Lopinavir and tenofovir interaction observed in non‐pregnant adults altered during pregnancy

What is known and objectiveTenofovir exposure is increased in non-pregnant adults when tenofovir disoproxil fumarate is coadministered with lopinavir/ritonavir. In pregnant women, tenofovir exposure is decreased. Our objective is to describe the effect of lopinavir/ritonavir on tenofovir pharmacokinetics during pregnancy.MethodsData were collected through the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s protocol. This was a nonrandomized, open-label, parallel-group and multicentre phase-IV prospective study in pregnant women with HIV. Intensive steady-state 24-h pharmacokinetic profiles were collected during the third trimester of pregnancy and postpartum. Tenofovir was measured in plasma using validated liquid chromatography-mass spectrometry method (quantification limit: 10 ng/ml). Statistical tests compared paired and between group pharmacokinetic data.Results and discussionIn women not receiving lopinavir/ritonavir (n = 28), tenofovir AUC0-24 was 27% lower (2.2 mcg·h/ml vs 2.8 mcg·h/ml, p = 0.002) and oral clearance was 27% higher (61 L/h vs 48 L/h, p = 0.001) during the third trimester compared to paired postpartum data. In women receiving lopinavir/ritonavir (n = 10), tenofovir AUC0-24 and oral clearance were not different antepartum compared to postpartum. Women with and women without concomitant lopinavir/ritonavir displayed no significant differences in postpartum tenofovir pharmacokinetics.What is new and conclusionTenofovir exposure during the third trimester was reduced compared to postpartum in pregnant women not receiving lopinavir/ritonavir, but not in pregnant women also receiving lopinavir/ritonavir. Our findings suggest that pregnancy confounds the expected decrease in tenofovir exposure with concomitant lopinavir/ritonavir in non-pregnant adults. These findings illustrate the need for drug-drug interaction studies in pregnant women as drug disposition differs significantly in pregnant women compared to non-pregnant adults

Interactions between etonogestrel-releasing contraceptive implant and 3 antiretroviral regimens

ObjectivesLong-acting reversible contraceptives are effective contraceptives for women with HIV, but there are limited data on etonogestrel implant and antiretroviral therapy pharmacokinetic drug-drug interactions. We evaluated etonogestrel/antiretroviral therapy drug-drug interactions, and the effects of etonogestrel on ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, and efavirenz pharmacokinetics.Study designWe enrolled postpartum women using etonogestrel implants and receiving ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, or efavirenz-based regimens between 2012 and 2015. Etonogestrel implants were inserted 2 to 12 weeks postpartum. We performed pharmacokinetic sampling pre-etonogestrel insertion and 6 to 7 weeks postinsertion. We measured antiretroviral concentrations pre and postetonogestrel insertion, and compared etonogestrel concentrations between antiretroviral regimens. We considered a minimum serum etonogestrel concentration of 90 pg/mL adequate for ovulation suppression.ResultsWe collected pharmacokinetic data for 74 postpartum women, 22 on ritonavir-boosted-atazanavir, 26 on ritonavir-boosted-lopinavir, and 26 on efavirenz. The median serum concentrations of etonogestrel when co-administered were highest with etonogestrel/ritonavir-boosted-atazanavir (604 pg/mL) and etonogestrel/ritonavir-boosted-lopinavir (428 pg/mL), and lowest with etonogestrel/efavirenz (125 pg/mL); p < 0.001. Minimum concentration (Cmin) of ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were lower after etonogestrel implant insertion, but overall exposure, predose concentrations, clearance, and half-lives were unchanged. We found no significant change in efavirenz exposure after etonogestrel insertion.ConclusionsUnlike efavirenz, ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were not associated with significant decreases in etonogestrel concentrations. Efavirenz was associated with a significant decrease in etonogestrel concentrations.ImplicationsThe findings demonstrate no interactions between etonogestrel and ritonavir-boosted-lopinavir or ritonavir-boosted-atazanavir, but confirm the decreased efficacy of etonogestrel with efavirenz-based antiretrovirals. This information should be used to counsel women with HIV who desire long-acting reversible contraceptives

Rilpivirine Plasma and Cervicovaginal Concentrations in Women During Pregnancy and Postpartum.

BackgroundConcentrations of antiretrovirals in the genital tract play a key role in preexposure prophylaxis. This study aims to describe rilpivirine (Edurant) concentrations in the genital tract in pregnant and postpartum women.MethodsInternational Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1026s is an ongoing, prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women that include a cohort receiving rilpivirine combination regimen. Intensive pharmacokinetics evaluations were performed at steady state during the second and third trimester, and postpartum. Plasma and directly aspirated cervicovaginal fluid (CVF) samples were collected at 4 time points around an observed dose and measured using high-performance liquid chromatography with ultraviolet detection, [plasma; lower limit of quantification (LLQ) = 10 ng/mL] or liquid chromatography-tandem mass spectrometry (CVF; LLQ = 1 ng/mL).ResultsA total of 24 women were included in the analysis. For all time points combined, median (interquartile range) rilpivirine concentrations were 70 ng/mL (23-121) in CVF and 92 ng/mL (49-147) in plasma. The CVF to plasma AUC(0-4) ratios were significantly higher in the second (0.90, 90% CI: 0.61 to 1.46) and third trimesters of pregnancy compared with postpartum (0.40, 90% CI: 0.19 to 0.87). Three of 189 (1.6%) plasma samples in 2 women were below the LLQ and the corresponding CVF concentrations. Seventeen additional CVF concentrations (10.6%) were below LLQ in 13 participants. No major safety concerns were noted.ConclusionsRilpivirine concentrations were higher in the CVF during pregnancy compared with postpartum. CVF Rilpivirine is likely to achieve inhibitory concentrations effective for preventing peripartum HIV transmission

Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV.

ObjectiveTo evaluate dolutegravir pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery.DesignOngoing, nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and infants.MethodsIntensive steady-state 24 h pharmacokinetic profiles after dolutegravir 50 mg once-daily were performed during the second trimester (2T), third trimester (3T) and postpartum. Maternal delivery and postnatal infant samples were collected after birth. Dolutegravir was measured by validated LC-MS/MS; quantitation limit was 0.005 μg/ml. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-subject comparisons.ResultsTwenty-nine enrolled participants had a median age of 32 years (range 21-42). Pharmacokinetic data were available for 15 (2T), 28 (3T) and 23 (postpartum) women. Median dolutegravir AUC0-24,Cmax and C24 were 25-51% lower in the 2T and 3T compared with postpartum. The median cord blood/maternal plasma concentration ratio was 1.25 (n = 18). In 21 infants, median elimination half-life was 32.8 h after in utero exposure. Viral load at delivery was less than 50 copies/ml for 27/29 women (93%). Twenty-nine infants were HIV-negative. Renal abnormalities noted on ultrasound in two infants were deemed possibly related to dolutegravir.ConclusionDolutegravir exposure is lower in pregnancy compared with postpartum in the same women on once-daily dosing. Median AUC0-24 during pregnancy was similar to, whereas trough concentrations were lower than, those seen in nonpregnant adults. Trough concentrations in pregnancy were well above dolutegravir EC90 (0.064 μg/ml). Dolutegravir readily crosses the placenta. Infant elimination is prolonged, with half-life over twice that of historical adult controls

Pharmacokinetics of Increased Nelfinavir Plasma Concentrations in Women During Pregnancy and Postpartum

This study aims to evaluate the safety, acceptability, and pharmacokinetics (PK) of an increased dose of nelfinavir (NFV) during the third trimester of pregnancy. The study was registered as part of the International Maternal Pediatric Adolescent AIDS Clinical Trials network (IMPAACT-P1026s), an ongoing multicenter prospective cohort study of antiretroviral PK during pregnancy (NCT00042289). NFV intensive PK evaluations were performed at steady state during the third trimester of pregnancy and 2-3 weeks postpartum. Plasma concentrations of NFV and its active metabolite, hydroxyl-tert-butylamide (M8) were measured using high-performance liquid chromatography with ultraviolet detection. A total of 18 women are included in the analysis. NFV area under the concentration-time curve (AUC) with the increased dose during the third trimester was nearly identical to the standard dose postpartum, with a geometric mean ratio for third trimester to postpartum AUC of 0.98 (90%CI 0.71-1.35). Despite the increased dose, M8 AUC was lower during the third trimester compared to postpartum (0.53, IQR [0.38-0.75]), as was the M8/NFV AUC ratio (0.51, IQR [0.42-0.63]). NFV AUC0-12 was above target in 15 of 18 (83%) of participants during the third trimester compared to 14 of 16 (88%) postpartum. No major safety concerns were noted. Increasing the NFV dose to 1875 mg twice daily during the third trimester achieved similar concentrations postpartum compared to standard dosing (1250 mg twice daily). Increased NFV dose regimens may still have some benefit to human immunodeficiency virus (HIV)-positive pregnant women living in countries where novel protease inhibitors are currently unavailable or in individuals who are intolerant to ritonavir-boosted HIV medications

Alteration in cytochrome P450 3A4 activity as measured by a urine cortisol assay in HIV-1-infected pregnant women and relationship to antiretroviral pharmacokinetics.

ObjectivesPregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6-β hydroxycortisol to cortisol (6βHF : F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)-treated HIV-1-infected women and to relate this change to ARV pharmacokinetics.MethodsWomen receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (>30 weeks) and postpartum with determination of 6βHF : F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau.Results6βHF : F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P=0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI), the antepartum vs. postpartum 6βHF : F comparison was marginally significant (P=0.058). When the change in the 6βHF : F ratio was related to the change in the dose-adjusted ARV area under the plasma concentration vs. time curve (AUC) between antepartum and postpartum, the 35 subjects in the lopinavir/ritonavir (LPV/r) arms demonstrated an inverse relationship (P=0.125), albeit this correlation did not reach statistical significance.ConclusionsA 35% increase in the urinary 6βHF : F ratio was measured during late pregnancy compared with postpartum, indicating that CYP3A induction occurs during pregnancy. The trend towards an inverse relationship between the change in the 6βHF : F ratio and the change in the LPV AUC antepartum vs. postpartum suggests that CYP3A induction may be one mechanism behind altered LPV exposure during pregnancy

Rilpivirine Plasma and Cervicovaginal Concentrations in Women During Pregnancy and Postpartum.

