Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States

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Non-Nucleoside Reverse Transcriptase Inhibitors

Rilpivirine (Edurant, RPV)

Last Updated: November 14, 2017; Last Reviewed: November 14, 2017

Rilpivirine is classified as Food and Drug Administration Pregnancy Category B.

Animal Studies

Carcinogenicity
Rilpivirine was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Rilpivirine was not carcinogenic in rats when administered at doses 3 times higher than exposure in humans at the recommended dose of 25 mg once daily. Hepatocellular neoplasms were observed in both male and female mice at doses 21 times that of human therapeutic exposure; the observed hepatocellular findings in mice may be rodent-specific.1

Reproduction/Fertility
No effect on fertility was observed when rilpivirine was tested in rats at maternal doses up to 400 mg/kg/day, resulting in systemic drug exposure equivalent to 40 times the recommended human dose.1

Teratogenicity/Adverse Pregnancy Outcomes
No evidence of embryonic or fetal toxicity or an effect on reproductive function was observed in rat and rabbit dams treated with rilpivirine during pregnancy and lactation. Exposures were 15 and 70 times higher in pregnancy and lactation, respectively, than exposure in humans at the recommended dose of 25 mg once daily.1

Placental and Breast Milk Passage
Studies in lactating rats and their offspring indicate that rilpivirine is present in rat milk.1

Pharmacokinetics
A study presenting pharmacokinetic (PK) and safety data from 32 pregnant women with HIV found median rilpivirine area under the curve (AUC) and trough concentrations were reduced by about 20% to 30% in the second and third trimesters, compared with postpartum. Median trough rilpivirine concentrations were significantly lower at 14 visits where the women had detectable HIV-1 RNA (30 ng/mL) compared to 62 visits with undetectable HIV-1 RNA (63 ng/mL). Ninety percent of women had trough concentrations above the protein-adjusted EC90 for rilpivirine. PK exposure was highly variable in this study.2 Another study in 16 pregnant women with HIV found similarly decreased exposure by approximately 50% in the third trimester compared to postpartum.3 These authors recommended therapeutic drug monitoring in the third trimester, and also ensuring that rilpivirine doses are taken with meals. Cervicovaginal fluid rilpivirine concentrations were described in a study of 24 women taking rilpivirine daily during pregnancy and postpartum, which showed cervicovaginal rilpivirine steady-state concentrations similar to those seen in plasma in the same women. Rilpivirine cervicovaginal fluid AUC compared to plasma AUC was higher during pregnancy than postpartum.4

Placental and Breast Milk Passage
One of the PK and safety studies described above included rilpivirine delivery concentration data from 21 mother-infant pairs, with median (range) cord blood rilpivirine plasma concentration of 29.2 ng/mL (<10.0 to 101.5 ng/mL), maternal delivery plasma rilpivirine concentration of 55.2 ng/mL (<10.0 to 233.8 ng/mL) and cord blood/maternal plasma ratio of 0.55 (0.3 to 0.8).2 Similarly, Colbers et al. found a median (range) cord blood-to-maternal plasma ratio of 0.5 (0.35–0.81) in 5 women.3 An ex vivo human cotyledon perfusion model also showed that rilpivirine crosses the placenta with fetal transfer rates ranging from 17% to 37%.5,6 No data exist on whether rilpivirine is excreted in breast milk in humans.

Teratogenicity/Developmental Toxicity
Among cases of first-trimester exposures to rilpivirine reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 0.5% (1 of 202 births; 95% CI, 0.0% to 2.7%) compared with a total prevalence of 2.7% in the U.S. population, based on Centers for Disease Control and Prevention surveillance.7

Excerpt from Table 9a
Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendations Use in Pregnancy
Rilpivirine
(RPV)
Edurant

(RPV/TDF/FTC)
Complera

(RPV/TAF/FTC)
Odefsey
RPV (Edurant)
Tablets:
  • 25 mg
Complera:
  • RPV 25 mg plus TDF 300 mg plus FTC 200 mg tablet
Odefsey:
  • RPV 25 mg plus TAF 25 mg plus FTC 200 mg tablet
Standard Adult Dose
RPV (Edurant):
  • 25 mg once daily with food
Complera:
  • 1 tablet once daily with food
Odefsey:
  • 1 tablet once daily with food

PK in Pregnancy:
  • RPV PK highly variable during pregnancy. RPV AUC and trough concentration reduced 20% to 50% in pregnancy compared with postpartum. While most pregnant women exceeded target exposure, those with detectable viral loads had lower RPV troughs.

Dosing in Pregnancy:
  • While RPV plasma concentration is reduced during pregnancy, higher-than-standard doses have not been studied. Insufficient data are available to recommend a dosing change in pregnancy. With standard dosing, viral loads should be monitored more frequently.
Moderate to high placental transfer to fetus.b

No evidence of human teratogenicity (can rule out 2-fold increase in overall birth defects).
a Individual antiretroviral drug dosages may need to be adjusted in renal or hepatic insufficiency (for details, see the Adult and Adolescent Guidelines Appendix B, Table 7).
b Placental transfer categories—Mean or median cord blood/maternal delivery plasma drug ratio:
          High: >0.6
          Moderate: 0.3–0.6
          Low: <0.3
c See Teratogenicity section for discussion of EFV and risks in pregnancy.
d Only indicated for use in chronic hepatitis B virus infection in adults
e Generic formulation available

Key to Acronyms: AUC = area under the curve; EFV = efavirenz; FTC = emtricitabine; PK = pharmacokinetic; RPV = rilpivirine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

References

  1. Rilpivirine [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202022s008lbledt.pdf. Accessed September 22, 2017.
  2. Tran AH, Best BM, Stek A, et al. Pharmacokinetics of rilpivirine in HIV-infected pregnant women. J Acquir Immune Defic Syndr. 2016. Available at http://www.ncbi.nlm.nih.gov/pubmed/26918544.
  3. Colbers A, Schalkwijk S, Konopnicki D, et al. Substantially lower rilpivirine plasma concentrations during pregnancy. Presented at: Conference on Retroviruses and Opportunistic Infections. 2017. Seattle, WA.
  4. Mirochnick M, Best B, Kashuba A, et al. Rilpivirine female genital tract concentrations in pregnant and postpartum women. Presented at: Conference on Retroviruses and Opportunistic Infections. 2016. Boston, MA.
  5. Mandelbrot L, Duro D, Belissa E, Peytavin G. Erratum for Mandelbrot et al., placental transfer of rilpivirine in an ex vivo human cotyledon perfusion model. Antimicrob Agents Chemother. 2015;59(9):5869. Available at http://www.ncbi.nlm.nih.gov/pubmed/26276897.
  6. Mandelbrot L, Duro D, Belissa E, Peytavin G. Placental transfer of rilpivirine in an ex vivo human cotyledon perfusion model. Antimicrob Agents Chemother. 2015;59(5):2901-2903. Available at http://www.ncbi.nlm.nih.gov/pubmed/25691637.
  7. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989–31 July 2016. 2016. Available at www.APRegistry.com.

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