Early data from dolutegravir use during pregnancy
22 March 2016. Related: Conference reports, Pregnancy, CROI 23 (Retrovirus) 2016.
Polly Clayden, HIV i-Base
Dolutegravir (DTG) exposures in pregnancy are similar to that in non-pregnant adults but lower compared with postpartum. [1] More data are needed before DTG can be widely recommended during pregnancy, according to findings shown at CROI 2016.
IMPAACT P1026s is an ongoing, non-randomised, open-label, parallel-group, multi-centre phase 4 prospective study of antiretroviral pharmacokinetics (PK) and safety in HIV positive pregnant women, which includes an arm for DTG. [2]
In this evaluation the investigators collected samples at 20 to 28, and 30 to 38 weeks gestation, and between 3 to 12 weeks after delivery: pre-dose, and 1, 2, 4, 6, 8, 12 and 24 hours post DTG 50 mg dose. They also collected infant washout samples if the child weighed >1000 grams at birth and had no severe malformations or medical conditions.
DTG was measured using a validated LC-MS/MS with a quantification limit of 0.005 mcg/mL. Two-tailed Wilcoxon signed rank tests compared within-participant PK parameters with a two-sided p-value <0.10.
Data were available for second trimester (n=9), third trimester (n=15) and infant washout (n=10). Women were: black (66%), white (14%), Latina (10%), Asian/Pacific Islander (5%) and Native American/Alaskan (5%). They were a median age of 31.8 years (range 21.6-42.3) at delivery.
The investigators found DTG AUC to be 25-30% lower in the second and third trimester compared with paired postpartum. The differences were not significant (n=4 for second and n=7 for third trimester comparisons with postpartum).
DTG Cmax was significantly lower in the third trimester compared with postpartum. C24 was 41% lower in the second and third trimester but differences were not significant. See Table 1 for maternal DTG PK parameters.
The investigators noted that 6/9 (67%) participants in the second trimester, 12/15 (80%) in the third trimester and 8/9 (89%) postpartum had an AUC above the 10th percentile (37.5 mcg*hr/mL) of non-pregnant adults (historical controls).
All 15 women had viral load <50 copies/mL at delivery.
| Parameter, median (IQR) | 2nd trimester n=9 | 3rd trimester n=15 | Postpartum n=9 | Historical control* Geometric mean (%CV) |
|---|---|---|---|---|
| AUC0-24 (mcg*hr/mL) | 58.4 (47.6-64.5) | 48.7 (40.3-57.6) | 71.1 (58.0-83.1) | 53.6 (27) |
| C0 (mcg/mL) | 0.88 (0.64-1.98) | 1.01 (0.75-1.42) | 1.76 (0.99-2.29) | – |
| Cmax (mcg/mL) | 4.59 (3.89-5.22) | 3.92 (3.36-4.44) | 5.10 (3.75-7.23) | 3.67 (20) |
| Tmax (hr) | 2 (2-4) | 4 (2-4) | 2 (2-4) | 2-3 |
| C24 (mcg/mL) | 0.86 (0.64-1.37) | 0.91 (0.74-1.21) | 1.70 (0.76-2.00) | – |
| Cmin (mcg/mL) | 0.86 (0.69-1.37) | 0.86 (0.55-1.13) | 1.70 (0.70-2.00) | 1.11 (46) |
| CL/F (L/hr) | 0.86 (0.78-1.05) | 1.03 (0.87-1.24) | 0.70 (0.60-0.86) | 1 |
| T1/2 (hr) | 10.5 (8.7-12.6) | 11.2 (10.3-13.00) | 12.3 (10.5-15.6) | 14 |
* From DTG package insert
Washout PK data were available for 10 infants. The elimination half-life was approximately 35 hours. See Table 2.
| Parameter | Median (IQR) |
|---|---|
| Cmax (mcg/mL) | 1.96 (1.42-2.48) |
| Tmax (hr) | 6.9 (3.3-8.6) |
| T1/2 (hr) | 34.5 (28.6-39.9) |
At the time of analysis nine infants were not infected and nine results were pending.
The investigators reported one maternal adverse event that was possibly treatment related: moderately increased ALT. They also observed two SAEs: pre-eclampsia and atypical pre-eclampsia.
They reported four infant congenital anomalies: total anomalous pulmonary venus return; polycystic right kidney and cystic fibrosis; congentital chin tremor; filum terminale and sacral dimple. Four infants had hypoglycaemia.
The investigators noted DTG AUC and trough appear to be lower in pregnancy compared with postpartum but are still similar to those seen in non-pregnant adults.
DTG infant elimination half-life was more than twice that of the mothers in the study and historical non-pregnant adult controls.
Comment
The DTG arm of IMPAACT 1026s now has 30 mother-infant pairs enrolled and is closed to new enrolments. The protocol takes up to eight months to complete for each mother-infant pair and in turn more data from the study to be presented.
The investigators are looking carefully at the four infants with possible congenital anomalies, to assess first trimester exposure to DTG and other drugs. At the time of analysis data were not available showing how long the mothers in the study were on treatment.
The investigators will also look into the family history of the infant with polycystic right kidney and cystic fibrosis. The congenital chin tremor resolved and the study sites did not consider the other anomalies to be related to DTG.
More data about the four infants will be released as more information is provided by the sites.
References:
- 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.
http://www.croiconference.org/sessions/dolutegravir-pharmacokinetics-hiv-infected-pregnant-and-postpartum-women-0 (Abstract)
http://www.croiwebcasts.org/console/player/29497 (Webcast) - US National Institutes of Health. Pharmacokinetic study of antiretroviral drugs and related drugs during and after pregnancy.
https://clinicaltrials.gov/ct2/show/NCT00042289