Disposition of zidovudine in obese pregnant women with human immunodeficiency virus type 1 infection.

To the Editor-A recently published retrospective analysis by Matheson et al. [1] of zidovudine use during pregnancy suggests that antenatal zidovudine therapy may be responsible for a considerable amount ofzidovudine's protective effect in preventing vertical transmission of human immunodeficiency virus type 1 (HIV). Current Centers for Disease Control and Prevention guidelines suggest administering oral zidovudine (500 mg/day) to the mother beginning at 14-34 weeks of gestation, followed by intravenous zidovudine therapy during labor, and then oral therapy for the newborn [2]. These recommendations are based on a study that demonstrated zidovudine therapy reduces vertical transmission by about two-thirds when administered in this manner [3]. Administration of the same standard dose of oral zidovudine, however, does not result in the same plasma concentrations among adults [4, 5]. The variability in plasma concentrations is a consequence of between-patient differences in the absorption, distribution , metabolism, and excretion of zidovudine. As determined on the basis of population pharmacokinetic information , the current dosage of zidovudine (100 mg five times daily) in a 70-kg person produces an average plasma concentration (Css) of ~0.7 u.M; however, this Css can range from 0.18 to 2.8 p.M [5]. While the effects of achieving and maintaining this average plasma concentration are unknown, suboptimal virologic results have been observed in patients receiving a 150-mg/day regimen of zidovudine [6]. Pregnancy introduces additional sources of variability in the disposition of zidovudine [7], likely as a result of an additional compartment (the fetus) and physiologic changes, such as increased hepatic blood flow and body weight. We studied the plasma concentrations of zidovudine in 2 obese pregnant women with HIV. Zidovudine concentrations measured by RIA and pharmacokinetic parameters were determined with a Bayesian estimation strategy. Results are presented in table 1. The Table I. Disposition of zidovudine in 2 obese pregnant women and the average population. Obese Obese Population Parameter patient 1 patient 2 average Total daily dosage (mg) 600 300 500 Dose (mg) 200 100 100 Peak concentration (f..tM) 1.7 0.87 2.0 Total body clearance (Llh) 413 217 126 Daily dosage required to maintain average plasma concentration (mg) 1800 1000 500-600 first woman weighed 142.5 kg and was in her eighth month of pregnancy when zidovudine concentrations were obtained. Her peak zidovudine concentration (1 h after a dose) was 1.7 p,M after receiving 200 mg of the drug. This is about half of the expected concentration, on the basis of the linear …