Maraviroc Pharmacokinetics in HIV-1-Infected Pregnant Women.
Journal: 2016/July - Clinical Infectious Diseases
ISSN: 1537-6591
Abstract:
OBJECTIVE
To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum.
METHODS
HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and ≥2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated.
RESULTS
Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60-.88) for the area under the curve over a dosing interval (AUCtau) and 0.70 (0.58-0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (Ctrough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03-0.56). The viral load close to delivery was <50 copies/mL in 13 women (76%). All children were HIV negative at testing.
CONCLUSIONS
Overall maraviroc exposure during pregnancy was decreased, with a reduction in AUCtau and maximum concentration of about 30%. Ctrough was reduced by 15% but exceeded the minimum Ctrough target concentration. Therefore, the standard adult dose seems sufficient in pregnancy.
BACKGROUND
NCT00825929 and NCT000422890.
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Clin Infect Dis 61(10): 1582-1589

Maraviroc Pharmacokinetics in HIV-1–Infected Pregnant Women

+9 authors
Correspondence: Angela Colbers, MSc, Radboud university medical center, Department of Pharmacy, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands (ln.cmuduobdar@srebloc.alegna).
Correspondence: Angela Colbers, MSc, Radboud university medical center, Department of Pharmacy, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands (ln.cmuduobdar@srebloc.alegna).
Received 2015 May 18; Accepted 2015 Jul 8.

Abstract

Objective. To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)–infected women during pregnancy and post partum.

Methods. HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and ≥2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated.

Results. Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60–.88) for the area under the curve over a dosing interval (AUCtau) and 0.70 (0.58–0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (Ctrough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03–0.56). The viral load close to delivery was <50 copies/mL in 13 women (76%). All children were HIV negative at testing.

Conclusions. Overall maraviroc exposure during pregnancy was decreased, with a reduction in AUCtau and maximum concentration of about 30%. Ctrough was reduced by 15% but exceeded the minimum Ctrough target concentration. Therefore, the standard adult dose seems sufficient in pregnancy.

Clinical Trials Registration.{"type":"clinical-trial","attrs":{"text":"NCT00825929","term_id":"NCT00825929"}}NCT00825929 and NCT000422890.

Keywords: MTCT, pharmacokinetics, pregnancy, HIV, maraviroc
Abstract

It is estimated that worldwide 16 million women were living with human immunodeficiency virus (HIV) in 2013, with about 1.3 million of them women giving birth [1, 2]. HIV-infected pregnant women may receive antiretrovirals both to protect their own health and to reduce the risk of mother-to-child transmission of HIV [3]. Combination antiretroviral therapy (cART) has been shown to be a highly effective strategy for prevention of mother-to-child transmission of HIV, reducing the risk from 15%–40% to <2% [3].

Maraviroc is an antagonist to C-C chemokine receptor type 5 (CCR5), which plays an important role in blocking HIV-1 entry into susceptible cells [4]. It is effective for treatment of CCR5-tropic HIV-1 as part of cART therapy. The standard recommended dose for maraviroc therapy in adults or adolescents is 300 mg twice daily, unless coadministered with a boosted protease inhibitor, in which case the dose is reduced to 150 mg twice daily [5]. There are no data available describing maraviroc pharmacokinetics and safety for use during pregnancy, and the US Department of Health and Human Services perinatal guidelines include no recommendations regarding maraviroc therapy or dosing regimens during pregnancy [6].

Pregnancy is associated with a myriad of physical changes that affect the pharmacokinetics of drugs [7, 8], mostly resulting in a reduction in drug exposure during pregnancy [9]. Decreased antiretroviral concentrations may lead to inadequate viral suppression and/or development of antiretroviral resistance and may increase the risk of mother-to-child transmission in HIV-infected pregnant women [3, 10]. Data describing maraviroc pharmacokinetics in pregnancy have not been published to our knowledge.

Specific safety issues for maraviroc during pregnancy include its influence on pregnancy duration and fetal development. Maraviroc is assigned to the Food and Drug Administration pregnancy category B, because animal reproduction studies failed to demonstrate a risk to the fetus but no adequate and well-controlled studies have been performed in pregnant women. Reports on the safety of maraviroc during human pregnancy are limited. The most recent Antiretroviral Pregnancy Registry interim report (through 31 January 2015) [11] includes only a few patients who received maraviroc, who did not exhibit any birth defects with exposure to maraviroc in the first trimester (n = 18) or second and third trimesters (n = 5). No data are available concerning the influence of maraviroc on pregnancy duration to our knowledge.

Current available data on transfer of maraviroc across the human placenta are limited to a single case report and data from an ex vivo placenta perfusion study both indicating minor placental transfer [12, 13]. Fetal antiretroviral exposure via placental transfer may provide preexposure prophylaxis against HIV infection for the fetus and newborn, possibly helping to prevent perinatal transmission of HIV but also possibly resulting in drug-related fetal teratogenicity and/or toxicity [6].

