Effect of HIV-1 infection and sex on the cellular pharmacology of the antiretroviral drugs zidovudine and lamivudine

Abstract

The cellular pharmacology of zidovudine (ZDV) and lamivudine (3TC) in vivo is not completely understood. This prospective longitudinal study investigated the relationship between HIV-1 serostatus, sex, race, and time on therapy with intracellular and plasma ZDV and 3TC concentrations. Of 20 HIV-seronegative and 23 HIV-seropositive volunteers enrolled, 16 (8 women) and 21 (5 women) completed all 12 study days, respectively. Volunteers began ZDV-3TC therapy (plus a third active drug in HIV-seropositive volunteers), and steady-state concentrations (C(ss)) were determined after days 1, 3, 7, and 12. A repeated-measures mixed model was utilized. HIV-seronegative status was associated with 22% (95% confidence interval [CI], 0%, 50%) and 37% (15%, 67%) higher C(ss) estimates compared to those of HIV-seropositive individuals for intracellular ZDV-TP and 3TC-TP levels, respectively. African-Americans had 36% (8%, 72%) higher ZDV-TP estimates than non-African-Americans. Sex was not associated with ZDV-TP or 3TC-TP (P > 0.19). Women had 36% (4%, 78%) higher plasma ZDV, but the effect was lessened when normalized by lean body weight (5% [-19%, 38%]; P = 0.68). Plasma 3TC was 19% (0%, 41%) higher in HIV-seropositive volunteers and 22% (0%, 48%) higher in African American volunteers, but these effects were not significant when corrected for creatinine clearance (7% [-9%, 20%] and -5% [-26%, 12%] for HIV serostatus and race, respectively; P > 0.35). These results suggest that HIV-seropositive status decreases and African American race elevates the cellular triphosphates of ZDV and 3TC. This information extends knowledge of ZDV and 3TC cellular pharmacology in vivo and provides new leads for future cellular pharmacology studies aimed at optimizing HIV prevention/treatment with these agents.

Figures

Fig 1

Boxplots of TP levels by day. Boxplots show medians and IQR of ZDV-TP (A) and 3TC-TP (B) Css. Unfilled circles represent data outside 1.5 IQR (whiskers).

Fig 2

Boxplots of plasma levels by day. Boxplots show medians and IQR of ZDV (A) and 3TC (B) plasma Css. Unfilled circles represent data outside 1.5 IQR (whiskers).

Fig 3

Covariate effects on TP levels. Parameter estimates by day for ZDV-TP (A) and 3TC-TP (B) Css. AA, African-American.

Fig 4

Covariate effects on plasma levels. Parameter estimates by day for ZDV (A) and 3TC (B) plasma Css. AA, African-American.

Fig 5

Boxplots of ZDV plasma levels by HIV serostatus. Boxplot showing medians and IQR of HIV-seronegative (A) and HIV-seropositive (B) Css. Unfilled circles represent data outside 1.5 IQR (whiskers).

Fig 6

Influence of ritonavir (/r) on ZDV plasma levels. The boxplot shows medians and IQR and whiskers (5th to 95th percentile) of ZDV plasma Css in HIV-seropositive subjects on days 0 and 12 of the study, separated by the third drug used in their highly active antiretroviral therapy regimen. NNRTI, nonnucleoside reverse transcriptase inhibitor; ATV/r, atazanavir/ritonavir; LPV/r, lopinavir/ritonavir.