Antiretroviral pharmacokinetics in pregnancy: update from IMPAACT P1026s
Polly Clayden, HIV i-Base
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1026s looks at antiretrovirals when used alone or with TB medicines.
It is an ongoing, non-randomised opportunistic, phase 4, prospective pharmacokinetic (PK) study of antiretrovirals in HIV positive women during pregnancy and postpartum.
Data from evaluations of tenofovir alafenamide (TAF) 25 mg with PK boosters, cobicistat boosted atazanavir and isoniazid, rifampicin and efavirenz from P1026s were presented at the 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs. There was also a presentation showing a US FDA physiologically-based PK model for rilpivirine that captured changes in exposure in pregnancy.
Plasma exposures to TAF 25 mg with PK boosters did not differ significantly between third trimester and postpartum, although confidence intervals were wide. 
When dosed at 25 mg unboosted, a previous IMPAACT 1026s evaluation found that TAF exposures during pregnancy were within the typical range of those in non-pregnant adults but higher than expected postpartum [2, 3]
Seventeen women receiving TAF 25 mg with ritonavir or cobicistat were eligible for the boosted arm and enrolled in the second or third trimester.
PK data were available from 6, 14, and 8 women during the second trimester, third trimester, and postpartum, respectively.
Cobicistat was the booster used by 83% women during the second trimester, 64% during the third trimester and 50% postpartum. The remaining women received ritonavir. The boosted protease inhibitors were darunavir and atazanavir.
Median AUC during the second trimester, third trimester and postpartum was: 133 ng*h/mL(IQR: 128 to 720), 335 ng*h/mL(IQR: 192 to 549) and 507 ng*h/mL (IQR: 221 to 693).
These exposures were comparable to or higher than historical data in adults receiving TAF 10 mg with cobicistat: mean 206.4 ng*h/mL.
Paired data in both second trimester and postpartum were only available in two women, so the investigators limited GMR comparisons to third trimester vs postpartum for this evaluation and await additional data.
GMR for AUC third trimester vs postpartum was: -6% (90% CI: 62 to 133), p=0.74. There were also no significant differences for other PK parameters evaluated (Cmax, CL/F, V/F and T12). But all confidence intervals were wide.
Median TAF plasma AUC was above the 10th percentile cut-off in 66%, 85.7% and 87.5% of women in the second trimester, third trimester and postpartum, respectively. AUC percentile data were similar to those seen in non-pregnant receiving elvitegravir/cobicistat/emtricitabine/TAF 10 mg (E/C/F/TAF).
All but one woman (94.1%) had viral load <50 copies/mL at delivery. Six infants were HIV negative, 7 indeterminate, 3 pending and 1 unknown.
Three congenital anomalies were not considered related to study drug: sacral dimple, Mongolian spot and microcephalia.
Analyses of maternal delivery, cord blood and infant washout samples in IMPAACT 1026s are underway. Data on long-term safety, efficacy and intracellular PK of TAF during pregnancy continue to be needed.
Pregnant women taking atazanavir in a co-formulation with cobicistat had lower exposure compared to postpartum, and compared to non-pregnant adults. 
The PK of atazanavir when co-administered with ritonavir have been described in pregnancy. But atazanavir boosted with cobicistat has not previously been investigated in pregnant women. This study looked at atazanavir exposure boosted with cobicistat (300/150 mg) during pregnancy and postpartum.
Six women were enrolled in the study. Atazanavir PK data were available for 3 women in second trimester, and 5 women in third trimester and postpartum.
The median 24-hour trough concentration at steady state was: 0.16 μg/mL (IQR: 0.14 to 0.22), 0.12 μg/mL (IQR: 0.09 to 0.19) and 0.45 μg/mL (IQR: 0.42 to 0.61) in second trimester, third trimester and postpartum, respectively. Atazanavir trough concentrations in the respective time periods were 80%, 85%, and 44% lower, than previously reported in non-pregnant adults receiving atazanavir/cobicistat.
One woman had a trough concentration below the lower limit of quantitation of the assay (0.047 μg/mL) which occurred in the third trimester.
All other trough concentrations were above the threshold of the historical population EC90 for atazanavir against wild-type HIV (0.014 μg/mL).
The minimum exposure target for atazanavir was the 10th percentile AUCtau in non-pregnant adults receiving once daily atazanavir/ritonavir (28.4 μg*hr/mL). The frequency of participants meeting the target AUCtau was 0/3 in second trimester, 1/5 in third trimester, and 2/5 postpartum.
Viral load at delivery was <50 copies/mL for all six women. Two of the six infants were HIV negative and four are indeterminate or pending.
The investigators are analysing cobicistat plasma concentrations from this study.
Additional PK, safety and outcome data in a larger cohort are needed before atazanavir/cobicistat can be recommended in pregnant women.
