Unbound dolutegravir plasma concentrations unchanged in pregnancy and standard dosing crosses the placenta in placental perfusion model
29 June 2018. Related: Conference reports, Pregnancy, PK and drug interactions, PK Workshop 19th 2018 Baltimore.
Dolutegravir (DTG) plasma Cmin is unchanged in the third trimester compared with postpartum. [1] And modelling suggests that 50 mg DTG once daily might also have potential for foetal pre-exposure prophylaxis. [2]
These findings from the PANNA Network were shown at the 19th International Workshop on Clinical Pharmacology.
Total DTG plasma exposure is 25–51% lower during pregnancy compared with postpartum. DTG is highly bound to human plasma proteins (>99.3% in vitro) and has a low extraction rate. Changes in the free fraction of a drug are not always proportional to that of the total.
Investigators from the PANNA Network – a European clinical network to investigate the pharmacokinetics (PK) of new antiretrovirals in pregnancy – evaluated unbound DTG plasma concentrations in HIV positive pregnant women in the third trimester and postpartum.
Pregnant women receiving DTG 50mg once daily had intensive steady-state 24-hour PK profiling under fed conditions in the third trimester and 3–7 weeks postpartum. Using these PK-curves, the investigators selected Cmin and Cmax samples for further evaluation of total and unbound DTG concentrations.
Nine women with a median age 30 years (range 21–42) were included in the analysis. Participants received DTG with TDF/FTC (n=4) ABC/3TC (n=4) or DRV/r + TDF (n=1). All participants had viral load <50 copies/mL at delivery. Three left the study before the postpartum visit so only six participants provided both third trimester and postpartum data.
In the third trimester, respective geometric mean (variance, CV%) for total plasma and unbound Cmin were: 710 (102) ug/L and 4.0 (80) ug/L and postpartum 1070 (61) ug/L and 4.2 (70) ug/L.
Geometric mean ratio (GMR) for total and unbound DTG Cmin in third trimester vs postpartum were: 0.72 (90% CI 0.40 to 1.29) and 0.98 (90% CI 0.55 to 1.75).
Third trimester median of the free fraction for Cmin was 0.63% (IQR 0.43 to 0.73) vs 0.33% (IQR 0.28 to 0.70) postpartum, p=NS.
Results for total and unbound Cmax plasma concentrations were in line with those for Cmin. The investigators noted this was due to the observed linear plasma protein binding. They concluded that, despite the small sample size, these findings, and the undetectable viral loads at delivery suggest uncompromised efficacy of DTG 50mg once daily in pregnancy.
The PANNA group also evaluated a pregnancy physiologically-based pharmacokinetic (p-PBPK) model which can help to assess maternal and foetal drug exposure.
In order to simulate foetal exposure, using this model, the investigators evaluated placental DTG transfer via ex vivo dual-side placental perfusion experiments. They then integrated the data into the p-PBPK model and simulated maternal and foetal DTG exposure in third trimester of pregnancy.
They established the p-PBPK model using a PBPK model for DTG exposure in healthy volunteers (performance was verified against clinical PK data from several DTG dosing regimens). Then the physiological parameters were modified to take into account maternal physiological changes during pregnancy. Ex vivo dual side placental perfusion experiments were performed using healthy term human placentas.
The model was used to simulate maternal and foetal exposure after maternal dosing and simulations were compared with available third trimester clinical PK data from PANNA and IMPAACT 1026s.
The simulations suggested that 50mg dolutegravir once daily would result in a maternal C24h of 0.98 mg/L, which is in line with the clinical PK data: C24h 0.7mg/L and 0.93mg/L, PANNA and IMPAACT respectively.
The simulations also suggested that 50 mg DTG once daily crosses the placenta in vivo and ex vivo and might have potential for foetal pre-exposure prophylaxis.
comment
These findings add to the data to suggest that, although there is a signal for risk with pre-conception exposure, DTG appears to be a good option for use in later stages of pregnancy.
References
- Bollen P et al. First report of dolutegravir unbound plasma concentrations during pregnancy in HIV-positive women. 19th International Workshop on Clinical Pharmacology, 22–24 May 2018, Baltimore. Oral abstract 8.
http://regist2.virology-education.com/presentations/2018/Antiviralpk/24_bollen.pdf (PDF) - Freriksen J et al. Assessment of maternal and fetal dolutegravir exposure by integrating ex vivo placental perfusion data and physiologically-based pharmacokinetic modeling. 19th International Workshop on Clinical Pharmacology, 22–24 May 2018, Baltimore. Oral abstract 14.
http://regist2.virology-education.com/presentations/2018/Antiviralpk/16_freriksen.pdf (PDF)