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Clinical Trial
. 2014 Dec 1;67(4):375-81.
doi: 10.1097/QAI.0000000000000318.

Raltegravir pharmacokinetics during pregnancy

D Heather Watts  1 , Alice Stek, Brookie M Best, Jiajia Wang, Edmund V Capparelli, Tim R Cressey, Francesca Aweeka, Patty Lizak, Regis Kreitchmann, Sandra K Burchett, David E Shapiro, Elizabeth Hawkins, Elizabeth Smith, Mark Mirochnick; IMPAACT 1026s study team
Affiliations
Clinical Trial

Raltegravir pharmacokinetics during pregnancy

D Heather Watts et al. J Acquir Immune Defic Syndr. .

Abstract

Objective: We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum.

Methods: International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is an ongoing prospective study of antiretroviral PK during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady-state 12-hour PK profiles performed during pregnancy and at 6- to 12-week postpartum. Targets were trough concentration above 0.035 μg/mL, the estimated 10th percentile in nonpregnant historical controls.

Results: Median raltegravir area under the curve was 6.6 μg·h/mL for second trimester (n = 16), 5.4 μg·h/mL for third trimester (n = 41), and 11.6 μg·h/mL postpartum (n = 38) (P = 0.03 postpartum vs second trimester, P = 0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester, and postpartum subjects, respectively, with wide variability (<0.010-0.917 μg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were <400 copies per milliliter in 92% of women at delivery. Adverse events included elevated liver transaminases in 1 woman and vomiting in 1. All infants with known status are HIV uninfected.

Conclusions: Median raltegravir area under the curve was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.

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Figures

Figure 1
Figure 1
Median raltegravir concentration-time curves during the second trimester, third trimester and postpartum. The dashed line represents the expected (50th percentile) concentration-time profile in nonpregnant adults.
Figure 1
Figure 1
Median raltegravir concentration-time curves during the second trimester, third trimester and postpartum. The dashed line represents the expected (50th percentile) concentration-time profile in nonpregnant adults.
Figure 1
Figure 1
Median raltegravir concentration-time curves during the second trimester, third trimester and postpartum. The dashed line represents the expected (50th percentile) concentration-time profile in nonpregnant adults.
Figure 2
Figure 2
Maternal delivery raltegravir concentrations, cord blood raltegravir concentrations and their ratio plotted against the time between maternal dosing and delivery. Filled circles represent maternal plasma raltegravir concentration at delivery, open circles represent cord blood raltegravir concentrations and filled diamonds represent the ratio of cord blood to maternal delivery raltegravir concentration.
Figure 2
Figure 2
Maternal delivery raltegravir concentrations, cord blood raltegravir concentrations and their ratio plotted against the time between maternal dosing and delivery. Filled circles represent maternal plasma raltegravir concentration at delivery, open circles represent cord blood raltegravir concentrations and filled diamonds represent the ratio of cord blood to maternal delivery raltegravir concentration.
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References

    1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services; [Accessed 01/30/2014]. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents; p. F-1. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
    1. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. [Accessed 01/30/2014]; Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.
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