530 Differential Phosphorylation of Zidovudine and Lamivudine Between Semen and Blood Mononuclear Cells in HIV-1 Infected Men S. Reddy*1, L. Troiani1, J. Kim1, J. Rodriguez2, S. Fiscus1, A. V. Kempen3, M. Cohen1, A. Kashuba1 1Univ of North Carolina, Chapel Hill; 2Univ of Puerto Rico; and 3GlaxoSmithKline
Background: Therapeutic concentrations of ARVs into the male genital tract may reduce viral replication and influence selection and transmission of resistant HIV-1 variants. We have previously reported that Zidovudine and Lamivudine (ZDV/3TC) seminal plasma exposure is ~2x and ~6x that of blood plasma, respectively. However, since ZDV/3TC undergo sequential phosphorylation by intracellular kinases to the active triphosphate (TP) moiety, we now are the first to compare the intracellular pharmacokinetics (PK) of ZDV-TP and 3TC-TP in MCs isolated from semen and blood.
Methods: Fourteen (14) men receiving ZDV/3TC as part of a stable antiretroviral regimen were recruited. Semen and blood plasma and MCs were collected at 3, 6, 9, and 12 hr post-dose over 2 wks under steady-state conditions. ZDV/3TC TP concentrations were determined by a validated LC/MS/MS method. HIV RNA was measured in SP and BP by Organon Teknika Nuclisens (BLQ < 400c/mL) and Roche Amplicor Monitor (BLQ < 50c/mL) kits, respectively. Non-compartmental PK and statistical analyses were performed using WinNonlin Pro (V3.1) and SAS JMP (V4.0.2). Data are reported as median (IQR).
Results: ZDV/3TC-TP in blood MCs were similar to previous reports. ZDV/3TC-TP concentrations in blood and semen remained relatively stable across the 12-h dosing interval. The semen:blood C ratio for 3TC-TP was 0.78 (0.57-1.20) and for ZDV-TP was 0.22 (0.17-0.44). The semen:blood AUC0-12hr ratio for 3TC-TP was 1.0 (0.62-1.30) and for ZDV-TP was 0.36 (0.30-0.37). In both semen and blood, there were poor correlations between ZDV and ZDV-TP exposure, and between 3TC and 3TC-TP exposure (r2<0.04). One subject with detectable seminal plasma RNA was noted to have the lowest seminal plasma ZDV/3TC-TP exposures. Throughout the investigation, HIV-1 RNA in the SP and BP were BLQ (BLQ-BLQ) and BLQ (BLQ-335) c/ml, respectively.
Conclusion: ZDV-TP and 3TC-TP concentrations were detectable in seminal MCs. Seminal 3TC-TP exposure was similar to blood MCs. However, seminal ZDV-TP exposure was only a fraction of blood, suggesting different kinase activities or cellular activation between the 2 compartments. These findings may have implications for compartmental NRTI efficacy.
