200 Multi-scale System Pharmacology Modelling Pipeline to Assess the Prophylactic Efficacy of Nrtis against Hiv-1 201 Joint Modelling of Plasma and Fecal Moxifloxacin Pharmacokinetics in Healthy Volunteers 202 Favipiravir Pharmacokinetics in Non-human Primates: Insights for Future Efficacy Studies a

Aims: Pharmacointervention strategies are promising tools to curb the HIV-1 epidemic. Two strategies have recently been proposed: (i) Treatment-as-prevention (TasP) targets potential transmitters by reducing the patients' virus load and thereby also their contagiousness. However, onwards transmission may preferentially occur early after infection when the individual is unaware of his/her serologic status and may not have initiated treatment [1]. (ii) Pre-exposure prophylaxis (PrEP) targets uninfected individuals at risk. Prophylactic drug intake reduces infection probabilities following viral exposure and has proven to effectively prevent vertical transmission [2]. Nucleotide reverse transcriptase inhibitors (NRTIs) are currently intensively investigated as PrEP compounds. While PrEP efficacy depends on a number of factors (e.g. the viral exposure, PK-PD, transmitted drug resistance), our primary focus was to build a modular multi-scale system pharmacology modelling pipeline allowing to combine parameters related to target-site pharmacokinetics (module I), the molecular mechanism of action (MMOA, module II), viral exposure and transmitter virology (module IV) to evaluate PrEP efficacy (module III) for the NRTIs tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). Moreover, the pipeline allows to translate in vitro testable parameters to measures of PrEP efficacy (modules II-III). Methods: While the PK and MMOA modules (I & II) have been developed and validated against clinical data in a previous work [3,4], here we analyze the effects of NRTIs in reducing infection (module III). In this regard, we derived a stochastic master equation, allowing to resolve the probability-and timing of infection after exposure. With regard to module IV, we developed a statistical model that computes viral exposure distributions in the recipient depending on the viral load of the transmitter, and the mode of transmission. The model was parametrized by available data from a large observational study (German Seroconverter Study), complemented and validated by literature data. Results: Combining all modules allowed to estimate the PrEP-efficacy for various schedules ('on demand' or 'chronic' administration with single drugs or combinations) in relation to the timing of viral exposure, with wild type or mutant strains. In contrast to the current beliefs [5], our pipeline revealed that FTC and 3TC were superior to TFV in inhibiting sexual infection with wild type virus, which was particularly evident for PrEP 'on demand'. However, due to its intracellular half-life TFV is more pharmacologically forgiving, in cases of incomplete or poor adherence. Figure 1: Concentration vs. Transmission Risk Reduction. The dotted lines represent the mean protection (% infection prevented) following homosexual intercourse …