Atazanavir pharmacokinetics not appreciably altered during late-stage pregnancy

The pharmacokinetics of atazanavir (Reyataz) during pregnancy appear to make it a viable antiretroviral agent for use during delivery, according to a study published in the November 30^th edition of the journal AIDS. Blood levels of ritonavir-boosted atazanavir appeared to be little affected by pregnancy, with therapeutic drug levels maintained at standard doses.

Little information has been available about the use of atazanavir during pregnancy, apart from a few small studies. These showed that the drug appeared to be safe for the mother and child, and effective at controlling the mother's viral load and preventing mother-to-child transmission (see the aidsmap report here).

However, other recent studies have found that the pharmacokinetics of several protease inhibitors are affected during pregnancy, causing significant reductions in drug levels during the third trimester and possibly jeopardising the continued success of therapy. (See e.g. the aidsmap report here.) This study by a team of Italian researchers evaluated the pharmacokinetics of atazanavir during pregnancy.

Participants were drawn from among the women receiving care at the HIV-positive mothers' programme at the Ospedali Riuniti, Bergamo, Italy. Eighteen women agreed to participate; one was withdrawn due to baseline genotypic resistance, leaving 17 who completed the entire study follow-up. Five were receiving anti-HIV therapy already and four had done so in the past; eight were antiretroviral-naïve. Their mean age was 30.7 years; racial origins were varied. At treatment initiation, the mean CD4 cell count was 420 cells/mm³ and the mean viral load was 11,308 copies/ml.

Antiretroviral therapy was started (or continued) in all women between weeks 0 and 26 of pregnancy. The fixed antiretroviral combination for all women was twice-daily Combivir (300mg zidovudine / 150mg lamivudine), plus a once-daily dose of 300mg atazanavir and 100mg ritonavir (Norvir).

Clinical visits and laboratory tests were conducted every two months. Two intensive, 24-hour pharmacokinetic profiles were obtained: during the third trimester of pregnancy, and between one to six months after delivery. (The women continued to receive the unchanged antiretroviral regimen until the final PK profile.) For the first and final profiles, nine serum samples were taken: immediately before the daily (morning) atazanavir dose, and at 0.5, 1, 2, 3, 4, 8, 10, and 24 hours following. Samples of maternal and umbilical cord blood were taken at the time of delivery (by caesarean section in all cases).

All women in the study maintained viral load levels below 50 copies/ml throughout the study. None experienced serious adverse events, or changed or discontinued therapy. All 17 children were born evidently healthy and well, with HIV viral load levels below 50 copies/ml at birth and again three months after birth. No children presented with the hyperbilirubinemia or jaundice which is often associated with atazanavir.

None of the atazanavir PK parameters were significantly different between the antepartum (during pregnancy) and postpartum (after delivery) profiles. The mean 24-hour area under the concentration-time curve (AUC_0–24) was 28,510 ng hr/l antepartum and 30,465 ng hr/l postpartum. The maximum plasma concentration (C_max) was 2,591 ng/ml antepartum and 2,878 ng/ml postpartum. The lowest concentration, measured at hour 24 (C_trough) was 486 ng/ml antepartum and 514 ng/ml postpartum.

The investigators describe the ante- and postpartum differences in AUC_0–24 and C_trough as not significant, although a slight blunting of C_max value was seen during pregnancy. T_max, the time from dose to maximum concentration, was slightly higher (3.2 vs. 2.8 hours) and much more variable during pregnancy, suggesting that delayed absorption could explain the differences in C_max.

C_trough levels, although not significantly different ante- and postpartum, were lower than those expected for individuals on boosted atazanavir: other studies have shown values of 663 to 862 ng/ml. However, all C_trough levels were consistently several fold higher than the 90% inhibitory concentration (IC₉₀) for atazanavir against wild-type HIV (14 ng/ml). (Ritonavir levels, which would affect atazanavir levels, were not measured in this study.)

Maternal blood and umbilical cord blood samples were also available for 14 mother/infant pairs. The mean ratio of cord/maternal atazanavir concentration was 0.13 with a low variability between pairs. Umbilical cord concentration could provide an estimate of the drug concentration in the placenta. However, as protease inhibitors do not generally cross the placenta to an appreciable degree, the significance of this fact, or the role atazanavir might play in preventing mother-to-child transmission, is unclear.

The researchers conclude that this, "the first study describing the pharmacokinetics of atazanavir in pregnant women," suggests that "a standard boosted atazanavir dose is a reasonable component of HAART during pregnancy." Overall drug exposure during the third trimester of pregnancy – the time at which pharmacokinetics are most likely to be disrupted – is "similar to that observed in the non-pregnant state" and that "therapeutic drug concentrations are maintained well above the wild-type HIV IC₉₀" throughout the 24-hour dosing interval.