Clinical Pharmacokinetics (2020) 59:1217–1236 https://doi.org/10.1007/s40262-020-00914-x REVIEW ARTICLE Drug–Drug Interactions with Antiretroviral Drugs in Pregnant Women Living with HIV: Are They Different from Non‑Pregnant Individuals? Vera E. Bukkems1 · Angela Colbers1 · Catia Marzolini2,3 · Jose Molto4,5,6 · David M. Burger1 Published online: 22 July 2020 © The Author(s) 2020 Abstract Background and Objective Although the separate effects of drug–drug interactions and pregnancy on antiretroviral drug pharmacokinetics have been widely studied and described, their combined effect is largely unknown. Physiological changes during pregnancy may change the extent or clinical relevance of a drug–drug interaction in a pregnant woman. This review aims to provide a detailed overview of the mechanisms, magnitude, and clinical significance of antiretroviral drug–drug interactions in pregnant women. Methods We performed a literature search and selected studies that compared the magnitude of drug–drug interactions with antiretroviral drugs in pregnant vs non-pregnant women. Results Forty-eight papers examining drug–drug interactions during pregnancy were selected, of which the majority focused on pharmacokinetic boosting. Other selected studies examined the drug–drug interactions between efavirenz and lumefan- trine, efavirenz and tuberculosis drugs, etravirine and tenofovir disoproxil fumarate, atazanavir and tenofovir disoproxil, and mefloquine and nevirapine in pregnant compared to non-pregnant women. The clinical significance of antiretroviral drug–drug interactions changed during pregnancy from a minimal effect to a contra-indication. In almost all cases, the clinical significance of a drug–drug interaction was more relevant in pregnant women, owing to the combined effects of pregnancy- induced physiological changes and drug–drug interactions leading to a lower absolute drug exposure. Conclusions Multiple studies show that the clinical relevance of a drug–drug interaction can change during pregnancy. Unfortunately, many potential interactions have not been studied in pregnancy, which may place pregnant women living with human immunodeficiency virus and their newborns at risk. Key Points More attention is needed from both researchers and clinicians to demonstrate which drug–drug interactions * Angela Colbers (DDIs) are clinically relevant in special populations. Angela.Colbers@radboudumc.nl The extent of a DDI may differ if the exposure of the 1 Department of Pharmacy, Radboud University Medical perpetrator changes during pregnancy. DDIs at the level Center and Radboud Institute for Health Sciences of intestinal transporters do not seem to be different in (RIHS), Geert Grooteplein Zuid 10, 6525 GA Nijmegen, pregnant women. the Netherlands 2 Division of Infectious Diseases and Hospital Epidemiology, The clinical significance of most DDIs in this review Departments of Medicine and Clinical Research, University changed during pregnancy when looking at the absolute Hospital of Basel and University of Basel, Basel, Switzerland drug exposure in pregnant women. The combined effects 3 Department of Molecular and Clinical Pharmacology, of the DDI and other pregnancy-related physiological University of Liverpool, Liverpool, UK changes may lead to a more pronounced reduction in 4 Fundació Lluita Contra La Sida, Badalona, Spain drug exposure, thereby exposing to the risk of therapeu- 5 Infectious Diseases Department, Hospital Universitari tic failure. Germans Trias I Pujol, Badalona, Spain 6 Universitat Autònoma de Barcelona (UAB), Barcelona, Spain Vol.:(0123456789) 1218 V. E. Bukkems et al. 1 Introduction of a DDI. A non-clinically relevant DDI leading to a margin- ally lower exposure of the ARV in a non-pregnant woman All patients living with human immunodeficiency virus may become relevant when adding the effect of pregnancy (HIV) must be exposed to an adequate concentration of causing a potential risk for virologic failure and mother- antiretroviral drugs (ARVs) to achieve and maintain viro- to-child transmission. As an example, labels were recently logic suppression. In pregnancy, the exposure, and thus the updated to discourage the use of cobicistat-boosted regimens efficacy of ARVs, can be modified by several factors such during pregnancy owing to a reduced exposure of cobicistat as drug–drug interactions (DDIs) and pregnancy-induced leading to insufficient concentrations of the boosted ARV physiological changes. These factors have to be taken into during pregnancy, whereas this effect is not observed in non- consideration when selecting an individual ARV regimen in pregnant women [16]. addition to side effects, resistance testing, previous antiviral Antiretroviral drug exposure is difficult to predict in preg- regimens, and practical aspects [1]. nant women, especially when the women are receiving inter- Several studies have demonstrated the clinically relevant acting co-medications. The ARV exposure is determined by effect of DDIs on the pharmacokinetics of ARVs. Protease the different pharmacokinetic processes in the body. A phar- inhibitors (PIs), non-nucleoside reverse transcriptase inhibi- macokinetic process, for example hepatic metabolism by tors, and the integrase strand inhibitor (INSTI) elvitegravir CYP3A4 enzymes, can be influenced by a DDI and physio- (EVG) are extensively metabolized by the cytochrome P450 logical pregnancy changes concurrently. Pregnancy hormones enzyme (CYP450) system leading to a variety of relevant induce CYP3A4 activity, while an interacting drug can inhibit DDIs [2, 3]. For example, the exposure of multiple ARVs CYP3A4 activity [14]. This is further complicated if the DDI is decreased as a result of CYP induction by rifampicin [4]. degree is concentration dependent because the concentration However, ARVs can also influence other co-medications: of the interacting drug can be impacted by the DDI itself and efavirenz (EFV) induces CYP3A4 activity and can, thereby, by the physiological changes related to pregnancy. These decrease the efficacy of several co-medications [5]. We also interrelated effects make it difficult to predict the magnitude make use of interactive effects, for example CYP3A4 inhibi- of DDIs in pregnant women, and studies examining DDIs in tion by ritonavir or cobicistat to increase the exposure to PIs pregnant women are, therefore, necessary to ensure adequate and EVG (pharmacokinetic boosting) [6]. Drug–drug inter- ARV exposure and efficacy. This article provides an overview actions are not limited to CYP interactions, but extend to of the current knowledge on DDIs with ARVs in pregnant non-CYP metabolism, drug transporters, and the absorption, women living with HIV. The inter-related effects of DDIs and distribution, and elimination of drugs. Inhibition of efflux physiological changes in pregnancy are further elucidated in transporter proteins in the gastrointestinal tract by cobicistat the results section with the examples from the literature. We can increase the absorption of substrates of this transporter discuss the mechanisms leading to altered ARV exposure and [7]. Drug absorption can also be affected by chelation with the effect in terms of clinical relevance. another drug and by pH-influencing drugs [8, 9]. Plasma protein displacement can affect the total plasma concentra- 2 Search Methodology tion and distribution of some highly protein-bound drugs [10]. PubMed and Embase searches were performed to find the It is also clearly demonstrated that physiological changes relevant articles about DDIs in pregnant women living with in pregnancy influence the pharmacokinetics of ARVs HIV. The following terms were used: (Pregnancy OR preg- and co-medications [11]. Drug absorption may be altered nant) AND drug interaction* AND anti human immuno- because of increased gastric pH and slower intestinal motil- deficiency virus agents. As boosting is not always referred ity [12, 13]. Physiological processes affect the ARV distri- to as being an interaction, a second search term was used: bution and changes in plasma protein concentrations can ‘Pharmacokinetic*’ AND ‘HIV’ AND ‘pregnant OR preg- affect the unbound ARV fraction of highly protein-bound nancy’ AND ‘ritonavir OR cobicistat’. In addition, regis- drugs [14]. Finally, changes in hepatic blood flow, metabolic tration information from the European Medicines Agency enzyme activity, glomerular filtration rate, and renal blood and the US Food and Drug Administration was used and flow may alter the metabolism and elimination of ARVs and abstracts of relevant international conferences (Conference co-medication [14, 15]. on Retroviruses and Opportunistic Infections, International In general, dosing recommendations and contra-indica- Workshop on Clinical Pharmacology of Antiviral Therapy, tions of ARVs are based on DDI studies in healthy volun- European AIDS Conference and International AIDS Confer- teers or individuals living with HIV, while pregnant women ence) were screened. are excluded. However, pregnancy-related physiological We selected studies comparing drug exposure in pregnant changes may influence the magnitude or clinical relevance women with exposure in women postpartum or non-preg- nant women. Drug–drug interactions in pregnant women Drug–Drug Interactions in HIV-Infected Pregnant Women 1219 are discussed for enzyme inhibition, enzyme induction, women living with HIV, mimicking the situation in Fig. 1b. transporter inhibition, and for other unknown mechanisms. These studies showed a 62–86% decrease in indinavir AUC​ For every interaction mechanism, three scenarios are dis- 0–8 h during pregnancy compared with postpartum [57–59]. cussed: (1) the effect of DDIs in non-pregnant individuals In one study, the decreased indinavir exposure corresponded (mostly studied in men); (2) the effect of pregnancy on drug to an increase in the urinary metabolic ratio of cortisol, a exposure in the absence of an interacting drug; and (3) the reliable marker for CYP3A4 activity, supporting that combined effect of DDIs and pregnancy on drug exposure in induced CYP3A4 activity contributed to decreased PI/EVG pregnant women. In addition, changes in the DDI magnitude exposure during pregnancy [59]. Another study reported the and the related clinical significance in pregnant women are metabolic ratio of cortisol to be 35% (1–81%) [median (95% discussed. confidence interval [CI])] higher during the third trimester of pregnancy compared to postpartum [60]. 