Pharmacokinetics of four antiretrovirals in pregnancy: data from the PANNA network

1 October 2015. Related: Conference reports, Pregnancy, PK and drug interactions, PK Workshop 16th 2015.

Polly Clayden, HIV i-Base

The European PANNA network – established to study the pharmacokinetics (PK) of antiretroviral drugs during pregnancy – showed data from women receiving antiretrovirals as part of routine care, at the 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy.

Physiological changes take place in pregnancy, which can influence the PK of antiretrovirals and might lead to decreased drug exposure. Results from four PANNA analyses – of darunavir/ritonavir (DRV/r), ritonavir (RTV), rilpivirine (RPV) and abacavir (ABC) – were presented as posters at the meeting. [1, 2, 3, 4]

Darunavir/ritonavir

Limited PK data from clinical studies to date show that the exposure to DRV/r is reduced during pregnancy: AUC0–tau and Ctrough reductions range from 17% to 31%.

The PANNA investigators used a population PK approach to characterise DRV/r PK with 800/100 mg once daily and 600/100 twice daily dosing during pregnancy.

The study included HIV positive pregnant women receiving DRV/r as part of their antiretroviral therapy (ART).

The investigators obtained a 12 or 24 hour PK curve after two weeks or more DRV treatment during the third trimester (ideally week 33) and at least two weeks post-partum (4–6 weeks post-partum). Blood sampling was pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12 and (if applicable) 24 hours post-dose at both time points.

They performed a population analysis using NONMEN software. The final PK model was used to simulate 1000 DRV concentration-time profiles during the third trimester of pregnancy with DRV/r 800/100 mg once daily or 600/100 mg twice daily dosing. DRV concentrations were compared with the DRV protein binding-adjusted inhibitory concentration (IC) for HIV strains with or without DRV resistance mutations.

A two-compartment model with an absorption lag-time (LAG), inter-individual variability (IIV) terms on clearance (CL/F) and V1/F, and proportional residual error best described DRV PK. The investigators noted that pregnancy influenced LAG as well as CL/F, and IIV in CL/F and in V1/F.

In the final model the population estimates of CL/F were 8.71 L/h for the third trimester and 4.18 L/h for postpartum. All DRV concentrations in the simulation with DRV/r 800/100 mg once-daily dosing during the third trimester of pregnancy were above the protein binding-adjusted IC for wild-type HIV (0.055 mg/L). And just 0.9% of simulated DRV trough concentrations with twice-daily DRV 600/100 mg were below the IC of HIV with DRV resistance mutations (0.55 mg/L).

The investigators concluded that the final population PK model described DRV concentrations with no systematic bias and adequate precision. They recommended that no DRV dose adjustment seems to be necessary in pregnancy for HIV positive women fully susceptible to DRV, despite noting that pregnancy had been identified as a major covariate influencing CL/F, explaining lower DRV concentrations in plasma during third trimester than postpartum.

Ritonavir

For RTV the investigators used data from women treated with boosted saquinavir (SQV), atazanavir (ATV) and DRV during pregnancy with 12- or 24-hour PK profiles in the third trimester and at least 2 weeks postpartum.

Cord blood and matching maternal blood samples were taken at delivery where possible in order to evaluate placental transfer. The investigators used a validated UPLC method and a lower limit of quantification of 0.045 mg/L to measure RTV concentrations.

A total of 49 women were included in the analysis: 5 receiving DRV/r 600/100mg twice daily, 9 DRV/r 800/100mg once daily, 26 ATV/r 300/100mg once daily and 9 SQV/r 1000/100mg twice daily.

Geometric mean ratios of third trimester/post-partum RTV (100 mg booster) AUCtau were: 0.74 (90% CI: 0.65-0.84) for DRV twice daily; 0.59 (90% CI: 0.42-0.83) for DRV once daily; 0.45 (90% CI: 0.37-0.53) for ATV; and 0.57 (90% CI: 0.39- 0.82) for SQV.

The investigators noted an effect of pregnancy on RTV PK parameters, with decreases in exposure of 26 to 55%. They looked at the correlation between the effect of pregnancy on the AUC of the protease inhibitor used and the effect of pregnancy on the AUC of RTV using a Spearman Correlation test. This test revealed a correlation coefficient of 0.590, p<0.01.

RTV concentrations were below the lower limit of quantification in all but one cord blood sample (25/26). The cord blood/maternal ratio was 0.05 (0.05/1.06 mg/L) for this participant. Almost half (12/25) the samples had RTV concentrations below lower limit of quantification with detectable maternal concentrations (range: 0.058-0.416 mg/L) at the same time point. The remaining 13 samples had both cord blood and maternal concentrations below the lower limit of quantification.

