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The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR.Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%–36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix.Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by ∼66% and reduced the exposure of plasma total radioactivity by ∼68%.The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged.CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV. The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR. Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%–36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix. Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by ∼66% and reduced the exposure of plasma total radioactivity by ∼68%. The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged. CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV.

Conservation agencies need information to guide planning activities and allocation of limited mitigation resources at regional scales. Utilization of hydrological modeling tools at sub-watershed scales can adequately represent existing conditions, but information on a few discrete uncoordinated efforts cannot be scaled up to the entire region. Conversely, large scale modeling studies suffer from overgeneralization caused by needed lumping of information. In this study, a multiscale and standardized procedure was sought to characterize water and nonpoint source pollution spatiotemporal dynamics at basin-scale but through detailed field-scale analysis. The AnnAGNPS watershed pollution model was enhanced with new capabilities for simulation of large areas based on an Integrated Technology for Evaluation and Assessment of Multi-scale-hydrological Systems (ITEAMS) approach. Comparisons between the standard and proposed ITEAMS approach indicated no difference in streamflow and small underestimation of suspended sediments during high intensity rainfall events. The ITEAMS approach was applied to a basin with a total area of 3,268,691 ha which was discretized into 469,628 sub-catchments with an average size of 6.8 ha. The resulting 366 linked AnnAGNPS simulations were executed hierarchically generating estimates of water and suspended sediment yield and loads. This pilot study revealed the ITEAMS approach is a viable alternative for modeling and simulating large areas but at high spatiotemporal resolution.