3 Studied Interactions in Pregnant Women As described in Fig. 1c and Table 1, the combined effects Living with HIV (pregnant women taking a boosted PI/EVG regimen) lead to lower PI/EVG exposures than non-pregnant women tak- In total, 48 relevant papers and abstracts were selected. ing a boosted PI/EVG regimen. The median (range) boosted The majority of these studies examined the DDI between a indinavir AUC​0–12 h was 27.1 (18.6–44.7) μg*h/mL during booster and PIs or EVG in pregnant compared to postpartum postpartum compared with 16.1 (7.5–39.9) μg*h/mL in the women. Other selected studies examined the DDI between third trimester, showing a 40% decrease for ritonavir-boosted EFV and lumefantrine (LF) [n = 1], EFV and tuberculosis indinavir during pregnancy (Table 1) [41]. The ritonavir drugs (n = 1), etravirine (ETR) and tenofovir disoproxil AUC​0–12 h was also decreased by 60% during pregnancy, fumarate (TDF) [n = 1], tenofovir alafenamide (TAF) and as a result of both pregnancy-related CYP induction and of cobicistat (n = 2), atazanavir (ATV) and TDF (n = 3), and other physiological changes (i.e., decreased plasma albumin) mefloquine and nevirapine [n = 1] in pregnant compared to [Fig. 1c, Table 1] [41, 46]. The comparison of unboosted and non-pregnant women. boosted indinavir pharmacokinetics shows that pregnancy has a smaller impact on ritonavir-boosted indinavir (~ 40%) 3.1 Enzyme Inhibition than unboosted indinavir (62–86%) and that the absolute indinavir exposure is higher for ritonavir-boosted indinavir 3.1.1 Boosters and Protease Inhibitors/Elvitegravir than for unboosted indinavir in pregnant women [41, 57–59]. This suggests that CYP3A4 inhibition by ritonavir, despite a The DDI between boosters (i.e., cobicistat and ritonavir) reduction in ritonavir exposure during pregnancy, compen- and PIs/EVG has been extensively studied in pregnant sates, to some extent, the CYP3A4 induction in pregnancy women living with HIV. The effect of pregnancy-related (Fig. 1c). physiological changes on the DDI was evaluated by com- Physiological changes in pregnancy seem to have a differ- paring the PI/EVG exposure during pregnancy and post- ent effect on ritonavir- and cobicistat-boosted regimens, as partum in the same women. A decreased PI/EVG exposure shown in Table 1. The darunavir (DRV) trough concentration was repeatedly confirmed in pregnant women during the (Ctrough) seems to be particularly lower during pregnancy first, second, and third trimester compared to postpartum. in cobicistat- compared to ritonavir-boosted DRV 800 mg The average area under the curve (AUC) decrease had once-daily regimens; boosting with cobicistat resulted in a a range of 5–56% for PIs and 7–44% for EVG (Table 1) 71–92% decrease in Ctrough vs 24–64% with ritonavir boost- [17–53]. ing [25, 26, 28–31, 33, 34]. Similarly, the ATV Ctrough is Figure 1 discusses the mechanism of this DDI in pregnant lower in cobicistat- compared to ritonavir-boosted regimens, women considering three scenarios, which all compare to and EVG Ctrough is also excessively decreased during preg- non-pregnant women using PIs or EVG without boosters. nancy on average by 81–89% [17–24, 35–38]. Because of Figure 1a depicts the DDI in the non-pregnant situation the pronounced reduction in Ctrough, which is considered to where the PI/EVG exposure is greatly increased owing to be mostly related to efficacy, cobicistat-boosted regimens are CYP3A4 inhibition by the booster [54–56]. Figure 1b shows no longer recommended during pregnancy [16]. The differ- the probable effect of pregnancy on PI/EVG and booster ence in booster efficacy in pregnant women can be caused exposures in the absence of the DDI. Hormonal changes in by multiple processes. pregnancy induce CYP3A4 activity, which results, likely in First, the decrease in cobicistat AUC and especially the combination with other physiological pregnancy changes, Ctrough seems larger compared to the decrease in ritonavir in decreased PI/EVG and booster exposures [14]. Pharma- AUC and Ctrough (Table 1). Cobicistat concentrations in preg- cokinetic assessments of unboosted indinavir, a PI primarily nant women largely drop below the half maximal inhibitory metabolized by CYP3A4, have been performed in pregnant concentration for CYP3A4 inhibition (i.e., 0.11 mg/L) to 1220 Table 1  Overview of studies that reported antiretroviral drugs (ARVs) and boosters pharmacokinetic parameters in pregnant women compared to non-pregnant women. Postpartum women were assumed to be physiologically similar to non-pregnant women Reference Population Outcome measure Comparison Ratio pregnant/non-pregnant women of ARV pharmacoki- Booster netic parameter AUC​ Ctrough Cmax AUC​ Ctrough Cmax Atazanavir 300 mg QD + ritonavir 100 mg QD [17] n = 103, 88% Self-calculated 1 T vs PP (intra) – 0.65# – – 1.38 – African, sparse ratio 2 T vs PP (intra) – 0.69# – – 0.86 – sampling, fasted/ 3 T vs PP (intra) – 0.72# – – 1 – fed unknown [18] n = 10, 70% white, LSM (90%CI) 3 T vs PP (intra) 0.66 (0.53–0.83) 0.64 (0.47–0.87) 0.65 (0.52–0.82) – – – intensive sam- pling, fed without concomitant TDF, 1 patient with 400/100 mg [19] n = 37, mostly His- Self-calculated 2 T vs PP (intra) 0.63# 0.54# 0.69# 0.34* 0.71 0.38* panic, intensive ratio sampling, fed without concomi- tant TDF [20] n = 20, 