Pharmacokinetics of atazanavir/ritonavir during pregnancy

Previous reports have shown plasma concentrations of some PIs are reduced in pregnant women.

A late breaker poster authored by Francesca Conradie and coworkers from the A1424182 study showed PK data from women receiving atazanavir/ritonavir (ATV/r) once daily during pregnancy.

This was a multicentre, open label, single arm phase I study with sites in South Africa, Puerto Rico and the USA. Women were enrolled who were between 12 and 32 weeks gestation with CD4 >200 cells/mm³.

This study determined multiple clinical and PK parameters during the second and third trimesters, and post-partum.

ATV was dosed ATV/r 300/100 mg (n=20) or ATV/r 400/100 mg (n=21) in combination with AZT/3TC 300/150 mg twice-daily during the third trimester. Second trimester and post partum dosing was ATV/r 300/100mg.

Third trimester exposures were compared to historical ATV 300/100mg exposures in non-pregnant adults. Foetal:maternal ratio was determined using cord blood samples. Infants were followed up for 6 months.

The investigators reported all mothers had fully suppressed viral load (<50 copies/mL) before or at delivery. At the time of analysis all infants (n=40) were HIV DNA negative. There were no infant deaths.

Maternal drug-related serious adverse events (SAEs) were: hyperbilirubinemia (n=1) and anaemia (n=4). Grades 3-4 hyperbilirubinemia occurred in 6/20 and 13/21 mothers in the 300/100mg and 400/100mg groups, respectively.

Three infants had drug-related SAEs. Infant bilirubins were within normal limits to day 14; 7 had Grade 3 hyperbilirubinemia after day 14 (maximum 8.5 mg/dL at day 15). One infant received 3 days phototherapy from day 3. This infant had other risk factors (low birth weight and prematurity).

For the 300/100mg group, they reported that Cmax and AUC during the third trimester were 27% and 21% lower and C24 was similar to historical data in non-pregnant HIV-positive patients taking ATV/r 300/100 mg once-daily.

For the 400/100mg group they found AUC and Cmax similar to, and C24 39% higher than, historical levels; post partum exposures were also higher than historical. The investigators noted that elevated levels have been observed with other PIs in the post partum period. Levels of ATV appeared to normalise by 16 weeks post partum.

The ATV foetal:maternal ratio was 0.19 and 0.12 for 300/100 and 400/100, respectively. This ratio indicates that ATV, like other PIs, has poor transplacental transfer.

The investigators concluded that this phase I study suggests that no dose modification of ATV 300/100mg once daily is necessary in the third trimester of pregnancy. Clinical outcomes indicate that this dose suppressed HIV viral load effectively in the participating women, and prevented vertical transmission of HIV to their infants, when used in combination with AZT/3TC twice daily. Treatment with ATV/r in the mothers appeared to be well tolerated.

Conradie F et al. The safety, efficacy, and steady state pharmacokinetics of atazanavir/ritonavir (ATV/r) once daily given in combination with twice daily AZT/3TC during pregnancy: results of study AI424182. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Poster abstract LBPEB06.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3732