In the present work, the pharmacokinetics of lamivudine in women, cord blood, and amniotic fluid were satisfactorily described by the proposed compartmental model. The following observations support the validity of this model: (i) in women, cord blood, and amniotic fluid, the population predicted concentrations were well correlated with the observed concentrations, and (ii) the population model was validated with the visual predictive checks (VPC) method. Moreover, pharmacokinetic parameters obtained from our population model were close to the values reported in previous studies (). The fetal elimination rate constant estimated with these amniotic fluid data is close to the elimination rate constant calculated with another PK model for neonates and children (5
Moodley et al. previously reported 3TC pharmacokinetics in women at week 38 of pregnancy and 1 week after delivery and concluded that there was a lack of an effect of pregnancy on lamivudine disposition (14
). In our study, we analyzed 3TC pharmacokinetics not only in late pregnancy but also from week 6 to week 39 of gestation, during labor, and after pregnancy. We observed that the rate of lamivudine clearance was about 22% higher in women during pregnancy. Lamivudine is eliminated predominantly in the urine as unchanged drug (15
). The rate of renal clearance of lamivudine is higher than the glomerular filtration rate (GFR), which implies that lamivudine is actively secreted into the renal tubule (8
). In pregnancy, the GFR and effective renal plasma flow increase to levels 50% to 80% above levels for nonpregnant women (2
). This increase occurs shortly after conception and persists throughout the second trimester (6
). A decrease in the GFR during the last 3 weeks of pregnancy was also reported previously, reaching postpartum values by the last week of pregnancy (2
). In our study, the increased clearance in pregnant women can be explained by these physiological changes in the GFR during pregnancy. The description of clearance as a function of gestational age probably failed because of the lack of concentration data in the first trimester, when the increase in the GFR occurs. Tubular secretion is dependent on saturable membrane transport proteins. Very little is known regarding the effect of pregnancy on tubular secretion and/or reabsorption (2
The level of 3TC exposure in pregnant women, although lower than the level of exposure in nonpregnant and parturient women, was relatively close to data reported previously for nonpregnant adults (), and no dosage adjustment seems to be necessary to reach the adult AUC value.
Few data on 3TC placental transfer have been reported. A previous study by Mandelbrot et al. described placental transfer by a simple cord blood-to-maternal concentration ratio, which is highly variable, from a negligible value up to 742% (12
). In our study, from one sample at delivery (at various times after drug administration) for each mother-cord pair, we were able to assess the maternal and cord blood concentration profiles over time. Placental transfer could be estimated as a fetal-to-maternal drug exposure ratio, which was estimated to be 86%.
The high 3TC amniotic fluid concentration can be explained as follows: 3TC diffuses from the maternal blood to fetal blood through the placenta, the fetal kidney removes 3TC from fetal blood and concentrates it in urine, and fetal micturition causes the rise in the concentration of 3TC in amniotic fluid. 3TC returns from amniotic fluid to fetal blood mainly because of fetal swallowing, and the larger part of this 3TC will again be excreted by the kidney into the amniotic compartment. This mechanism is satisfactorily described by our model and seems to be applicable to other substances cleared mainly by kidney, as was described previously for para
). This model allowed us to estimate the capacity for fetal elimination into the amniotic fluid compartment. We could also draw the 3TC PK profile for the amniotic fluid and thus express the accumulation into this compartment via an exposition constant ratio of 3. The high 3TC amniotic fluid concentrations may have clinical implications for the fetus, either beneficial or detrimental. Indeed, the lamivudine swallowed may account for an oral loading dose for the fetus; it can also be protective against concomitant exposure to infectious HIV by the oral route. On the other hand, the potential toxicity of perinatal exposure to nucleoside analogs may be of concern.
In conclusion, maternal, fetal, and amniotic fluid lamivudine pharmacokinetics were accurately described by the proposed model. The apparent rate of clearance of lamivudine was increased by 22% in pregnant women compared to nonpregnant or parturient women. As rates of exposure in pregnant women are close to values reported previously for nonpregnant adults, no dose adjustment should be needed. Maternal-to-fetal transfer was assessed by using an exposure ratio that was about 86%. The fetal elimination rate constant of 3TC for the amniotic fluid was estimated to be 0.181 h−1. The accumulation in the amniotic fluid compartment expressed as an AUC ratio was 3.