Project overview
In places with a high HIV burden, such as low- and middle- income countries (LMICs), family planning is vital. This is further evident from statistics showing around 99% of the world’s maternal mortality also occur in LMICs. For women living with HIV, effective contraception provides options, however, places with the highest levels of HIV have the lowest levels of contraception use.
The World Health Organisation recommend progestin-containing implants as the preferred method of long-acting reversible contraception for women living with HIV. However, drug-drug interactions between antiretroviral therapies (ART) to treat HIV and hormonal contraceptives have been reported. Efavirenz was the preferred first-line ART, but it’s giving rise to the most clinically significant DDIs with levonorgestrel, which can lead to unexpected pregnancies in women actively trying not to get pregnant.
In a collaborative effort with the UNMC, CELT aimed to use physiologically based pharmacokinetic (PBPK) modelling to evaluate if there are possible dose changes that could eliminate DDIs between efavirenz and levonorgestrel, followed by UNMC moving forwards with clinical trials to test the findings.
CELT's objectives
- Use PBPK modelling from existing clinical and in vitro data to investigate clinically applicable strategies to overcome these DDIs between levonorgestrel and efavirenz
- To qualify the model against existing clinical data evaluating efavirenz-levonorgestrel DDIs in women living with HIV over 48 weeks
- To use a qualified PBPK model to predict what effects reducing the daily dose of the efavirenz would have on standard dose levonorgestrel plasma concentrations
- To implement a qualified PBPK model to evaluate if doubling the dose of levonorgestrel would overcome the DDI with efavirenz.
Project findings
- CELT’s PBPK modelling work found that reducing the daily dose of efavirenz did not significantly alter the efavirenz – levonorgestrel DDI, so it is unlikely to mitigate the risk of contraceptive failure
- However, CELT’s PBPK modelling did suggest that doubling the dose of levonorgestrel, while the efavirenz dose stayed the same, increased simulated levonorgestrel plasma concentrations to levels comparable to those in women not taking efavirenz
- From the modelling findings, UNMC went on to undertake clinical trials and found that, while it reduced the DDI, doubling the dose of levonorgestrel implants didn’t fully overcome the interaction with efavirenz. They concluded that the contraceptive effectiveness of this method, therefore, remains uncertain.
Awarding body
Related publications
- Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug-drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART
Roberts, O., Rajioli, R.K.R., Back, D.J., Owen, A., Darin, K.M., Fletcher, C.V., Lamorder, M., Scarsi, K.K., & Siccardi, M. (2018) - Development, validation and utilization of a highly sensitive LC-MS/MS method for quantification of levonorgestrel released from a subdermal implant in human plasma
Cirrincione, L.R., Dilly Penchala, S., Scarsi, K.K., Podany, A.T., Winchester, L.C., Back, D.J., Khoo, S.H., Fletcher, C.V., Siccardi, M., & Else, L.J. (2018) - CROI abstract | Double-dose Levonorgestrel Implant Does Not Fully Overcome Interaction with Efavirenz
presented by Scarsi, K. (2019) - CROI webcast | Double-dose Levonorgestrel Implant Does Not Fully Overcome Interaction with Efavirenz
presented by Scarsi, K. (2019)