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Pharmacokinetics of Antiretrovirals in Pregnancy: Rilpivirine, Etravirine and Raltegravir

June 2015

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Three posters at CROI 2015 described pharmacokinetics (PK) of antiretrovirals in pregnancy: rilpivirine, etravirine and raltegravir.1-3 None of the studies suggested that dose adjustment is required.


Rilpivirine

Data from IMPAACT P1026s showed extensive variability in rilpivirine (RPV) exposure during pregnancy and post partum. But no dose adjustment is needed for pregnant women as AUC and Cmin remained above targets with the standard RPV dose.

IMPAACT Protocol P1026s is an ongoing, multicentre, non-blinded prospective phase 4 study, supported by the US National Institute of Health. The study investigates the PK of antiretrovirals in pregnant HIV positive women receiving ART as part of clinical care and includes a RPV arm.

Thirty-two women receiving ART regimens including 25mg RPV once daily were enrolled at IMPAACT sites in the US. The women underwent intensive steady-state 24 hour PK profiles during the 2nd trimester (20 to 26 weeks gestation), 3rd trimester (30 to 38 weeks) and postpartum (6 to 12 weeks after delivery). Maternal and cord blood samples were taken at delivery.

Plasma RPV concentrations were measured using liquid chromatography-mass spectrometry (lower limit of quantification 0.010 mcg/mL). Target AUC24 was at least 0.88 mcg*hr/mL, which is the 10th percentile AUC for non-pregnant adults. The median AUC in non-pregnant adults is 2.1 mcg*hr/mL.

At the time of analysis results were available for: 19 women in 2nd trimester, 31 in 3rd trimester and 30 women postpartum. All women received concomitant TDF/FTC, five also received AZT and one received darunavir/ritonavir during pregnancy.

The evaluation revealed high variability in RPV PK parameters. C24 and AUC24 were reduced during the 3rd trimester. C24 was reduced during the second trimester. When the investigators compared the 2nd and 3rd trimesters, C0 and Cmin were increased, while Vd/F and T1/2 were reduced during 2nd trimester. All comparisons p<0.05. See Table 1.


Table 1: PK Parameters RPV in Pregnancy and Postpartum
Parameter 2nd trimester 3rd trimester Postpartum
AUC24 (mcg*hr/mL) 1.97 (0.87 to 12.4) 1.70 (0.56 to 4.31) 2.39 (0.19 to 6.74)
C0 (ng/mL) 101 (31 to 550) 61 (<10 to 210) 66 (<10 to 285)
Cmax (ng/mL) 146 (43 to 669) 146 (49 to 267) 134 (48 to 407)
Tmax (hr) 4 (0 to 6) 4 (0 to 6) 4 (0 to 8)
C24 (ng/mL) 65 (37 to 517) 56 (<10 to 181) 81 (<10 to 299)
Cmin (ng/mL) 68 (29 to 416) 52 (<10 to 136) 58 (<10 to 200)
Tmin (hr) 24 (0 to 24) 1 (0 to 24) 5 (0 to 24)
Vd/F (L) 750 (148 to 12035) 1210 (155 to 30626) 695 (74 to 23571)
CL/F (L/hr) 13 (2 to 29) 15 (6 to 45) 10 (4 to 133)
T1/2 (hr) 37 (5 to 552) 63 (7 to 836) 35 (6 to 1375)

Median (range)


The investigators reported that the AUC target was met in 15/16 (94%) 2nd trimester women, 27/29 (93%) of 3rd trimester women and 23/26 (88%) of post partum women with available data.

For 9 women where maternal plasma and umbilical cord samples were available: cord blood RPV was 53.8 ng/mL (range <10.1 to 219.7) and maternal delivery plasma RPV was 103 ng/mL (<10.0 to 273.4), giving a cord blood/maternal plasma ratio of 0.55 (0.38 to 0.83).

Despite the reduced RPV exposure at some time points, AUC and Cmin remain well above targets in pregnant women receiving standard adult doses. The investigators recommended that no dosing adjustment is needed for RPV during pregnancy.


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Etravirine

Data from the etravirine (ETV) arm of P1026s combined with that from the European PANNA study (with a similar design) were presented. This evaluation found that although 2nd trimester and postpartum ETV PK were similar to non-pregnant adult PK, 3rd trimester ETV exposure was significantly higher than postpartum and historical controls. No ETV dose adjustment is needed during pregnancy.

Median ETV trough concentration in non-pregnant adult studies was 275 ng/mL, and median AUC was 4.4 mcg*hr/mL.

Results were available for: 5 women in 2nd trimester, 13 in 3rd trimester and 9 women postpartum. One woman took 400 mg once daily and the remainder took 200 mg twice daily. For the once daily dosed woman only Cl/F, Vd/F, t1/2, and AUC12 were presented.

The results showed higher ETV maximum and 12-hour concentrations and lower clearance in the 3rd trimester of pregnancy compared to postpartum, p<0.05. See table 2. 3rd trimester AUC trended towards a significant increase compared to postpartum. All other parameters were similar at all time points.

