In the present work, the pharmacokinetics of TFV in women were satisfactorily described by a two-compartment model. The following observations support the validity of this model. (i) The population predicted concentrations correlated well with and observed concentrations, and (ii) the population model was validated by to the visual predictive check method. Moreover, the pharmacokinetic parameters obtained from our population model were close to the values reported in previous studies ().
Pharmacokinetics of TFV in pregnant women were also described in two previous studies. Hirt et al. (9
) reported the TFV pharmacokinetics in women on the day of delivery and 1 week postpartum, and Rodman et al. (16
) investigated the pharmacokinetics of TFV after a single dose at the start of labor, the two studies concluded that a maternal 600-mg TDF administration at the start of labor produces the same concentrations as a 300-mg administration in other adults (9
). A more recent study confirmed the necessity of an increased dose of TDF during labor (7
) and noted that the administration of 600 mg and 900 mg of TDF was safe and well tolerated in HIV-infected women in active labor or prior to caesarean section. In our study, women were treated by TDF during their pregnancy and during delivery by the same 300-mg TDF dose, we confirmed the increase of clearance in parturient women and thus the necessity to increase TDF dose in these women.
Burchett et al. (5
) observed a lower TDF exposition in the third trimester of pregnancy compared to postpartum. The magnitude of the AUC decrease in pregnancy was only ca. 15%, however. In our study, we could analyze TFV pharmacokinetics not only in late pregnancy but from weeks 2 to 41 of gestation, during labor, and after pregnancy. We observed that TFV clearance was ca. 39% higher in women during pregnancy compared to nonpregnant women. TFV is primarily excreted by the kidney by a combination of glomerular filtration and active tubular secretion system, with ca. 70 to 80% of the dose excreted unchanged in the urine (15
). In pregnancy, the glomerular filtration rate (GFR) and effective renal plasma flow increase to levels 50 to 80% above nonpregnant levels (1
). This increase occurs shortly after conception and persists throughout the second trimester (6
). In our study, the increased clearance observed during pregnancy could be explained by these physiological changes in GFR during pregnancy. However, no information was available about serum creatinin levels or GFR in our population to confirm it. In addition to the glomerular filtration, TFV undergoes active tubular secretion dependent on hOAT1, hOAT2, and MRP4 (15
). Very little is known
regarding the effect of pregnancy on these transporters (1
In our study, the ages of the woment ranged from 16 to 62 years, and this wide range allowed us to describe the age effect on TFV clearance. Indeed, TFV clearance seemed to decrease slightly but significantly with age, a finding in agreement with the pattern of the GFR decline with aging that has been described in the Kidney Disease Outcomes Quality Initiative (13
). The subject age range was higher for nonpregnant women (62 years versus 43 years), but the effect of pregnancy was observed with or without the older nonpregnant women. We found that lopinavir-ritonavir cotreatment had no effect on the apparent clearance of TFV, in contrast to previous studies.
Since no relationship between TFV plasma concentration and virologic response has been established, a reasonable goal for TFV dosing during pregnancy is to achieve plasma exposure in pregnant women equivalent to that observed in nonpregnant adults treated with the standard 300-mg TDF dose. In our study, the Cmin values for nonpregnant women were similar to those reported in nonpregnant adults (), and their mean TFV exposures expressed as AUCs were slightly lower but not significantly different from nonpregnant adult values (2.4 versus 2.65, P = 0.3). Since TDF is only available in 300-mg tablets, we simulated pregnant women AUCs and Cmin values following the administration of two tablets of TDF (600 mg of TDF, 272 mg of TFV). It appears that the exposure of pregnant women to TFV is low after the administration of one tablet of TDF but may be too high after the administration of two tablets ().
In conclusion, TFV pharmacokinetics in women were accurately described by a two-compartment model. TFV's apparent clearance was increased by 39% in pregnant women. In order to obtain an exposure similar to the known exposure in adults and to guarantee similar trough concentrations as expected in adults, a TFV dose escalation should be considered for women from the second trimester to delivery. Since there is only limited clinical experience with doses higher than the therapeutic 300-mg TDF dose, further investigations are needed.