85% black, GMR (90% CI) 2 T vs PP (intra) 0.79 (0.61–1.03) 1.00 (0.65–1.54) 0.83 (0.65–1.06) – – – intensive sam- 3 T vs PP (intra) 0.79 (0.63–0.99) 1.01 (0.73–1.39) 0.73 (0.56–0.96) – – – pling, fasted/fed unknown [21] n = 18, 67% black, Self-calculated 3 T vs PP (intra) 0.72* 0.58* 0.88# 0.44* BLOQ 0.44* intensive sam- ratio pling, fed without concomitant TDF [22] n = 25, 52% Cau- Self-calculated 1 T vs PP (intra) – 0.53 – – 0.43 – casian, sparse ratio 2 T vs PP (intra) – 0.85* – – 0.35* – sampling, fasted/ 3 T vs PP (intra) – 0.66* – – 0.25* – fed unknown [23] n = 17, 53% African, GMR (90% CI) 3 T vs PP (intra) 0.94 (0.80–1.11) 0.96 (0.82–1.13) 0.94 (0.74–1.11) – – – intensive sam- pling, fasted/fed unknown Atazanavir 300 mg QD + cobicistat 150 mg QD [24] n = 6, 67% black, Self-calculated 2 T vs PP (intra) 0.77 0.36 – – – – intensive sam- ratio 3 T vs PP (intra) 0.62 0.27 – – – – pling, fasted/fed unknown V. E. Bukkems et al. Table 1  (continued) Reference Population Outcome measure Comparison Ratio pregnant/non-pregnant women of ARV pharmacoki- Booster netic parameter AUC​ Ctrough Cmax AUC​ Ctrough Cmax Darunavir 600 mg BID + ritonavir 100 mg BID [25] n = 6, Europe (66% GMR (90%CI) 3 T vs PP (intra) 0.78 (0.60–1.00) 0.89 (0.58–1.36) 0.76 (0.53–1.11) 0.74 (0.65–0.84) 0.72 (0.56–0.92) 0.63 (0.53–0.76) black), intensive sampling, fed [26] n = 34, USA (41% Self-calculated 2 T vs PP (intra) 0.74* 0.84# 0.72* – – – Caucasian), ratio 3 T vs PP (intra) 0.74* 0.88# 0.71* – – – intensive sam- pling, fasted/fed unknown [27] n = 16, USA and LSM ratio 2 T vs PP (intra) Total: 0.76 Total: 0.71 Total: 0.72 0.72 (0.44–1.17) 0.57 0.66 (0.41–1.08) Puerto Rico (63% (90%CI) or self- (0.63–0.90) Unbound: 0.98 (0.61–0.86) Drug–Drug Interactions in HIV-Infected Pregnant Women black), intensive calculated ratio Unbound: 0.92 Unbound: 0.78 sampling, fasted/ (0.66–1.30) (0.52–1.18) fed unknown 3 T vs PP (intra) Total: 0.83 Total: 0.88 Total: 0.81 0.67 (0.43–1.04) 0.58 0.63 (0.40–0.98) (0.72–0.97) Unbound: 1.18 (0.69–0.96) Unbound: 0.93 Unbound: 0.82 (0.69–1.24) (0.57–1.16) Darunavir 800 mg QD + ritonavir 100 mg QD [28] n = 16, USA and LSM ratio (90% 2 T vs PP (intra) Total: 0.66 Total: 0.70 Total: 0.66 54.71 (46.72– 0.58 54.16 (44.08– Puerto Rico (41% CI) or self-cal- (0.60–0.74) Unbound: 0.91 (0.59–0.75) 62.82) 66.54) white), intensive culated ratio Unbound: 0.76 Unbound: 0.75 sampling, fasted/ (0.67–0.85) (0.65–0.87) fed unknown 3 T vs PP (intra) Total: 0.65 Total: 0.67 Total: 0.69 53.44 (43.47– 0.61 50.85 (41.34– (0.57–0.74) Unbound: 0.88 (0.63–0.77) 65.70) 62.54) Unbound: 0.80 Unbound: 0.84 (0.71–0.89) (0.74–0.96) [25] n = 18, European GMR (90% CI) 3 T vs PP (intra) 0.67 (0.56–0.82) 0.58 (0.44–0.78) 0.78 (0.65–0.95) 0.59 (0.42–0.83) 0.72 (0.47–1.10) 0.59 (0.42–0.82) (50% Caucasian), intensive sam- pling, fed [26] n = 32, USA (53% Self-calculated 2 T vs PP (intra) 0.62* 0.36* 0.83* – – – black), intensive ratio 3 T vs PP (intra) 0.61* 0.42* 0.71* – – – sampling, fasted/ fed unknown [29] n = 20, 60% black Self-calculated 2 T vs PP (intra) – 0.55# – – – – sparse sampling, ratio 3 T vs PP (intra) 0.47* fasted/fed unknown 1221 Table 1  (continued) 1222 Reference Population Outcome measure Comparison Ratio pregnant/non-pregnant women of ARV pharmacoki- Booster netic parameter AUC​ Ctrough Cmax AUC​ Ctrough Cmax [30] n = 5, Spain (50% GMR (90% CI) 3 T vs PP (intra) Total: 0.69 Total: 0.53 Total: 0.73 – – – Caucasian), inten- (0.35–1.35) (0.19–1.52) (0.41–1.32) sive sampling, fed Unbound: 0.76 Unbound: 0.76 Unbound: 0.71 (0.44–1.32) (0.26–2.25) (0.44–1.16) [31] n = 33, 67% black, Self-calculated 1 T vs PP (intra) 1.08 sparse sampling, ratio 2 T vs PP (intra) 0.51* fed 3 T vs PP (intra) 0.46* Darunavir 800 mg BID + ritonavir 100 mg BID [32] n = 24, 50% black, GMR (90% CI) 2 T vs PP (intra) 0.62 (0.44–0.88)# 0.66 (0.39–1.12)# 0.81 (0.64–1.01)# 0.88 (0.61–1.27)# 0.85 (0.67–1.08)# 0.92 (0.68–1.23)# intensive sam- 3 T vs PP (intra) 0.64 (0.55–0.73)* 0.58 (0.49–0.69)* 0.71 (0.62–0.81)* 0.65 (0.52–0.82)* 0.67 (0.41–1.11)# 0.67 (0.54– pling, fasted/fed 0.83)* unknown Darunavir 800 mg QD + cobicistat 150 mg QD [33] n = 7, 71% black, LSM (90% CI) 2 T vs PP (intra) Total: 0.44 Total: 0.08 Total: 0.51 0.37 (0.17–0.79) 0.17 (0.05–0.61) 0.50 (0.28–0.91) intensive sam- (0.24–0.80) (0.01–0.50) (0.30–0.86) pling, fed Unbound: 0.55 Unbound: 0.08 Unbound: 0.59 (0.28–1.06) (0.02–0.42) (0.34–1.02) 3 T vs PP (intra) Total: 0.50 Total: 0.11 Total: 0.63 0.51 (0.33–0.80) 0.17 (0.04–0.74) 0.73 (0.52–1.02) (0.37–0.66) (0.04–0.30) (0.50–0.79) Unbound: 0.60 Unbound: 0.12 Unbound: 0.77 (0.44–0.83) (0.05–0.27) (0.59–1.00) [34] n = 29, USA (62% GMR (90% CI) 2 T vs PP (intra) 0.67 (0.34–1.33) 0.29 (0.10–0.81) 0.74 (0.44–1.26) – – – black), fasted/fed 3 T vs PP (intra) 0.52 (0.37–0.74) 0.25 (0.13–0.49) 0.64 (0.50–0.82) – – – unknown Elvitegravir 150 mg QD + cobicistat 150 mg QD [35] n = 30, USA (67% GMR (90% CI) 2 T vs PP (intra) 0.76 (0.57–1.0) 0.19 (0.10–0.35) 0.92 (0.71–1.2) 0.56 (0.37–0.85) 0.39 (0.21–0.7) 0.72 (0.49–1.1) black), intensive 3 T vs PP (intra) 0.56 (0.42–0.73) 0.11 (0.081–0.15) 0.72 (0.55–0.93) 0.41 (0.30–0.57) 0.33 (0.23–0.47) 0.62 (0.46–0.84) sampling, fed [36] n = 1, intensive Self-calculated 3 T vs PP (intra) Total: 0.93 