Entry and Attachment Inhibitors

Maraviroc (Selzentry, MVC)

Animal Studies

Carcinogenicity
Maraviroc (MVC) was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Long-term carcinogenicity studies of MVC in rats showed no drug-related increases in tumor incidence at exposures that were approximately 11 times those observed in humans who received the therapeutic dose.

Reproduction/Fertility
No adverse effects were observed on the fertility of male or female rats at doses of MVC that produced exposures (based on area under the curve [AUC]) up to 20-fold higher than those seen in humans given the recommended 300 mg, twice-daily dose.

Teratogenicity/Adverse Pregnancy Outcomes
In animal reproduction studies, no evidence of adverse developmental outcomes was observed in animals that received MVC. During organogenesis in the rat and rabbit, systemic exposures to MVC (based on AUC) were approximately 20 times (in rats) and five times (in rabbits) the exposure seen in humans given the recommended 300 mg, twice-daily dose. In a rat prenatal and postnatal development study, maternal MVC AUC was about 14 times the exposure observed in humans given the recommended 300 mg, twice-daily dose.¹

Placental and Breast Milk Passage
A study in rhesus macaques showed that single-dose MVC had poor placental transfer and rapid clearance from infant monkeys’ blood.² Studies in lactating rats indicate that MVC is secreted extensively into rat milk.¹

Human Studies in Pregnancy

Pharmacokinetics
A U.S./European intensive pharmacokinetic (PK) study measured 12-hour PK profiles in the third trimester and at least 2 weeks postpartum included 18 women who were taking MVC as part of clinical care.³ Sixty-seven percent of the women in the study were taking MVC 150 mg twice daily with a protease inhibitor; 11% took MVC 300 mg twice daily, and 22% took an alternative regimen. The geometric mean ratio for third-trimester AUC versus postpartum AUC was 0.72; the geometric mean ratio for maximum MVC concentration in the third trimester versus maximum MVC concentration postpartum was 0.70. Despite an overall 30% decrease in MVC AUC during pregnancy and a 15% decrease in trough concentration (C_trough), C_trough exceeded the minimum target concentration of 50 ng/mL in all participants except for one woman, who had a C_trough below 50 ng/mL during both pregnancy and the postpartum period. These data suggest that the standard adult dose adjusted for concomitant antiretroviral (ARV) drugs is appropriate in pregnancy. A review of interactions between ARV drugs and oral contraceptives found that it is safe to coadminister oral contraceptives with MVC.⁴

Placental and Breast Milk Passage
An ex vivo human placental cotyledon perfusion model demonstrated minimal placental passage of MVC.⁵ In a study of six mother–infant pairs, the median ratio of MVC concentration in cord blood to MVC concentration in maternal plasma was 0.33 (with a range of 0.03–0.56).³ Whether MVC is secreted into human milk is unknown.

Teratogenicity/Adverse Pregnancy Outcomes
In a prospective study, 30 cases of first-trimester exposure to MVC have been reported to the Antiretroviral Pregnancy Registry to date,⁶ and other first-trimester exposure data are available.⁷ Data are still insufficient, however, to determine the risk of birth defects for infants who were exposed to MVC.

Other Safety Information
A retrospective study from an English-Irish cohort of 857 pregnant women showed an increased rate of hepatotoxicity among the 492 women who started ARV therapy during pregnancy.⁸ MVC, efavirenz, and nevirapine were associated with an increased risk of liver enzyme elevation during pregnancy; the adjusted hazard ratio for MVC was 4.19 (1.34–13.1, P = 0.01). In a model that used human placental BeWo cells, MVC inhibited transplacental passage of two fluorescent organic cations, suggesting that it might influence placental drug transfer and cause drug–drug interactions.⁹

Excerpt from Table 10

References

1. Maraviroc (Selzentry) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022128Orig1s019,208984Orig1s002lbl.pdf
2. Winters MA, Van Rompay KK, Kashuba AD, et al. Maternal-fetal pharmacokinetics and dynamics of a single intrapartum dose of maraviroc in rhesus macaques. Antimicrob Agents Chemother. 2010;54(10):4059-4063. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20696881.
3. Colbers A, Best B, Schalkwijk S, et al. Maraviroc pharmacokinetics in HIV-1-infected pregnant women. Clin Infect Dis. 2015;61(10):1582-1589. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26202768.
4. Tittle V, Bull L, Boffito M, et al. Pharmacokinetic and pharmacodynamic drug interactions between antiretrovirals and oral contraceptives. Clin Pharmacokinet. 2015;54(1):23-34. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25331712.
5. Vinot C, Gavard L, Treluyer JM, et al. Placental transfer of maraviroc in an ex vivo human cotyledon perfusion model and influence of ABC transporter expression. Antimicrob Agents Chemother. 2013;57(3):1415-1420. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23295922.
6. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989–31 January 2020. Wilmington, NC: Registry Coordinating Center. 2020. Available at:http://www.apregistry.com.
7. Floridia M, Mastroiacovo P, Tamburrini E, et al. Birth defects in a national cohort of pregnant women with HIV infection in Italy, 2001-2011. BJOG. 2013;120(12):1466-1475. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23721372.
8. Huntington S, Thorne C, Anderson J, et al. Does pregnancy increase the risk of ART-induced hepatotoxicity among HIV-positive women? J Int AIDS Soc. 2014;17(4 Suppl 3):19486. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25393995.
9. Nabekura T, Kawasaki T, Kamiya Y, et al. Effects of antiviral drugs on organic anion transport in human placental BeWo cells. Antimicrob Agents Chemother. 2015;59(12):7666-7670. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26416870.