Drug–Drug Interactions with Antiretroviral Drugs in Pregnant Women Living with HIV: Are They Different from Non-Pregnant Individuals?

Bukkems, Vera E.; Marzolini, Catia; Moltó, José; Burger, David M.

doi:10.1007/s40262-020-00914-x

Cited by 10 publications

(11 citation statements)

References 106 publications

(164 reference statements)

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“…Various studies using probes suggested that CYP3A enzymes activity is increased during pregnancy [ 11 , 20 ]. However, drug markers for measuring CYP3A enzymes activity have some limitations in pregnant women [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…A modeling study indicates that CYP3A enzymes activity increases from the first to the third trimester [ 10 ]. The impact of pregnancy on the activity of the CYP3A enzymes may result in altered clinical outcomes [ 11 ], indicating the need for a continuous monitoring of drug–drug interaction and of the clinical efficacy of drugs during pregnancy. Given the advantages over midazolam, the 4β-OHC/Chol ratio can be used in clinical studies involving pregnant women.…”

Section: Introductionmentioning

confidence: 99%

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Pregnancy Increases CYP3A Enzymes Activity as Measured by the 4β-Hydroxycholesterol/Cholesterol Ratio

Mlugu

Minzi

Kamuhabwa

et al. 2022

IJMS

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Changes in cortisol and other hormones during pregnancy may alter CYP3A enzymes activity, but data from sub-Saharan Africa are sparse. We investigated the effect of pregnancy and CYP3A5 genotypes on CYP3A enzymes activity using the plasma 4β-hydroxycholesterol (4β-OHC)/cholesterol (Chol) ratio, a known endogenous biomarker. Tanzanian pregnant women (n = 110) and non-pregnant women (n = 59) controls were enrolled. Plasma 4β-OHC and Chol were determined in the second and third trimesters for pregnant women and once for non-pregnant women using gas chromatography–mass spectrometry. Genotyping for CYP3A5 (*3, *6, *7) was performed. Wilcoxon Signed-Rank Test and Mann–Whitney U test were used to compare the median 4β-OHC/Chol ratio between trimesters in pregnant women and between pregnant and non-pregnant women. Repeated-measure ANOVA was used to evaluate the effect of the CYP3A5 genotypes on the 4β-OHC/Chol ratio in pregnant women. No significant effect of the pregnancy status or the CYP3A5 genotype on the cholesterol level was observed. The plasma 4β-OHC/Chol ratio significantly increased by 7.3% from the second trimester to the third trimester (p = 0.02). Pregnant women had a significantly higher mean 4β-OHC/Chol ratio than non-pregnant women, (p < 0.001). In non-pregnant women, the mean 4β-OHC/Chol ratio was significantly lower in carriers of defective CYP3A5 alleles (*3, *6 or *7) as compared to women with the CYP3A5*1/*1 genotypes (p = 0.002). Pregnancy increases CYP3A enzymes activity in a gestational-stage manner. The CYP3A5 genotype predicts CYP3A enzymes activity in the black Tanzanian population, but not during pregnancy-mediated CYP3A enzyme induction.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pregnancy Increases CYP3A Enzymes Activity as Measured by the 4β-Hydroxycholesterol/Cholesterol Ratio

Mlugu

Minzi

Kamuhabwa

et al. 2022

IJMS

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“…Although a low number of women were included in the cobicistat co-administration subgroup and high variability was observed, no difference in TAF exposure could be observed between the subgroups with and without cobicistat co-administration. Cobicistat levels are known to substantially decreased during pregnancy, but this lack of difference suggests cobicistat still inhibits P-gp transport during pregnancy [ 18 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Tenofovir Alafenamide Plasma Concentrations Are Reduced in Pregnant Women Living With Human Immunodeficiency Virus (HIV): Data From the PANNA Network

Bukkems¹,

Necsoi

Tenorio

et al. 2021

Clinical Infectious Diseases

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Background Tenofovir alafenamide (TAF), a prodrug of tenofovir (TFV), is included in the majority of the recommended first-line antiretroviral regimens for patients living with HIV, but there are limited data on TAF use in pregnant women. We aimed to examine the plasma pharmacokinetics of TAF and TFV in pregnant women from Europe. Methods Pregnant women living with HIV were included from treatment centers across Europe, and intensive pharmacokinetic sampling in the third trimester and postpartum was performed. Pharmacokinetic parameters of TAF and TFV were determined with noncompartmental analysis. The proportion of women with a TAF AUCtau below the target of 53.1 ng*h/mL was determined. Clinical efficacy and safety outcome parameters were reported. Results In total, 20 pregnant women living with HIV were included. At the third trimester, geometric mean TAF AUClast and Cmax were decreased by 46% and 52%, respectively, compared with postpartum. TFV AUC0-24h, Cmax, and Ctrough decreased by 33%, 30% and 34%, respectively. The proportion of women with a TAF AUClast <53.1 ng*h/mL was 6% at third trimester and 0% postpartum. One out of 20 women had a viral load >50 copies/mL at third trimester and no mother-to-child transmission occurred. Conclusions TAF plasma concentrations were reduced by about half in women living with HIV during third trimester of pregnancy, but remained above the predefined efficacy target in the majority of the pregnant women. TFV concentrations were reduced by approximately 30% during third trimester. Despite the observed exposure decrease, high virologic efficacy was observed in this study.

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“…10 A previous review examining drug-drug interactions in pregnancy demonstrated that multiple studies show the clinical relevance of a drug-drug interaction can change during pregnancy. 11 The objective of this analysis was to determine the effect of lopinavir/ritonavir on tenofovir exposure in pregnant women.…”

Section: What Is K Nown and Objec Tivementioning

confidence: 99%

“…Subtherapeutic concentrations of tenofovir could increase the risk of viral replication while elevated tenofovir exposure is linked to increased kidney dysfunction in non‐pregnant adults 10 . A previous review examining drug‐drug interactions in pregnancy demonstrated that multiple studies show the clinical relevance of a drug‐drug interaction can change during pregnancy 11 . The objective of this analysis was to determine the effect of lopinavir/ritonavir on tenofovir exposure in pregnant women.…”

Section: What Is Known and Objectivementioning

confidence: 99%

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

et al. 2021

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What is known and objective: Tenofovir 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. Methods: Data 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 discussion: In women not receiving lopinavir/ritonavir (n = 28), tenofovir AUC 0-24 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 AUC 0-24 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 conclusion:Tenofovir 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.

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Drug–Drug Interactions with Antiretroviral Drugs in Pregnant Women Living with HIV: Are They Different from Non-Pregnant Individuals?

Cited by 10 publications

References 106 publications

Pregnancy Increases CYP3A Enzymes Activity as Measured by the 4β-Hydroxycholesterol/Cholesterol Ratio

Pregnancy Increases CYP3A Enzymes Activity as Measured by the 4β-Hydroxycholesterol/Cholesterol Ratio

Tenofovir Alafenamide Plasma Concentrations Are Reduced in Pregnant Women Living With Human Immunodeficiency Virus (HIV): Data From the PANNA Network

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

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