BackgroundConcentrations of antiretrovirals in the genital tract play a key role in preexposure prophylaxis. This study aims to describe rilpivirine (Edurant) concentrations in the genital tract in pregnant and postpartum women.MethodsInternational Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1026s is an ongoing, prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women that include a cohort receiving rilpivirine combination regimen. Intensive pharmacokinetics evaluations were performed at steady state during the second and third trimester, and postpartum. Plasma and directly aspirated cervicovaginal fluid (CVF) samples were collected at 4 time points around an observed dose and measured using high-performance liquid chromatography with ultraviolet detection, [plasma; lower limit of quantification (LLQ) = 10 ng/mL] or liquid chromatography-tandem mass spectrometry (CVF; LLQ = 1 ng/mL).ResultsA total of 24 women were included in the analysis. For all time points combined, median (interquartile range) rilpivirine concentrations were 70 ng/mL (23-121) in CVF and 92 ng/mL (49-147) in plasma. The CVF to plasma AUC(0-4) ratios were significantly higher in the second (0.90, 90% CI: 0.61 to 1.46) and third trimesters of pregnancy compared with postpartum (0.40, 90% CI: 0.19 to 0.87). Three of 189 (1.6%) plasma samples in 2 women were below the LLQ and the corresponding CVF concentrations. Seventeen additional CVF concentrations (10.6%) were below LLQ in 13 participants. No major safety concerns were noted.ConclusionsRilpivirine concentrations were higher in the CVF during pregnancy compared with postpartum. CVF Rilpivirine is likely to achieve inhibitory concentrations effective for preventing peripartum HIV transmission

Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV.

OBJECTIVE:To evaluate dolutegravir pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery. DESIGN:Ongoing, nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and infants. METHODS:Intensive steady-state 24 h pharmacokinetic profiles after dolutegravir 50 mg once-daily were performed during the second trimester (2T), third trimester (3T) and postpartum. Maternal delivery and postnatal infant samples were collected after birth. Dolutegravir was measured by validated LC-MS/MS; quantitation limit was 0.005 μg/ml. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-subject comparisons. RESULTS:Twenty-nine enrolled participants had a median age of 32 years (range 21-42). Pharmacokinetic data were available for 15 (2T), 28 (3T) and 23 (postpartum) women. Median dolutegravir AUC0-24,Cmax and C24 were 25-51% lower in the 2T and 3T compared with postpartum. The median cord blood/maternal plasma concentration ratio was 1.25 (n = 18). In 21 infants, median elimination half-life was 32.8 h after in utero exposure. Viral load at delivery was less than 50 copies/ml for 27/29 women (93%). Twenty-nine infants were HIV-negative. Renal abnormalities noted on ultrasound in two infants were deemed possibly related to dolutegravir. CONCLUSION:Dolutegravir exposure is lower in pregnancy compared with postpartum in the same women on once-daily dosing. Median AUC0-24 during pregnancy was similar to, whereas trough concentrations were lower than, those seen in nonpregnant adults. Trough concentrations in pregnancy were well above dolutegravir EC90 (0.064 μg/ml). Dolutegravir readily crosses the placenta. Infant elimination is prolonged, with half-life over twice that of historical adult controls

Pharmacokinetics of tenofovir during pregnancy and postpartum.

ObjectivesTenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum.MethodsInternational Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography-mass spectrometry (LC-MS). The target area under the concentration versus time curve from time 0 to 24 h post dose (AUC) was ≥ 1.99 μg h/mL (nonpregnant historical control 10th percentile).ResultsThe median tenofovir AUC was decreased during the second (1.9 μg h/mL) and third (2.4 μg h/mL; P = 0.005) trimesters versus postpartum (3.0 μg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women [73%; 95% confidence interval (CI) 56%, 86%] in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P > 0.05). Median second/third-trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median third-trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2 kg, respectively; P = 0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected.ConclusionsThis study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90 kg) or inadequate HIV RNA response

Reduced indinavir exposure during pregnancy.

AimTo describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period.MethodsIMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100 mg twice daily during pregnancy through to 6-12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks post-partum. PK targets were the estimated 10(th) percentile IDV AUC (12.9 μg ml(-1)h) in non-pregnant historical Thai adults and a trough concentration of 0.1 μg ml(-1), the suggested minimum target.ResultsTwenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12 h) and Cmax during the second trimester and post-partum (ante : post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12 h) and Cmax ratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml(-1) at delivery. All 26 infants were confirmed HIV negative.ConclusionIndinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and ∼30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100 mg twice daily may be preferable to ensure adequate drug concentrations