Dolutegravir pharmacokinetics in pregnancy
Polly Clayden, HIV i-Base
Dolutegravir exposure and trough concentrations in third trimester of pregnancy appear to be similar to postpartum, according to data from the PANNA Network presented at the 18th International Workshop on Clinical Pharmacology of Antiviral Therapy.
PANNA is a European clinical pharmacology network to investigate the pharmacokinetics (PK) of new antiretrovirals in HIV positive pregnant women receiving them as part of routine care.
The study objectives were to describe dolutegravir: PK in the third trimester and postpartum; safety and efficacy for mothers and infants; and placental transfer.
It enrolled nine women receiving dolutegravir 50mg once daily at four European hospitals (June 2015 to June 2017). Of these three women had only third trimester PK results and one woman was excluded from the PK analysis
At delivery women were a median age of 30 years old (range 21-42) and 38 weeks (range 34-40) gestation. Infant birth weight was a median of 3180 grams. Maternal ART regimens were dolutegravir plus: 4 (44%) tenofovir DF/emtricitabine; 4 (44%) abacavir/lamivudine; and 1(12%) darunavir/ritonavir + tenofovir DF.
The investigators performed PK sampling in the third trimester at approximately 33 weeks and postpartum 4-6 weeks after delivery (reference). Blood samples were taken: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. Cord blood was also taken at delivery to determine cord blood/maternal blood (CB/MB) ratio.
The resulting PK parameters for dolutegravir in third trimester and postpartum are described in Table 1.
|Parameter||Third trimester (n=8)||Postpartum (n=5)||GM ratio (90% CI)|
|AUC 0-24h (h*mg/L)||42.9 (39)||44.8 (56)||0.95 (0.60 to 1.48)|
|Cmax (mg/L)||3.4 (33)||3.0 (41)||1.07 (0.78 to 1.47)|
|C24h (mg/L)||0.7 (109)||1.1 (71)||0.66 (0.32 to 1.36)|
|Tmax (h)||3.0 (1.0-4.5)||3.8 (0.5-8.0)||–|
|CL/F (L/h)||1.2 (39)||1.1 (56)||1.06 (0.67 to 1.66)|
|T1/2 (h)||9.9 (50)||14.9 (27)||0.75 (0.58 to 0.98)|
Values are geometric mean (CV%); except for Tmax, median (range).
When the investigators looked at individual exposure and Ctrough in some women they observed a decresase in pregnancy but in others exposures were higher.
They also noted that levels at the end of the dosing interval remained above the IC90 for dolutegravir.
CB/MB ratio (n=5) was 1.4 (0.35-1.6) suggesting efficient placental transfer but limited by the small number of maternal infant pairs.
All women had a viral load <50 copies/mL approaching delivery. At the time of analysis seven infants were uninfected and one infant’s status was unknown.
There was one intrauterine foetal death at 34 weeks gestation due to cholestasis pregnancy syndrome. No further birth defects were reported.
There were two serious adverse events, not related to study drug that required hospital admissions to rule out pre-eclampsia.
The PK parameters in third trimester are comparable with those from the IMPAACT P1026s reported at CROI last year. But the postpartum exposure is higher in the IMPAACT study. The reason for that difference is not clear.
Further data on dolutegravir in pregnancy will be presented at IAS 2017.
Bollen P et al. A comparison of the pharmacokinetics of dolutegravir in pregnancy and postpartum. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy. 14-16 June 2017, Chicago. Oral abstract 0_7.