Total: 0.30 Total: 0.94 0.76 0.67 sampling, fed ratio Unbound: 1.28 Unbound: Unbound: 1.45 BLOQ [37] n = 1, black, Self-calculated 3 T vs PP (intra) 1.07 0.4 1.09 0.57 BLOQ intensive sam- ratio pling, fasted/fed unknown [38] n = 14, European GMR (90% CI) 3 T vs PP (intra) 0.66 (0.53–0.83) 0.23 (0.14–0.39) 0.79 (0.65–0.97) – – (71% black), intensive sam- pling, fed V. E. Bukkems et al. Table 1  (continued) Reference Population Outcome measure Comparison Ratio pregnant/non-pregnant women of ARV pharmacoki- Booster netic parameter AUC​ Ctrough Cmax AUC​ Ctrough Cmax Fosamprenavir 700 mg BID + ritonavir 100 mg BID [39] n = 10, 50% black, GMR (90% CI) 2 T vs PP (intra) 0.65 (0.47–0.89) 0.64 (0.45–0.93) 0.63 (0.47–0.85) 0.38 (0.23–0.64) 0.40 (0.23–0.71) 0.32 (0.17–0.60) 50% Hispanic, 3 T vs PP (intra) 0.75 (0.57–1.00) 0.62 (0.48–0.92) 0.81 (0.62–1.06) 0.91 (0.58–1.71) 0.86 (0.52–1.42) 1.00 (0.58–1.71) intensive sam- pling, fasted/fed unknown [40] n = 29, 52% His- GMR (90% CI) 2 T vs PP (intra) 0.68 (0.44–1.04) 0.48 (0.14–1.65) 0.83 (0.56–1.22) 0.51 (0.28–0.91) 0.71 (0.24–2.14) 0.65 (0.37–1.12) panic, intensive 3 T vs PP (intra) 0.60 (0.49–0.72) 0.56 (0.43–0.72) 0.74 (0.58–0.93) 0.72 (0.55–0.95) 0.70 (0.53–0.91) 0.83 (0.61–1.11) sampling, fasted/ fed unknown Indinavir 400 mg BID + ritonavir 100 mg BID Drug–Drug Interactions in HIV-Infected Pregnant Women [41] n = 26, Thailand, Self-calculated 2 T vs PP (intra) 0.55 0.46 0.72 0.40 0.44 0.37 intensive sam- ratio 3 T vs PP (intra) 0.59 0.46 0.67 0.41 0.50 0.32 pling, fasted and fed Lopinavir 400 mg BID + ritonavir 100 mg BID [42] n = 27, Brazil Self-calculated 2 T vs PP (intra) 0.72 0.74 0.75 0.57 0.47 0.62 tablet, intensive ratio 3 T vs PP (intra) 0.71 0.71 0.76 0.60 0.56 0.59 sampling, fasted/ fed unknown [43] n = 33, 61% Self-calculated 2 T vs PP (intra) 0.54* 0.51* 0.58* 0.61 0.74 0.53 Hispanic, tablet, ratio intensive sam- pling, fed [44] n = 42, 70% black, Self-calculated 1 T vs PP (intra) Total: 0.88 Total: 0.69* – – – – tablet or soft-gel, ratio Unbound: 1.09 Unbound: 0.79# sparse sam- 2 T vs PP (intra) Total: 0.73 Total: 0.68* – – – – pling, fasted/fed Unbound: 0.85# Unbound: 0.79# unknown 3 T vs PP (intra) Total: 0.74 Total: 0.69* – – – – Unbound: 0.74# Unbound: 0.79# [45] n = 41, 83% Cauca- GMR (95% CI) 3 T vs non-preg- - 0.87 (0.62–1.32) – – – – sian, tablet, sparse nant (inter) sampling, fed [46] n = 12, 75% black, Self-calculated 2 T vs PP (intra) Total: 0.63 Total: 0.72 Total: 0.77 0.48 0.43 0.56 tablet, intensive ratio Unbound: 0.62 Unbound: 0.62 Unbound: 0.64 sampling, fed 3 T vs PP (intra) Total: 0.71 Total: 0.68 Total: 0.85 0.46 0.54 0.58 Unbound: 0.69 Unbound: 0.69 Unbound: 0.86 1223 Table 1  (continued) 1224 Reference Population Outcome measure Comparison Ratio pregnant/non-pregnant women of ARV pharmacoki- Booster netic parameter AUC​ Ctrough Cmax AUC​ Ctrough Cmax [47] n = 10, 50% black, GMR (95% CI) 3 T vs PP (intra) 0.60 (0.25–1.43) 0.36 (0.14–0.92) soft-gel, 4 sam- ples, fed [48] n = 17, 41% black, GMR (90% CI) 3 T vs PP (intra) 0.72 (0.54–0.96) 0.44 (0.32–0.60) 0.77 (0.61–0.97) 0.84 (0.65–1.08) 0.82 (0.56–1.18) 0.86 (0.64–1.16) 41% Hispanic, soft-gel, intensive sampling, fed Lopinavir soft-gel 533 mg BID + ritonavir 133 mg BID [49] n = 26, 42% black, Self-calculated 3 T vs PP (intra) 0.58* 0.53* 0.58* intensive sam- ratio pling, fed Lopinavir tablet 600 mg BID + ritonavir 150 mg BID [42] n = 26, Brazil, Self-calculated 2 T vs PP (intra) 0.91 0.87 0.95 0.90 0.85 0.98 tablet, intensive ratio 3 T vs PP (intra) 0.85 0.76 0.93 0.83 0.76 1.01 sampling, fasted/ fed unknown Saquinavir 1000 mg BID + ritonavir 100 mg BID [50] n = 14, 71% white, Self-calculated 2 T vs PP (intra) 0.86 1.08 1.19 0.47 0.34 0.63 intensive sam- ratio 3 T vs PP (intra) 0.44 0.30 0.82 0.36 0.34 0.61 pling, fed [51] n = 28, Germany, GMR (90% CI) 3 T vs non-preg- 0.65 (0.37–1.14) 0.75 (0.68–0.90) 0.65 (0.37–1.16) 0.53 (0.33–0.86) 0.61 (0.39–0.97) 0.50 (0.29–0.89) intensive sam- nant (inter) pling, fed [52] n = 37, 38% black, Self-calculated 2 T vs PP (intra) 0.94 1.05 0.92 0.74 0.90 0.79 intensive sam- ratio 3 T vs PP (intra) 0.95 1.08 0.94 0.64 0.94 0.61 pling, fed Tenofovir alafenamide 10 mg QD + cobicistat 150 mg QD [53] n = 27, USA GMR (90% CI) 2 T vs PP (intra) 0.79 (0.50–1.27) – – – – – (52% Hispanic), 3 T vs PP (intra) 0.86 (0.66–1.12) – – – – – intensive sam- pling, fasted/fed unknown Tenofovir alafenamide 25 mg QD + cobicistat 150 mg QD/ritonavir 100 mg QD [53] n = 17, USA GMR (90% CI) 3 T vs PP (intra) 0.94 (0.38–1.33) – – – – – 1 T first trimester, 2 T second trimester, 3 T third trimester, AUC​area under the curve, BID twice-daily dosing, BLOQ below level of quantification, CI confidence interval, Cmax maximum con- centration, Ctrough trough concentration, GMR geometric mean ratio, inter inter-individual, intra intra-individual, LSM least-squares mean, PP postpartum, QD once-daily dosing, self-calculated ratio ratio of published mean values calculated by the authors *Reported significant difference V. E. Bukkems et al. #Reported non-significant difference Drug–Drug Interactions in HIV-Infected Pregnant Women 1225 A. Only interaction B. Only pregnancy C. Pregnancy + interaction CYP3A4 activity ↑ Exposure to Pregnancy PI/EVG ↓ ** CYP3A4 activity ↓ Other physiological Booster ↓-↓↓ * Exposure to ? Booster CYP3A4 activity ↓↓↓ changes PI/EVG ↑↑↑ ? Exposure to *** PI/EVG ↑ - ↑↑ CYP3A4 activity ↑ Pregnancy Other physiological ? Pregnancy Exposure to changes booster ↓ - ↓↓ Other physiological changes ? Fig. 1  Hypothesis of the drug–drug interaction of protease inhibitors c Co-treatment with a booster in pregnant women increases the PI/ (PIs)/elvitegravir (EVG) and boosters in pregnant women explained EVG exposure, although less than in non-pregnant women because using three situations. The depicted situations are in comparison to of a decreased booster exposure resulting in less cytochrome P450 PI/EVG exposure in non-pregnant women without booster co-treat- (CYP) 3A4 inhibition. indicates a positive effect, \ indicates a nega- ment. a Co-treatment with boosters increases PI/EVG exposure in tive effect, — indicates causes, - -> indicates a decreased positive non-pregnant individuals. b Physiological changes by pregnancy are effect, --\-indicates a decreased negative effect, *, ** and *** show expected to decrease PI/EVG exposure, as well as booster exposure. inter-related effects trough concentrations < 0.05 mg/L during the dosing inter- Although there is a clinically different interaction in val [33, 35, 38, 61]. Cobicistat exposure is significantly pregnant women taking a cobicistat-boosted regimen, decreased in the third trimester compared with non-pregnant some experts also believe that the result of pregnancy- women resulting in a decreased cobicistat-boosting effect related physiological changes are clinically relevant for [36]. Conversely, ritonavir trough concentrations in pregnant some ritonavir-boosted regimens [70, 71]. Alternative women do still exceed the half maximal inhibitory concen- dosing regimens are recommended for ritonavir-boosted tration for CYP3A4 inhibition of 0.08 mg/L after twice-daily ATV, DRV, and lopinavir to ensure an adequate C trough dosing [25, 39, 42, 43, 46, 48, 50, 51, 61, 62], although not during pregnancy [70, 71]. Because of the abundance of after once-daily dosing [17, 19, 21, 22, 25, 28]. alternative regimens, no increased dose of EVG or addi- Second, ritonavir is a more robust booster as CYP3A4 tional cobicistat dosing has been evaluated in pregnant inhibition by ritonavir may last at reduced exposures. A dose women treated with a cobicistat-boosted EVG-based regi- reduction from 100 to 50 mg of ritonavir has been shown men. However, it would be interesting to evaluate whether to cause no change in saquinavir concentrations and did not dosing modification of EVG or cobicistat leads to adequate affect ATV concentrations (median [interquartile range] EVG exposure during pregnancy. ATV Ctrough 0.13 [0.10–0.23] and 0.16 [0.11–0.21] mg/L for 100 mg and 50 mg of ritonavir, respectively) [63, 64]. In con- 3.2 Enzyme Induction trast, a dose reduction from 150 to 100 mg in cobicistat has been shown to substantially influence ATV concentrations 3.2.1 Efavirenz and Lumefantrine (mean [% coefficient of variation] ATV Ctau 0.13 [42.7%] and 0.08 [58.8%] mg/L for 150 mg and 100 mg of cobicistat, Adegbola et al. examined the DDI between the antiretrovi- respectively) [65]. Boosting by ritonavir has also been shown ral EFV and the antimalarial LF in pregnant women com- to be more robust in the presence of inducers like ETR. No pared to women postpartum [72]. Lumefantrine is primarily clinically significant DDI was observed when co-administer- metabolized by CYP3A4 and EFV induces CYP3A4 activ- ing ETR with DRV/ritonavir whereas ETR caused a signifi- ity, resulting in a decreased LF exposure in non-pregnant cant decrease in DRV/cobicistat Ctrough [66–68]. patients as showed in Fig. 2a [72, 73]. Pregnant women Third, both boosters are highly protein bound, and treated with LF have ~ 30% lower LF concentrations at day for ritonavir similar unbound (“active”) concentrations 7, a marker for therapeutic efficacy, compared with non- have been repeatedly reported in pregnancy [22, 36, 46]. pregnant women [74–77]. A higher metabolic or elimination Despite a large decrease in total ritonavir concentrations, rate was observed in some of the pharmacokinetic studies, unbound ritonavir concentrations are similar in pregnancy, indicating induced CYP3A4 activity during pregnancy [14, this indicates that the driver for altered total ritonavir 75–77]. Altered distribution of the lipophilic LF is also concentrations is the altered protein binding in pregnancy hypothesized to decrease LF exposure during pregnancy and [69]. For cobicistat, this is still unclear, but a case report is represented by other physiological changes in Fig. 2b [74]. suggests similar unbound cobicistat concentrations during The study of Adegbola et al. also showed that the EFV mid- pregnancy as well [36]. Altogether, available data suggest dose concentration (C12h) significantly decreased in preg- that ritonavir boosting is more robust during pregnancy nant women treated with EFV compared with non-pregnant compared with cobicistat. women (median 1820 ng/mL vs 2760 ng/mL, respectively). 