Menstrual Cycle and Zidovudine Pharmacokinetics in HIV-Infected Women

Objective To examine the pharmacokinetics of zidovudine during each menstrual cycle phase in women with HIV-1 infection. Design Open-label, nonblinded study. Setting The immunodeficiency clinic at the Erie County Medical Center, Buffalo, New York. Patients 12 HIV-seropositive women started and completed the study. Inclusion criteria for subjects included an acceptable medical history, chemistry profile, a complete blood count with differential, lymphocyte profile, urinalysis and history of regular menstrual cycles. Interventions All patients received a 100mg dose of zidovudine in a fasted state on three occasions. Main Outcome Measures 8-hour pharmacokinetic profiles in the 12 women were obtained during the menstrual, follicular and luteal phases of the menstrual cycle. Serum estradiol, progesterone, cortisol and CD4+ and CD8+ cell counts were also obtained during each menstrual cycle phase. Results Considerable intra- and interpatient variability in zidovudine pharmacokinetics was evident. Plasma concentrations declined in a linear fashion over 4 hours following drug administration, with a prolonged elimination phase for most subjects. The overall mean elimination half-life of zidovudine was 1.6 ± 0.76h (range 0.56 to 3.7h) and the overall mean oral clearance was 2.32 ± 0.88 L/h/kg (range 1 to 4.7 L/h/kg). Time to maximum plasma drug concentration was 0.58 ± 0.27h, 0.77 ± 0.64h and 0.63 ± 0.29h during the menstrual, follicular and luteal phases, respectively (p = 0.555). The mean peak plasma concentration of zidovudine was 684 ± 502 μg/L, 666 ± 562 μg/L and 527 ± 210 μg/L during the three phases, respectively (p = 0.472). The mean zidovudine area under the concentration-time curve (AUC) during the studied phases was 781 ± 279 μg h/L, 875 ± 391 μg h/L and 693 ± 176 μg h/L, respectively (p = 0.128). The AUC was negatively correlated with estradiol serum concentration (r = −0.329, p < 0.05). Conclusion: There were no significant differences in the zidovudine pharmacokinetic parameters across the menstrual cycle phases, but there was high inter-subject variability during each cycle phase. A significant negative relationship was found between zidovudine AUC and estradiol concentrations, suggesting that zidovudine glucuronidation may change in relation to the menstrual cycle phase. Hormonal variation and fluctuations in women, especially estrogen, may therefore explain in part the unpredictability of zidovudine exposure after an oral dose. This may impact plasma concentrations of zidovudine and potentially cause fluctuating concentrations throughout prolonged periods each month.