Sixty per cent of women in the 2nd trimester, 100% in the 3rd trimester, 89% postpartum had AUCs above the 10th percentile in non-pregnant historical controls.

The investigators noted that there was no difference in exposure between women taking or not taking boosted protease inhibitors.


Table 2: PK Parameters ETV in Pregnancy and Postpartum
Parameter 2nd trimester 3rd trimester Postpartum
AUC24 (mcg*hr/mL) 4.5 (3.4 to 10.7) 8.3 (2.7 to 31.0) 5.7 (2.1 to 16.4)
C0 (ng/mL) 261 (69 to 1053) 635 (<5 to 2640) 430(<5 to 1210)
Cmax (ng/mL) 696 (442 to 1053) 1023 (264 to 3470) 631(301 to 1600)
Tmax (hr) 2 (0 to 8) 4 (2 to 6) 4 (1 to 4)
C12 (ng/mL) 356 (80 to 750) 540 (77 to 1940) 378 (67 to 1140)
Cmin (ng/mL) 253 (69 to 750) 473 (<5 to 1940) 378 (<5 to 1140)
Tmin (hr) 12 (0 to 12) 1.5 (0 to 12) 6 (0 to 12)
Vd/F (L) 44 (19 to 59) 432 (154 to 3563) 657 (225 to 1758)
CL/F (L/hr) 13 (2 to 29) 24 (7 to 75) 35 (12 to 95)
T1/2 (hr) 45 (5 to 45) 10 (6 to 82) 23 (5 to 37)

Median (range)


For 6 women where maternal plasma and umbilical cord samples were available: cord blood ETV was 222 ng/mL (range 68 to 2890) and maternal delivery plasma ETV was 339 ng/mL (188 to 680), giving a cord blood/maternal plasma ratio of 0.76 (0.19 to 4.25).

The investigators explained that the metabolism of ETV is complex: unlike other cytochrome P450 (CYP) 3A4 substrates, ETV exposure trends towards being higher in the 3rd trimester compared to postpartum. But 2nd trimester and postpartum exposure are similar to non-pregnant historical controls.

ETV is metabolised by CYP 3A4, 2C9 and 2C19, which have increased (3A4, 2C9) or decreased (2C19) activities in pregnancy. The investigators suggested that the decreases in CYP2C19 activity or altered absorption might be associated with the increase in 3rd trimester exposure. "More data are needed on etravirine in pregnancy to make dosing recommendations" they wrote.


Raltegravir

Raltegravir (RAL) PK was evaluated in a single centre, observational, descriptive study conducted in Paris. Pregnant women treated with twice-daily RAL 400mg containing ART regimens were included. Maternal plasma concentrations 2nd trimester, 3rd trimester and cord blood concentrations 12 hours post dose were performed.

Of 23 women enrolled in the study, 11 received RAL to intensify their existing regimen. All participants received RAL with a boosted PI and 2 NRTIs except for one woman who received RAL plus 2 NRTIs. Boosted PIs were: darunavir/ritonavir (DRV/r) 600 mg twice daily (n=16), DRV/r 800 mg once daily (n=1), lopininavir/ritonavir 400/100 mg twice daily (n=4), and saquinavir/ritonavir 100/100 mg twice daily (n=1).

Median RAL C12h at 2nd, early and late 3rd trimesters was: 85ng/mL (40 to 228, n=19), 74 ng/mL (22 to 238, n=18) and 63 ng/mL (34 to 207, n=22) respectively, p=0.96.

Cord blood/maternal plasma concentration ratio was: 3.56 (2.27 to 4.69, n=4).

The investigators wrote that RAL plasma concentrations are not modified during pregnancy and are similar to historical data in a non-pregnant adult population receiving a twice-daily 400 mg dose. They also noted good placental transfer (cord blood/maternal plasma concentration ratio >1.0) in the small sample of women with available data.


Comment

Also see report from 5th International HIV & Workshop on HIV and Women which showed similar data for ETV in pregnancy.


References

References are to the programme and abstracts of the Conference on Retroviruses and Opportunistic Infections (CROI) 2015, 23-26 February, Seattle, Washington, unless otherwise stated.

  1. Mirochnick M et al. Pharmacokinetics of rilpivirine in HIV-infected women during pregnancy and postpartum. Poster abstract 894.
  2. Best BM et al. Etravirine pharmacokinetics during pregnancy and postpartum. CROI 2015, Seattle. Poster abstract 892.
  3. Belissa E et al. Raltegravir plasma concentrations on HIV-1 infected pregnant women. CROI 2015, Seattle. Poster abstract 891.
  4. Ramgopal M et al. Pharmacokinetics of etravirine in HIV-1-infected pregnant women. CROI 2015, Seattle. CROI 2015, Seattle. Poster abstract 893.

Links to other websites are current at date of posting but not maintained.




This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
 


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