1226 V. E. Bukkems et al. The largest study of EFV pharmacokinetics during preg- 3.2.2 Efavirenz plus an Anti‑Tuberculosis Drug: Additional nancy showed a more modest effect. The 24-h concentration Influence of Genotype was significantly and marginally lowered during pregnancy (geometric mean ratio [90% CI] 0.92 [0.77–1.09], p = 0.01), The CYP-metabolizing genotype may also influence the while no-effect on the AUC​0–24 h was seen (geometric mean clinical significance of a DDI in pregnant women. This is ratio [90% CI] 1.09 [0.90–1.32]) [78]. This modest reduction illustrated by the example of EFV, isoniazid, and rifampicin. in EFV pharmacokinetics is supported by other intensive Efavirenz is metabolized predominantly by CYP2B6 and to pharmacokinetic studies and occurs possibly because of a lesser extent by CYP2A6 and CYP3A4. Efavirenz plasma decreased plasma proteins or CYP2B6 induction as depicted concentrations are highly variable, and most variability can in Fig. 2b [79, 80]. be explained by the CYP2B6 genotype [83]. A smaller reduction in LF exposure is surprisingly Co-treatment with rifampicin, a CYP inducer, was shown observed in pregnant women compared with postpartum to decrease EFV concentrations modestly and to increase co-treated with EFV in the study of Adegbola et al. This inter-patient variability as shown in Fig. 3a [83, 84]. The suggests that the magnitude of the DDI is mitigated during effect of rifampicin was shown to vary depending on the pregnancy. The authors hypothesized that the reduced EFV CYP2B6 genotype; in patients with an extensive CYP2B6 exposure during pregnancy may lead to less CYP3A4 induc- genotype, rifampicin caused a larger DDI magnitude [85]. tion, as shown in Fig. 2c. This suggests that the decreased Current treatment guidelines suggest that a dose adjustment CYP3A4 induction by EFV is not compensated by the hor- of EFV is not necessary in the general population [83]. In mone-related CYP3A4 induction in pregnancy (Fig. 2c). pregnant women, EFV exposure is modestly decreased likely Although CYP3A4 induction by EFV has been showed as a result of CYP2B6 induction and decreased plasma pro- to be concentration dependent, it is debated if the modest teins and does not warrant a dose adjustment (Fig. 3b) [79, EFV during pregnancy leads to less induction of CYP3A4 80]. However, Dooley et al. demonstrated that pregnant [81]. The lack of an appropriate control group in the study women with an extensive CYP2B6 genotype are at a par- by Adegbola et al. may have led to an inadequate conclu- ticular high risk for low EFV concentrations [83] and, there- sion. Efavirenz is primarily metabolized by CYP2B6 and fore, this special patient population might require an increase the CYP2B6 metabolizer status of the pregnant and non- in EFV dose. The cumulative effects of rifampicin interac- pregnant control group was not determined. Possibly, the tion, physiological pregnancy alterations, and an extensive non-pregnant control group consisted of more CYP2B6 slow CYP2B6 genotype may result in a clinically relevant interac- metabolizers leading to higher EFV concentrations, which is tion (Fig. 3d). It has been reported that 36% of the pregnant correlated with lower LF concentrations [82]. women treated with rifampicin, isoniazid, and EFV had a Importantly, a considerable proportion of pregnant minimum concentration < 1 μg/mL, compared with 23% women were shown to have a LF concentration 7 days post- of the pregnant women not treated with tuberculosis drugs drug intake below the 280-ng/mL cut-off previously consid- [83]. Thus, the modest DDI between EFV and rifampicin ered for LF therapeutic efficacy [82]. Thus, the DDI between may become relevant in pregnant women with an extensive EFV and LF remains clinically relevant in pregnant women. CYP2B6 genotype, justifying an EFV dose increase. Addi- tionally, the magnitude of the EFV and rifampicin DDI may be increased as rifampicin exposure is modestly increased A. Only interaction B. Only pregnancy C. Pregnancy + interaction CYP3A4 ↑ Pregnancy Exposure to LF ↓↓ ? CYP3A4 ↑ ? Other physiological EFV ↓ * changes ? EFV CYP3A4 ↑↑ Exposure to LF ↓↓ *** Exposure to LF ↓ ? CYP3A4 ↑ Pregnancy ? Other physiological Pregnancy Exposure to changes EFV ↓ Other physiological changes Fig. 2  Hypothesis of the drug–drug interaction of efavirenz (EFV) c Co-treatment with EFV in pregnant women decreases the LF expo- and lumefantrine (LF) in pregnant women explained using three situ- sure less than in non-pregnant women because of a decreased EFV ations. The depicted situations are in comparison to EFV exposure in exposure. indicates a positive effect, \ indicates a negative effect, — non-pregnant women without the drug–drug interaction. a Co-treat- indicates causes, - -> indicates a decreased positive effect, *, ** and ment with EFV decreases LF exposure. b Physiological changes by *** show inter-related effects pregnancy decrease LF exposure, as well as EFV exposure slightly. Drug–Drug Interactions in HIV-Infected Pregnant Women 1227 during pregnancy, possibly as a result of decreased clearance co-treated with cobicistat in fixed-dose combinations [89]. due to cholestatic changes [86]. In contrast to this interaction, pregnancy-related physiologi- Isoniazid, a CYP2A6 inhibitor, may further increase EFV cal changes decrease TAF exposure (Fig. 4b); TAF expo- concentrations in pregnant women with a CYP2B6 slow- sure decreased