Pharmacokinetics of antiretrovirals in pregnancy: tenofovir, nelfinavir, lopinavir/r
Polly Clayden, HIV i-Base
Physiological changes that occur during pregnancy may alter drug handling and in turn predispose women to virological failure if drug exposure is too low. Four posters reported findings from studies evaluating PK parameters of two commonly used protease inhibitors and the nucleotide analogue tenofovir in pregnancy. The posters were also presented as a poster discussion session.
John Rodam and co-workers reported findings from the PACTG 394 study, which looked at pharmacokinetics, safety and tolerance of tenofovir in pregnant women and their infants .
Besides potential benefit to maternal health, tenofovir could offer advantage over current mother to child transmission (MTCT) reduction strategies, most particularly in relation to development of NNRTI resistance conferred by single dose nevirapine.
In this study oral tenofovir was administered at the onset of labour and was evaluated in a dose escalation trial to provide a regimen for future phase 3 trials for reduction of MTCT.
Women received 600 mg either at the onset of labour with a vaginal delivery or four hours prior to scheduled caesarian section with standard AZT prophylaxis.
Seven maternal blood samples over 24 hours, a cord blood sample, and three infant samples over 36 hours post-delivery, were obtained and measured for tenofovir by LC/MS-MS.
Tenofovir was safe and well tolerated in 15 mother/infant pairs. Complete evaluable PK data were available from 10 mothers. All samples obtained from the infants had tenofovir concentrations less than the level of quantification by the assay (<25ng/mL). No infants were HIV positive.
The median age of the mothers was 23.5 years (range 20-44 years); the median viral load was 1.85 log10 copies/mL (range1.08-2.64 log10 copies/mL). Background maternal ART was: 4 women received 2 NRTIs and a PI, 2 women 2 NRTIs and nevirapine and 4 women received 3 NRTIs. 5/10 women had caesarean sections. The median time from tenofovir dose to delivery was 5.6 hours (range 2-19.5 hours).
The authors reported maternal tenofovir concentration medians of: AUC 2492 ng/mL (range 1344-4480 ng/mL); Cmax 249 ng/mL (range 83-595 ng/mL); Tmax 1 hour (range 1-12 hours); C24h 49.0 ng/mL (range 34.2-93.7ng/mL) and T1/2 9.3 (range 5.00-23.00).
Median cord blood tenofovir was 76 ng/mL (0 to 309 ng/mL) with cord blood/maternal ratio of 0.65 (0.35 to 1.1) for 8 of 10 mother/infant pairs.
The authors reported no significant maternal or infant adverse events.
They concluded: Maternal tenofovir concentrations were lower than in adult receiving TDF 600mg single dose and similar to HIV-infected subjects receiving chronic therapy with TDF 300mg daily. Additionally, they found that although tenofovir placental transfer is sufficient to achieve cord blood concentrations with antiretroviral activity, maternal inter-subject pharmacokinetics and cord blood tenofovir variability is substantial.
They wrote: Low tenofovir infant post-delivery concentrations allows immediate postpartum TDF administration. A higher maternal TDF dose with infant dosing will be evaluated in a second cohort to more consistently achieve tenofovir concentrations likely to be effective in preventing MTCT.
A poster from Marie-Aude Khoung-Josses reported findings from a study measuring nelfinavir exposure in pregnant women, which found low trough levels in the third trimester consistent with previous data .
Plasma trough levels (Cmin) were measured two weeks following initiation of nelfinavir containing therapy, or during the second or third trimester of pregnancy in women who were already receiving treatment. CD4 cell count and viral load were measured prior to starting treatment and at the time of nelfinavir level measurement.
A minimum of one plasma trough concentration was available in 40 women (35 black, 3 white, 2 Asian; median age 30 years; median weight 73 kg).
Nelfinavir was dosed at either 1250 mg twice daily (n = 36) or 750 mg three times daily (n= 4). The authors reported the average nelfinavir Cmin was 1.27±0.86 ug/mL and below the recommended trough level (1 ug/mL) in 18/45 women (45%).
The median viral load decreased from 4.12 log to 2.02 log10, after a median of 15 days from initiation of therapy. The nelfinavir dose was increased in 8/18 women, whose Cmin were <1 ug/mL, to 1500 mg twice daily. Nelfinavir levels remained <1 ug/mL in 2/ 8 women.
Of the 37 women with viral load at the time of delivery, 25 were undetectable (<50 copies/mL), and 5 had viral load >500 copies/mL. None of the infants were HIV positive.
Women with NFV C min<1 ng/mL were compared with those with C min >1 ug/mL. No significant difference was observed between these two groups regarding age, CD4 cell count, HIV viral load, or trimester of pregnancy. A trend toward lower decline in HIV plasma viral load was observed in women with low trough level (1.49 vs. 1.85 log10, p= 0.08).
The authors wrote: The recommended NFV Cmin threshold was not achieved in almost half of our pregnant women treated with this PI, with a trend toward lower decline in viral load in these patients.
