxicology data in in vitro systems and preclinical species in order to develop flagellin towards clinical use as an add-on to the standard of care with antibiotics [ 70 ].…”