Generally, no information is available about new drugs during pregnancy owing to exclusion from clinical trials during pregnancy. For the new antiretroviral drug rilpivirine, no safety or pharmacokinetic information during pregnancy is available to date . Rilpivirine is a once-daily dosed nonnucleoside reverse transcriptase inhibitor, available as a single 25 mg tablet (Edurant) and also coformulated with tenofovir and emtricitabine (Eviplera) to accomplish a one tablet/day regimen. Rilpivirine is indicated for the treatment of HIV type 1 infection in combination antiretroviral treatment (cART)-naive adult patients with a viral load of 100 000 or less HIV-1 RNA copies/ml .
A European network studies pharmacokinetics and transplacental passage of newly developed antiretrovirals during pregnancy (PANNA; http://www.pannastudy.com/ClinicalTrials.gov NCT00825929). It is a nonrandomized, open-label, multicentre phase IV study, see Colbers et al. for the methods used. Here, we describe two cases of rilpivirine use during pregnancy from the PANNA study.
Case 1 was a 19-year-old black woman, abstinent from nicotine and alcohol use, was diagnosed with HIV in 2011, when she immediately started Eviplera. Conception occurred after approximately 14 weeks of Eviplera use. When pregnancy was established, Eviplera was interrupted (week 5 gestational age). This was restarted in week 25 gestational age (viral load 3543 copies/ml) and continued for the rest of the pregnancy and after delivery.
In week 32 gestational age, a pharmacokinetic curve was recorded (Fig. 1a): AUC0-24 h was 1.25 mg*h/l; Cmax was 0.07 mg/l, C0 h was 0.04 mg/l and thalf was 30 h. Viral load was undetectable (<50 copies/ml). At week 38 gestational age, she was admitted to the hospital because of irregular contractions. This hospital admission was reported as a serious adverse event, judged not to be related to Eviplera use.
Vaginal delivery took place at 39 weeks and 5 days gestational age; viral load was undetectable. A healthy girl (no congenital abnormalities), 3620 g, 53 cm, head circumference 34 cm, APGAR score of 10 after 1, 5, 10 min, was born. An HIV DNA PCR test 2 weeks after delivery was negative.
At delivery, a cord blood (rilpivirine 0.016 mg/l) sample and maternal sample (rilpivirine 0.021 mg/l) were collected 16 h after the last maternal rilpivirine intake. The cord blood/maternal blood ratio was 0.74.
Forty-five days after delivery, a postpartum pharmacokinetic curve was collected, which represents the normal situation. AUC0-24 h was 1.79 mg*h/l; Cmax was 0.11 mg/l, C0 h was 0.07 mg/l and thalf was 43 h.
Case 2 was a 24-year-old white woman, smoking more than 10 cigarettes/day, no alcohol use, was diagnosed with HIV in 2010. In September 2011, she started cART: atazanavir/ritonavir 300/100 mg daily (q.d.) and zidovudine/lamivudine (Combivir); in August 2012, she switched to Eviplera. At conception, she was using Eviplera for 10 weeks.
At week 32 gestational age, a pharmacokinetic curve was taken (Fig. 1b): AUC0-24 h was 1.42 mg*h/l; Cmax was 0.14 mg/l, C0 h was 0.04 mg/l and thalf was 33 h. Viral load was undetectable.
Nonelective Caesarian section (due to nonprogressing dilatation) was performed at 38 weeks and 5 days gestational age. Two weeks before delivery, viral load was 77 copies/ml; 4 weeks after delivery, viral load was undetectable again. A healthy girl, 2945 g, 51.5 cm, head circumference 35.8 cm, APGAR score after 1 and 5 min: 8 and 10, was born. The infant was tested for HIV 1 day and 18 days after birth and the tests were negative (DNA PCR).
Thirty-six days after delivery, a postpartum pharmacokinetic curve was collected: AUC0-24 h was 2.49 mg*h/l; Cmax was 0.15 mg/l, C0 h was 0.09 mg/l and thalf was 48 h.
Exposure (AUC0-24 h) during pregnancy was 30–43% lower during pregnancy (comparable to the decrease seen for protease inhibitors). Postpartum AUC0-24 h of these two cases is in line with the mean steady-state AUC0-24 h in patients (2.397 mg*h/l) . The lower exposure during pregnancy is possibly driven by a shorter rilpivirine half-life; however, accurate determination of the half-life under steady-state conditions is difficult. A suggested rilpivirine target trough concentration is 0.040 mg/l, derived from the exposure–response relationship in phase III studies . For both cases, the Ctrough concentrations in the third trimester and the maternal sample at delivery were 0.040 mg/l or less, indicating subtherapeutic exposure during pregnancy. However, no mother-to-child transmission of HIV was observed, but should be confirmed by at least 4 months of age. A limitation is that no unbound rilpivirine concentrations were determined: lower protein binding during pregnancy might (partly) compensate for lower total concentrations. No major safety issues were reported for these two cases.
In our case, rilpivirine moderately crosses the placenta and exposure during pregnancy is decreased by approximately 30–43%. More data regarding rilpivirine in pregnancy are needed to confirm these first findings, but therapeutic drug monitoring for rilpivirine during pregnancy is strongly recommended.
A.C. and D.B. are the primary authors who conceived and designed the study. A.G., M.E. and B.R. were directly involved in the design and conduct of the PANNA study and included the patients. A.C. was primarily responsible for conducting analyses of the data and the writing of the manuscript. All authors collectively contributed to interpreting the results and the editing of the article.
The PANNA network is financially supported by ‘European AIDS Treatment Network (NEAT)’, European Commission, DG Research, 6th Framework program, contract LSHP-CT-2006-037570, BMS, MSD and Janssen Pharmaceuticals N.V. We thank the patients for participating in this study and the laboratory personnel at the Laboratory of the Department of Pharmacy of the Radboud University Medical Center, Nijmegen, for analysing the samples. We thank the staff from the centres participating in the PANNA network.
Conflicts of interest
The PANNA network is financially supported by the ‘European AIDS Treatment Network (NEAT)’, European Commission, DG Research, 6th Framework program, contract LSHP-CT-2006-037570, BMS, MSD and Janssen Pharmaceuticals N.V.