Pharmacokinetics, pharmacodynamics, efficacy and drug resistance selection of injectable long-acting lenacapavir pre-exposure prophylaxis (PrEP) against HIV.

Oral pre-exposure prophylaxis (PrEP) denotes an effective strategy to reduce the risk of HIV infection. However, many individuals encounter difficulties adhering to the once-daily regimen, which highlights the need for a broader portfolio of PrEP options. The novel HIV capsid inhibitor lenacapavir (LEN), when injected every six month, has shown potential in the recently completed clinical trials. However, clinical trials may not enable to accurately estimate prophylactic efficacy and protective concentration benchmarks. Moreover, since LEN may persist up to two years, there may be a risk for de novo resistance emergence after stopping PrEP. We developed an integrated pharmacokinetic-pharmacodynamic (PK-PD) model of LEN and incorporated observed variability from Phase III clinical data into our analysis. The model was used to quantify prophylactic efficacy against wild type (WT) and resistant virus, as well as to quantify risks of de novo drug resistance emergence when LEN-PrEP is stopped. We estimated a 95% preventive plasma concentration