The discussion, following this presentation, addressed the clinical implications of these findings. In reply to the question, What action did you take? Dr Khoung-Josses explained that if the virological outcome was good they ignore pharmacology, but if there is a blip in the third trimester after a woman was previously undetectable they would usually dose increase after TDM. Responding to questions about how to dose adjust with the new 625mg formulation and what this group prescribe now she replied boosted PI.
Two posters reported conflicting findings concerning lopinavir concentrations.
Following Alice Steks late breaker at the Bangkok conference – in which she reported findings from a small study suggesting approximately 50% lower lopinavir exposure during the third trimester of pregnancy compared to non-pregnant controls and to post partum exposure  Fiona Lyons and coworkers from St Thomas Hospital in London evaluated lopinavir exposure in their own pregnant cohort . The mothers received standard dose of three capsules (400mg/100mg) twice a day and trough lopinavir levels were taken at steady state in the third trimester.
Resistance testing performed prior to lopinavir/r initiation did not demonstrate any relevant protease inhibitor (PI) or nucleoside reverse transcriptase inhibitor (NRTI) mutations.
Between April 2004 and January 2006, 21 women initiated lopinavir/r as part of HAART in pregnancy.
The median gestation at lopinavir/r initiation was 25 weeks (range 14 to 31 weeks). Median pre-treatment CD4 and HIV viral load 291 cells/mm3 (range 65 to 846 cells/mm3) and 4824 copies/mL (49 to 59,637 copies/mL) respectively. Median time from lopinavir initiation to trough sampling was 70 days (16 to 147 days). Median time from last dose to trough sampling was 13 hours (10 to 15 hours).
The mean lopinavir trough level was 4022 ug/ml. One woman had lopinavir levels below the limit of quantification (250 ug/ml) with an associated viral load of 116 copies/ml and significant adherence problems.
Eighteen (86%) women had undetectable viral loads at the time of trough lopinavir sampling. The three with detectable viral loads had low viral loads (116, 523 and 137 copies/mL). Two had adherence issues identified and one had previously had an undetectable viral load. The third was fourteen days on treatment at the time of lopinavir sampling and subsequently had an undetectable viral load at 38 days of therapy. None of the infants are HIV positive.
The authors wrote: In this cohort the majority achieved virological suppression (86%) at the time of therapeutic drug monitoring with standard lopinavir/r dosing.
For the non-pregnant population decreased antiretroviral drug levels has been associated with incomplete virological suppression and development of antiretroviral resistance. In pregnancy, the physiological alterations in drug disposition mean that the measured plasma levels may not accurately reflect the levels of free active drug. Therefore, plasma drug levels must be interpreted with caution. Nonetheless, the majority had adequate lopinavir trough plasma levels (95%) in the third trimester.
They added: In our practice use of lopinavir/rtv at standard dosing, in the absence of adherence issues, is associated with good virological response and adequate plasma levels.
This group does not generally recommend a dose increase to four capsules twice a day.
Directly following Mark Mirochnick from Alice Steks group presented an analysis to determine lopinavir exposure during the second and third trimesters of pregnancy and two weeks postpartum with the higher lopinavir/r dose .
The PACTG 1026s is an ongoing, prospective, non-blinded study of antiretroviral pharmacokinetics in HIV positive pregnant women that includes a cohort receiving lopinavir/r 400 mg/100 mg twice daily during the second trimester, and 533 mg/133 mg twice daily during the third trimester through to two weeks postpartum.
Intensive, steady state, 12-hour pharmacokinetic profiles were performed during the third trimester and at two weeks postpartum, and were optional during the second trimester. Maternal and cord blood samples were obtained at delivery. Target lopinavir AUC was > estimated 10th percentile lopinavir AUC (>52 mcg*hr/mL) in non-pregnant historical controls taking the standard dose (mean AUC=80 mcg*hr/mL).
Median maternal CD4 at delivery was 317 cells/mm3 (range 190-1339 cells/mm3), 23/24 had viral load <400 copies/mL at delivery.
Data from the second trimester were available for 8 women, from the third trimester for 26 women and at two weeks post partum for 22 women.
The authors reported median AUC concentrations of 57.3 mcg*hr/mL (range 30.2-101.9 mcg*hr/mL); 87.5 mcg*hr/mL (range 32-153.5mcg*hr/mL) and 151.7 mcg*hr/mL (range 49.1-228.4 mcg*hr/mL) in the second and third trimesters and two weeks post partum respectively.