Overall, available data are too limited to make grounded recommendations regarding maraviroc use and dosing regimens during pregnancy, highlighting the exclusion of pregnant women from clinical trials during the development of new drugs, mainly owing to concerns about potential risks to the fetus [14]. As a result, HIV-infected pregnant women are currently receiving maraviroc as part of clinical care in the absence of pregnancy specific safety and pharmacokinetic data. Two protocols—the IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials) Network P1026 protocol and the PANNA (Study on Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women) Network—have been developed to study the safety and pharmacokinetics during pregnancy of antiretroviral drugs used for clinical care that lack safety and pharmacokinetic data obtained during pregnancy. For the current report, these networks have collaborated to describe the pharmacokinetics, transplacental transfer, and safety of maraviroc in pregnant HIV-infected women.

Notes

Acknowledgments. We thank the patients for participating in the studies and the laboratory personnel at the Laboratory of the Ottawa Hospital Research Institute, Ontario, Canada for analyzing the pharmacokinetic samples. We thank the staff from the centers participating in the PANNA network: M. E. van der Ende, MD, PhD, Erasmus MC Rotterdam, the Netherlands; A. J. A. M. van der Ven, MD, PhD, Radboud university medical center, Nijmegen, the Netherlands; J. Nellen, MD, PhD, Academisch Medisch Centrum, Amsterdam, the Netherlands; J. Moltó, MD, PhD, Hospital Universitari Germans Trias I Pujol, Badalona, Spain; A. Antinori, MD, IRCSS, Rome, Italy; E. Nicastri, MD, National Institute for Infectious Diseases “L. Spallanzani,” Rome; C. Giaquinto, MD, PhD, University of Padua, Italy; K. Weizsäcker, MD, PhD, Klinik für Geburtsmedizin, Charité Universitätsmedizin, Berlin, Germany; A. Gingelmaier, MD, PhD, Klinikum der Universität München, Frauenklinik Innenstadt, Munich, Germany; F. Lyons, MD, St James's Hospital Dublin, Ireland; J. Lambert, MD, PhD, Mater Misericordiae University Hospital Dublin; C. Wyen MD, PhD, and G. Faetkenheuer, MD, PhD, University of Cologne, Germany; J. K. Rockstroh MD, PhD, and C. Schwarze-Zander, MD, University of Bonn, Germany; S. Tariq Sadiq, MD, PhD, Institution for Infection and Immunity, St George's, University of London, London, United Kingdom; Y. Gilleece, MD, Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom; and C. Wood, MD, North Middlesex Hospital, London.

The IMPAACT investigators included the following: 3801 Texas Children's Hospital (Clinical Research Center [CRS]) (Shelley Buschur, RN, CNM; Chivon Jackson, RN, BSN, ADN; Mary Paul, MD); 4201 University of Miami Pediatric Perinatal HIV/AIDS (CRS) (Claudia Florez, MD; Patricia Bryan, BSN, MPH; Monica Stone, MD); 5013 Jacobi Medical Center, Bronx (National Institute of Child Health and Human Development [NICHD] CRS) (Mindy Katz, MD; Raphaelle Auguste, RN; Andrew Wiznia, MD); 5018 University of South Florida–Tampa (NICHD CRS) (Karen L. Bruder, MD; Gail Lewis, RN; Denise Casey, RN); 5082 Hospital General de Agudos, Buenos Aires, Argentina (NICHD CRS) (Marcelo H. Losso, MD; Silvina A. Ivalo, MD; Alejandro Hakim, MD); 5093 Miller Children's Hospital (NICHD CRS) (Audra Deveikis, MD; Jagmohan Batra, MD; Janielle Jackson Alvarez, RN); 6501 St Jude Memphis, Tennessee (CRS) (Katherine M. Knapp, MD; Nina Sublette, FNP, PhD; Thomas Wride, MS); 6601 University of Puerto Rico Pediatric HIV/AIDS Research Program (CRS) (Irma L. Febo MD; Ruth Santos, RN, MPH; Vivian Tamayo, MD).

Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH).

Financial support. The PANNA network is supported by the European AIDS Treatment Network, the European Commission, DG Research, Sixth Framework Programme (contract LSHP-CT-2006-037570), Bristol-Myers Squibb, Merck Sharp &amp; Dohme, and Janssen Research. Overall support for IMPAACT was provided by the National Institute of Allergy and Infectious Diseases, NIH (grants UM1AI068632; [IMPAACT Leadership and Operations Center], UM1AI068616; [IMPAACT Statistical and Data Management Center], and UM1AI106716 [IMPAACT Laboratory Center]), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health.

Potential conflicts of interest. All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Notes

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