Standard once-daily dolutegravir dosing achieves target levels during pregnancy

23 February 2018. Related: Pregnancy.

Polly Clayden, HIV i-Base

Dolutegravir exposure is lower in pregnancy compared to postpartum in the same women receiving once-daily dosing. Trough concentrations were lower than those in non-pregnant adults but above dolutegravir EC90.

IMPAACT 1026s is an ongoing non-randomised, open label, parallel-group, multicentre, phase 4 prospective pharmacokinetic (PK) study. It recruits HIV positive women receiving newly approved antiretrovirals in routine clinical care at IMPAACT sites in the US. [1]

Interim data from 15 women pregnant women in the dolutegravir arm of the study were first presented at CROI 2016. [2, 3] The full data set including 29 women receiving dolutegravir in pregnancy was published ahead of print on 23 January in AIDS. [4]

The 29 women had a median age of 32 years (range 21 to 42). Paired post-partum data were available for 12 of 15 women with second trimester visits and 22 with third trimester visits.

Median (IQR) dolutegravir AUC0-24 in the second, third trimester and postpartum were respectively: 47.6 mcg*hr/mL (33.4 to 63.7), 49.2 mcg*hr/mL (36.4 to 62.0) and 65mcg*hr/mL (47.8 to 88.4). Dolutegravir AUC0-24 was 29% lower in the third trimester compared to postpartum p=0.0003; and 37% lower in the second trimester, p=0.002.

Dolutegravir Cmax was 26% lower in the second trimester and 25% lower in the third trimester compared to paired postpartum data, respectively p=0.0098 and p=0.0025. And dolutegravir C24 was 51% lower in the second trimester and 34% lower in the third trimester compared to paired postpartum data, respectively p=0.0039 and p=0.0062.

Two women had pre-dose concentrations below the limit of quantification at the postpartum visit, which the authors suggested might be linked to recent non-adherence.

Median (IQR) concentrations of dolutegravir in cord blood and maternal plasma at delivery were respectively: 1.67 mcg/mL (1.17 to 2.00) and 1.24 mcg/mL (0.57 to 1.68). The ratio of cord blood to maternal plasma was 1.25 (1.07 to 1.40).

Infant median dolutegravir Cmax (washout data) was 1.85 mcg/mL (1.42–2.48) at a median 6.9 hours (3.5 to 9.2) after birth. At the final infant washout PK evaluation (between 5–9 days of life), all samples still had measurable dolutegravir (>0.005 mcg/mL).

One of 16 infants with washout PK data was breast fed but the study did not evaluate dolutegravir concentrations in breast milk. Plasma dolutegravir concentrations in this infant were 4.57 mcg/mL, 1.94 mcg/mL, 1.66 mcg/mL, and 0.44 mcg/mL at 7, 25, 46, and 150 hours after delivery. Excluding this breast fed infant – for whom the authors noted half-life could not be reliably calculated – median (IQR) dolutegravir half-life was 32.8 hours (25.9–35.9).

Grade 3 adverse events were reported in eight women: low haemoglobin (n=3), pre-eclampsia (n=2), and pre-term delivery, nausea/vomiting, cesarean wound infection/fever, blurry vision/headache, low albumin, and proteinuria (each n=1).

In the third trimester, 28/28 (100%) of women had viral load <50 copies/mL; and 27/29 (93%) at delivery (one >400 copies/mL). At postpartum PK visit, 14/19 (74%) women had viral load <50 copies/mL.Infants were born at a median of 38.9 weeks of gestation (range: 34.9–42.3). Four were pre-term, five small for gestational age, and four were low birth weight (one very low birth weight). All infants were HIV negative (based on best available data): 24 confirmed uninfected and five indeterminate (due to incomplete testing).

The authors reported clinical abnormalities at or shortly after birth in seven infants. Three were considered to be normal variants: one each with congenital filum terminale fibrolipoma, two vessel umbilical cord without other abnormalities, and post-axial polydactyly. The authors judged these unrelated to dolutegravir exposure.

Total anomalous pulmonary venous return was diagnosed in one infant – also considered unrelated to dolutegravir. One infant had increased jitteriness and chin tremors that resolved over the first months of life, these were also judged unrelated to dolutegravir exposure.

Two infants with renal abnormalities were deemed possibly related to dolutegravir exposure: one whose mother began dolutegravir treatment during week 12 of gestation, had an isolated renal cyst in the left kidney; the other whose mother began dolutegravir treatment during week 11 of gestation, had a multicystic dysplastic right kidney.

Other adverse events were reported in five infants. Two had transient low blood glucose shortly after birth. The infant with the multicystic dysplastic right kidney was also diagnosed with cystic fibrosis and experienced numerous adverse events over the first months of life. One infant had neonatal abstinence syndrome following maternal opiate use during pregnancy and respiratory failure. The fifth was diagnosed with sickle cell trait.

The authors summarised the PK, “dolutegravir exposure is decreased in pregnancy compared to postpartum, but remains at therapeutic concentrations during pregnancy with standard once daily dosing” and noted that further data are needed to assess infant safety.

References

1. US National Institutes of Health. Pharmacokinetic study of antiretroviral drugs and related drugs during and after pregnancy.
   https://clinicaltrials.gov/ct2/show/NCT00042289
2. Mulligan N et al. Dolutegravir pharmacokinetics in HIV-infected pregnant and postpartum women. Conference on Retroviruses and Opportunistic Infections (CROI) 2016. 22–25 February 2016. Boston, Massachusetts. Poster abstract 438.
   www.croiconference.org/sessions/dolutegravir-pharmacokinetics-hiv-infected-pregnant-and-postpartum-women-0 (Abstract)
   http://www.croiwebcasts.org/console/player/29497 (Webcast)
3. Clayden P. Early data from dolutegravir use during pregnancy. HTB. 22 March 2016.
   https://i-base.info/htb/29856
4. Mulligan N et al. Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV. AIDS. 23 January 2018. Publish ahead of print doi: 10.1097/QAD.0000000000001755.
   https://journals.lww.com/aidsonline/Abstract/publishahead/Dolutegravir_pharmacokinetics_in_pregnant_and.97307.aspx