In conclusion it appears that pregnancy has a substantial influence on RTV concentrations and this is independent of the protease inhibitor being boosted. Less RTV boosting can contribute to lower protease inhibitor exposure in pregnancy. RTV appears to hardly reach the foetus during pregnancy, the investigators noted.

Rilpivirine

The group presented preliminary data on third trimester exposure to RPV with the same study design.

RPV plasma concentrations were determined with a validated UPLC method with a lower limit of quantification of 0.0063 mg/L. Based on an analysis of ECHO/THRIVE PK data the minimum effective concentration of RPV was defined as 0.040 mg/L.

There were 7 participants included in this interim analysis: 4 black, 1 white, 1 Asian and 1 other. They were a median age of 29 years (range: 19-32). All received RPV with FTC/tenofovir; one participant also received lopinavir/ritonavir.

Evaluable, paired PK curves third trimester/postpartum were available for 6 participants. Median PK values in the third trimester and post partum respectively were: AUC0-24h (mg*h/L) 1.73 (range 1.25-3.66) and 2.82 (range: 1.77-6.32); Cmax (mg/L) 0.13 (range: 0.074-0.20) and 0.16 (range: 0.11-0.32); Tmax (h) 3.0 (range: 0.5-4.2) and 4.00 (range: 0.0- 0.6); and Ctrough (mg/L) 0.056 (range: 0.041-0.14) and 0.11 (range: 0.066-0.25).

Median ratios of PK parameters third trimester/post-partum were: AUC0-24 0.63 (range: 0.29-1.16); Cmax 0.69 (range: 0.37-1.20); and Ctrough 0.54 (range: 0.27-1.07). Three participants had a Ctrough of or below 0.04 mg/L in the third trimester.

In 2 participants with available data, the ratios of cord blood/maternal plasma RPV concentrations were 0.74 and 0.81 respectively.

The investigators wrote that in this small study exposure to rilpivirine was lower during pregnancy (third trimester) than postpartum, and possibly inadequate in 3/7 participants. RPV has good placental transfer and they suggested the drug might have potential for pre-exposure prophylaxis. Data from a larger group are needed.

Abacavir

The final poster showed an analysis using the same study design of 9 participants receiving ABC 600 mg once daily in their ART regimen. They were a median age of 34 years (range: 25-39); 4 black and 5 white. All participants also received 3TC; 7 a protease inhibitor, 1 an NNRTI and 1 received 3 NRTIs.

Geometric mean for AUC0-24h, Cmax and T1/2 in the third trimester were: 13.7 mg*h/L (95% CI: 10.1-18.6), 3.83 mg/L (95% CI: 3.17-4.64) and 3.8 h (95% CI: 2.4-6.0), respectively. Geometric mean for AUC0-24h, Cmax and T1/2 postpartum were: 12.6 mg*h/L (95% CI: 10.5-15.1), 4.11 mg/L (95% CI: 3.44-4.92) and 3.2 h (95% CI: 2.1-4.9), respectively. Third trimester/postpartum ratios AUC0-24h, Cmax and T1/2: 1.08 (90% CI: 0.92-1.28); 0.93 (90% CI: 0.75-1.17); and 1.19 (90% CI: 1.03-1.37), respectively.

Ratio of cord blood /maternal ABC concentration ratios in 2 participants were 0.73 and 1.01 respectively.

The investigators concluded that ABC PK parameters are not influenced by pregnancy so 600 mg once daily is an appropriate dose in pregnancy. Placental transfer of ABC is substantial.

Comment

Like IMPAACT 1026s, PANNA enrols pregnant women receiving new antiretrovirals. Pregnancy can effect drug disposition significantly and originator companies do not always investigate new drugs in pregnant women.

Placental drug transport is another important aspect of PK for which few data exist for many antiretrovirals. Transport of antiretrovirals from mother to foetus might provide protection from vertical transmission of HIV across the placenta and at the time of birth.

References:

Unless stated otherwise, references are to the programme and abstracts 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, 26-28 May 2015, Washington DC.

1. Moltó J et al. Population pharmacokinetic analysis of darunavir/ritonavir in HIV-infected pregnant women. Poster abstract 26.
2. Colbers A et al. Ritonavir pharmacokinetics during pregnancy and postpartum. Poster abstract 27.
3. Colbers A et al. A Comparison of the pharmacokinetics of rilpivirine during pregnancy and postpartum. Poster abstract 28. 4. Schalkwijk S et al. A comparison of the pharmacokinetics of abacavir during pregnancy and postpartum. Poster abstract 32.