Table 1: lopinavir/r PK parameters
|Median (range)||2nd trimester 400mg/100mg bid n=8||3rd trimester 533mg/133mg bid n=26||Postpartum 533mg/133mg bid n=22|
|AUC (mcg*hr/mL)||57.3 (30.2-101.9)||87.5 (32.0-153.5)||151.7 (49.1-228.4)|
|Cpredose (mcg/mL)||2.8 (1.2-8.2)||6.4 (BDL-13.3)||11.0 (0.05-20.00)|
|Cmax (mcg/mL)||8.0 (3.8-12.9)||9.7 (4.4-15.2)||15.0 (6.0-23.2)|
|C12hour (mcg/mL)||2.5 (1.3-7.6)||4.6 (0.8-9.8)||8.6 (2.4-16.5)|
Additionally, cord blood and maternal samples were obtained from 23 mother-infant pairs at delivery. The authors noted that both cord blood and maternal lopinavir concentrations were below the limit of detection of the assay in 2 mother-infant pairs. Lopinavir was measurable in cord blood and maternal samples from 21 mother-infant pairs.
Table 2: lopinavir/r cord blood measurements
|Cord blood LPV concentration (mcg/mL)||0.9 (0.1-11.2)|
|Maternal LPV concentration at delivery (mcg/mL)||4.9 (0.4-10.1)|
|Cord blood/maternal ratio||0.23 (0.08-1.11)|
The authors concluded that the higher lopinavir/r dose was well tolerated and provided adequate lopinavir exposure during the 3rd trimester, but resulted in excessive AUC at 2 weeks post partum. They found lopinavir AUC was low with standard dosing during the 2nd trimester. Additionally, they reported poor lopinavir placental transport, with a median cord blood to maternal ratio of 23%.
They recommended: The higher LPV/r dose should be used in 3rd trimester pregnant women and that it should be considered in 2nd trimester pregnant women, especially those who are protease inhibitor experienced. Postpartum lopinavir/r dosing can be reduced to standard dosing by 2 weeks after delivery.
They also explained that since this study was performed using the recently phased out soft gel formulation (133mg/33mg per capsule), a follow up study of the new 200mg/50mg film coated tablet formulation during pregnancy is under development.
Discussion, following the presentation, included the observation that the women in this North American pregnant cohort had a higher median weight at delivery than would be expected in a Western European equivalent (80.6 kg [range 60.4 121.8kg]).
Antiretroviral therapy is widely used in pregnancy. However, as these studies demonstrate, there are considerable gaps in our knowledge of how best to use these agents. The correct use of protease inhibitors in pregnancy has been debated for some time, and although these studies on nelfinavir and lopinavir/ritonavir further our knowledge, the fundamental question of the correct dose remains. Many prescribers have, like Dr Khuong-Josses, already switched from nelfinavir to a boosted PI, but even then there is uncertainty.
Can the virological success of therapy be used as a surrogate measure of pharmacological activity? Or will lower total drug concentrations of PIs in pregnancy increase the risk of later treatment failure due to resistance? To date, all pharmocokinetic studies of PIs in pregnancy have measured total drug concentration. However, PIs are highly protein-bound, and only the protein-free fraction is available for intracellular activity. Small changes in protein-binding could therefore have a large effect on the concentration of the active drug. Should we aim for total PI concentrations to be the same in pregnancy as in non-pregnancy women? Or is this both unnecessary and potentially more toxic?
Given the high inter-patient variability of lopinavir plasma concentrations, should a higher dose of Kaletra be prescribed routinely in the 3rd trimester of pregnancy, or only if subtherapeutic levels are observed? Hopefully, current studies of lopinavir/ritonavir that include assessment of the effect of protein-binding will help unravel this problem. Meanwhile, the recommendation of the BHIVA is to consider measuring PI plasma concentrations during pregnancy.
The study of Rodman et al, whilst limited to the use of tenofovir in labour or prior to pre-labour caesarian section, indicates that plasma concentrations are lower than expected in non-pregnant women, but do not provide any correlation with either intracellular concentration of active compound or anti-viral efficacy. Despite the inherent difficulties in such studies, there is an urgent need to have a better understanding of the pharmacokinetics of tenofovir and other newer antiretroviral therapies. While these drugs ar not licensed for use in pregnancy, they are increasingly relied on as the standard of care for HIV-positive adults. Further studies will help to ensure that pregnant women are not disadvantaged; by increasing access to latest treatments, and because safety concerns with these newer drugs will be better understood.
- Rodman J, Flynn P, Shapiro D et al. Pharmacokinetics and safety of tenofovir disoproxil fumarate in HIV-1-infected pregnant women and their infants. 13th CROI. Abstract 708.
- Khuong-Josses M-A, Boussaïri A et al. Nelfinavir plasma concentrations in 40 pregnant women. 13th CROI. Abstract 707.
- Stek A, Mirochnick M, Capparelli E et al. Reduced lopinavir exposure during pregnancy: preliminary pharmacokinetic results from PACTG 1026. XV Intl AIDS Conference, Bangkok. Abstract LbOrB08.
- Lyons F, Lechelt M, Magaya V et al. Adequate trough lopinavir levels with standard dosing in pregnancy. 13th CROI, Denver. Abstract 709.
- Mirochnick M, Stek A, Capparelli E et al. Adequate lopinavir exposure achieved with a higher dose during the third trimester of pregnancy. 13th CROI, Denver. Abstract 710.