Pharmacokinetics of zidovudine phosphorylation in peripheral blood mononuclear cells from patients infected with human immunodeficiency virus

Abstract

As part of an effort towards optimization of dosing of zidovudine (ZDV), formation and elimination of total phosphorylated ZDV (ZDVPt) in peripheral blood mononuclear cells were examined in 21 asymptomatic human immunodeficiency virus-infected patients during their first 24 weeks of therapy (AIDS Clinical Trials Group Protocol 161). Intracellular concentrations of ZDVPt were measured with a previously described and validated radioimmunoassay technique. Although ZDV phosphorylation occurred readily upon initiation of therapy, it declined with time; the area under the concentration-time curve (AUC) at week 4 (mean + standard deviation, 3.41 ± 0.93 pmol -h/106 cells) was significantly greater than that at week 24 (2.19 ± 1.10 pmol -h/106 cells). Plasma ZDV AUC did not change with time and did not correlate with ZDVPt AUC. In dose-response experiments (20 to 100 mg orally), phosphorylation did not proportionally increase with increasing plasma ZDV concentrations. Similarly, compared with a single dose, two doses of ZDV over an 8-h period resulted in little ZDVPt increase in cells relative to increases in plasma ZDV concentrations. The halt-life of intracellular ZDVPt was twice that of plasma ZDV (4 versus 2 h), suggesting that an every-8-h dosing regimen is justifiable. These findings suggest that metabolism of ZDV to its active intracellular forms may be saturable in some patients, is poorly correlated with plasma concentrations, and diminishes over time. These findings have implications for future development and management of anti-human immunodeficiency virus nucleoside therapy.Zidovudine (ZDV) currently remains the recommended initial therapy for the treatment of human immunodeficiency virus (HIV) infection. Although effective in slowing the progression of HIV disease, the benefits of ZDV therapy appear to be transient, with patients eventually succumbing to opportunistic infections and/or neoplasms associated with immunosuppression. Its use is associated with several well-documented side effects, most notably anemia and neutropenia (17). The plasma pharmacokinetics of ZDV have been thoroughly studied (5, 12), but a therapeutic concentration range in plasma has not been established. Recommended dosing regimens still vary from country to country and are only weakly supported by pharmacokinetic data; the optimal dosing regimen remains to be determined. There has been one published report of a link between the occurrence of opportunistic infections and area under the concentration-time curve (AUC) in plasma (6), but more comprehensive studies have found little evidence of such relationships between concentrations in plasma or cerebrospinal fluid and clinical effects (4, 25).A thymidine analog, ZDV is phosphorylated at the 5' position by a series of cellular kinases after diffusion into the cell. (8). Similarly, toxicity is attributed to the inhibition of cellular DNA polymerases and termination of cellular DNA elongation and may be further complicated by inhibition of phosphorylation of endogenous thymidine (8) an...

Determinants of Individual Variation in Intracellular Accumulation of Anti-HIV Nucleoside Analog Metabolites

“…Consistent with our findings, some studies have shown an association between gender and levels of intracellular metabolites of NRTIs (1). Some of these studies report higher rates of toxicity and effective antiviral response in women than in men (1,22,44), while others report the opposite (3,6). In other studies, response rate and survival were not dependent on gender but, rather, were dependent on individualized dose adjustments (9,43).…”

“…However, no ethnic difference in the concentrations of intracellular metabolites of NRTIs has been reported to date. Our finding that there is no association between ethnicity and intracellular accumulation of NRTIs is consistent with that of others (44).…”

Zidovudine and Lamivudine for HIV Infection

“…69 Another study also found higher ZDV phosphates (MP plus DP plus TP) among 5 women versus 16 men (1.4-fold; P < 0.01), and a third study found higher 3TC-TP in female compared with male infants despite similar plasma concentrations (1.8-fold; P = 0.04). 61,81 However, a separate study found lower ZDV-triphosphates in female compared with male adults although plasma concentrations were similar. 82 An in vitro study evaluated the effects of progesterone, estrogen, and testosterone on conversion of ZDV and 3TC to ZDV-TP and 3TC-TP in PBMCs and found no major effects, but some minor lowering on 3TC-TP for progesterone and testosterone (all differences were below 50% versus control).…”

Considerations for the Antiretroviral Management of Women in 2008

“…In one study, women had statistically higher intracellular zidovudine and lamuvidine triphosphate concentrations compared with men enrolled in the clinical trial, and were noted to suppress their HIV RNA level to less than 50 copies/ml twice as fast as men [18]. In a second Phase I study of the pharmacokinetics of total zidovudine phosphates (the sum of the mono-, di-and tri-phosphates in peripheral blood mononuclear cells), women's mean total zidovudine phosphate area under the curve was 45% higher compared with men [19]. A third study had conflicting results for zidovudine and found that men exhibited significantly higher zidovudine-monophosphate and zidovudine-triphosphate exposure following zidovudine oral administration compared with women [20].…”

“…NRTIs are considered to be prodrugs, since their active moiety is the triphosphate anabolite that is formed intracellularly [16]. NRTI pharmacokinetic information is limited because of the difficult procedures needed to measure NRTI anabolites [17], but four studies have been performed investigating relationships between intracellular nucleoside triphosphate concentrations, sex and ARV response among persons taking zidovudine, lamivudine or abacavir [18][19][20][21]. In one study, women had statistically higher intracellular zidovudine and lamuvidine triphosphate concentrations compared with men enrolled in the clinical trial, and were noted to suppress their HIV RNA level to less than 50 copies/ml twice as fast as men [18].…”