Isoniazid, rifampicin and efavirenz
Low isoniazid concentrations in pregnant and postpartum women treated for TB regardless of efavirenz-based ART co-treatment. 
Women in this study received first-line TB treatment in fixed-dose combination tablets according to WHO guidelines. HIV positive women also received efavirenz-based ART. Data were shown for 25 women: 14 African, 6 Thai and 5 other. Eleven women were HIV positive and receiving efavirenz-based ART.
Isoniazid and rifampicin PK data in second trimester, third trimester and postpartum were available for 7, 10 and 7 women in the ART-group and 5, 11 and 8 women in the non-ART-group.
Isoniazid median AUC0-∞ was 7.9, 8.4 and 8.7 ug·h/mL and 6.2, 10.9 and 14.8 ug·h/mL in the second trimester, third trimester and postpartum groups with and without ART respectively. Isoniazid median Cmax was 2.8, 3.3, and 3.0 ug/ml and 3.0, 3.5 and 3.6 ug/mL respectively.
There was no significant difference between the the second trimester, third trimester and postpartum groups. But, isoniazid exposure was much lower than in historical controls (South African non-pregnant adults) across all groups: AUC0-∞ 32.5 ug·h/ml and Cmax 6.5 ug/mL.
Rifampicin median AUC0-∞ was 36.8, 35.8 and 31.2 ug·h/mL and 30.6, 41.4 and 32.7 ug·h/mL respectively. Rifampicin median Cmax was 8.4, 6.1, and 6.6 ug/mL and 4.5, 6.9 and 7.9 ug/mL respectively.
There was no statistical significant difference between the groups and concentrations were similar to the control group.
The investigators are analysing pregnancy outcomes, TB treatment outcomes and safety outcomes. The clinical implication of low isoniazid exposure in pregnant women with TB needs to be assessed.
US FDA physiologically-based pharmacokinetic modelling
FDA physiologically-based pharmacokinetic (PBPK)model for rilpivirine captured changes in exposure in pregnancy. 
PBPK modelling might be used to assess the effect of pregnancy on drug PK. To evaluate PBPK predictive performance in pregnant women with HIV, the FDA developed a PBPK model using rilpivirine.
A PBPK model for non-pregnant adults predicted rilpivirine PK within a two-fold error range of the mean observed clinical values.
In pregnant women, the predicted values were within ± 50% of the mean in second (n=30) and third (n=57) trimester clinical values for Cmax, Tmax, AUC, and Cmin.
There is a reduction in rilpivirine exposure in the second and third trimester of pregnancy, clinical data shows 30–40% decrease in both AUC and Cmin. The PBPK model captured these changes, with a predicted decrease in exposure of about 30% for both AUC and Cmin compared with postpartum.
The investigators suggested that this PBPK model for rilpivirine could capture the effects of pregnancy on maternal exposure from 20–38 weeks gestation. The model included changes in plasma binding proteins, CYP3A4 enzyme activity, and glomerular filtration rate resulting in differences in volume of distribution, unbound fraction and clearance between the non-pregnant and pregnant populations.
This group will look at the effects of using laboratory values from the P1026s study to modify the HIV negative pregnant population to represent that of women with HIV. They plan modelling with other antiretrovirals to continue this assessment pregnancy PBPK.
Data from P1026s is usually the first publicly presented information on new antiretrovirals in pregnant women.
TAF is not currently recommended during pregnancy due to insufficient data describing its use in this population. This has been a bit of a sticking point for global recommendations. Despite TAF being considered a possible candidate for optimised ART for a while now and until such data are available it will remain stuck.
Both cobicistat-boosted darunavir and elvitegravir are not recommended in pregnancy due to low drug exposure, so these data for atazanavir are unsurprising.
- Brooks K et al. Pharmacokinetics of tenofovir alafenamide 25 mg with PK boosters during pregnancy and postpartum. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs. Noordwijk, the Netherlands. 14–16 May 2019. Oral abstract 12.
- Momper JD et al. Tenofovir alafenamide pharmacokinetics with and without cobicistat in pregnancy. AIDS 2018. Amsterdam. 23–27 July 2018. Oral abstract THAB0302.
- Clayden P. TAF exposures during pregnancy and postpartum appear adequate but more data are needed. HTB. 19 September 2018.
- Momper J et al. Pharmacokinetics of atazanavir boosted with cobicistat during pregnancy and postpartum. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs. Noordwijk, the Netherlands. 14–16 May 2019. Oral abstract 10.
- Van Schalkwyk M et al. Low isoniazid concentrations in pregnant and postpartum women treated for tuberculosis irrespective of efavirenz-based ART co-treatment. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs. Noordwijk, the Netherlands. 14–16 May 2019. Oral abstract 11.
- Gockenbach M et al. Physiologically-based pharmacokinetic modeling of rilpivirine during pregnancy. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs. Noordwijk, the Netherlands. 14–16 May 2019. Oral abstract 16.