by approximately 35% in the third trimester metabolizer genotype, as in this situation CYP2A6 metab- in women treated with 25 mg of unboosted TAF [53, 90]. olism becomes more relevant [83]. A median minimum This decrease probably does not result from an alteration in concentration of 6.54 μg/mL has indeed been reported in transporter activity as indicated by an animal study showing co-infected pregnant women with a slow-metabolizer geno- similar P-glycoprotein activity in pregnant and non-pregnant type receiving tuberculosis treatment, making EFV-related mice [14]. side effects of concern [83]. In the combined situation of pregnant women co-treated with cobicistat, there is a marginal and insignificant decrease 3.3 Transporter Inhibition in TAF exposure compared with postpartum, see Table 1 and Fig. 4c [53, 90, 91]. This suggests that the DDI compensates 3.3.1 Etravirine and Tenofovir Disoproxil Fumarate: for the reduced exposure as a result of the physiological An Additional Compartment pregnancy changes (Fig. 4b). Theoretically, this is inconse- quent because cobicistat exposure is greatly reduced during Another pitfall is that additional interactions may exist dur- pregnancy, as mentioned earlier. Possibly the magnitude ing pregnancy because an additional compartment is present of the DDI is not influenced by physiological pregnancy in pregnant women: the fetus. Transplacental transport to changes and the decreased cobicistat exposure. The intesti- the fetus is susceptible to DDIs. Research showed for exam- nal transporter inhibition by cobicistat might be caused by ple that ETR inhibits placental ABC transporter BCRP local (intestinal) cobicistat concentrations, and to a lesser (ABCG2) in vitro, and ritonavir inhibits several placental extent by (decreased) systemic cobicistat concentrations ABC transporters at physiological concentrations [87, 88]. [92]. This inconsistency can also be explained by the large Etravirine and ritonavir can, therefore, increase the fetal variability and uncertainty in these data because TAF plasma exposure of co-administered PIs or lamivudine, which are concentrations are difficult to measure and often below the known substrates of the placental ABC transporters [88]. limit of quantification. It is unclear yet whether the intra- cellular concentration of the active tenofovir anabolite is 3.3.2 Cobicistat and Tenofovir Alafenamide sustained during pregnancy. The clinical significance of the interaction between TAF Although cobicistat is contraindicated in pregnancy since and cobicistat is lower in pregnant compared with non-preg- 2018, we discuss this interaction as this provides insight into nant women. The exposure of TAF is similar in pregnant transporter interactions during pregnancy. Interaction data in women co-treated with TAF 25 mg and cobicistat (median pregnancy are available from prior to 2018. When combined AUC​0–24 h 335 ng*h/mL [91]) and non-pregnant patients with cobicistat, TAF exposure is strongly increased by the treated with TAF 25 mg (median AUC​0–24 h 308 ng*h/mL inhibition of efflux transporter proteins in the gastrointes- [93]), which is considered to be a safe and regular treatment tinal tract (i.e., P-glycoprotein and breast cancer resistance option. Based on these limited data, TAF exposure is not protein) as shown in Fig. 4a [7]. Therefore, a dose reduc- clinically significantly altered in pregnant women co-treated tion from 25 to 10 mg of TAF is recommended in patients with cobicistat. A. Only interaction B. Only pregnancy C. Pregnancy + interaction D. Pregnancy + interaction + extensive metabolizer ? CYP2B6 ↑ ? ? Extensive Exposure to Pregnancy genotype EFV ↓ Other physiological Metabolism: Metabolism: ? RIF ↑ changes * CYP2B6 ↑↑? * CYP2B6 ↑↑↑ ? Exposure to RIF ↑ RIF CYP2B6 ↑ ? Exposure to EFV ↓ Exposure to *** EFV ↓↓ ? *** CYP2B6 ↑ Pregnancy ? EFV ↓↓↓ ? Exposure to Other physiological Other physiological Pregnancy RIF ↑ Pregnancy Other physiological changes changes changes Fig. 3  Hypothesis of the drug–drug interaction of efavirenz exposure slightly [86]. c Co-treatment with RIF in pregnant women (EFV) and rifampicin (RIF) in pregnant women with an extensive decreases the EFV exposure more than in non-pregnant women. d cytochrome P450 (CYP) 2B6 genotype explained using four situa- Co-treatment with RIF in pregnant women and an extensive CYP2B6 tions. The depicted situations are in comparison to EFV exposure in genotype decreases the EFV exposure even more, owing to a higher non-pregnant women without the drug–drug interaction. a Co-treat- CYP metabolism activity. indicates a positive effect, \ indicates a ment with RIF decreases EFV exposure. b Physiological changes negative effect, *, ** and *** show inter-related effects by pregnancy decrease EFV exposure slightly, and increase RIF 1228 V. E. Bukkems et al. A. Only interaction B. Only pregnancy C. Pregnancy + interaction Elimination: Efflux transporters Exposure to Pregnancy TAF ↓ Other physiological Elimination: Cobicistat ↓↓ changes *Efflux transporters ↓ Elimination: Exposure to Cobicistat Exposure to Efflux transporters ↓ TAF ↑↑ *** Elimination: TAF ↑ Efflux transporters Exposure to Pregnancy Other physiological Pregnancy cobicistat ↓↓ Other physiological changes changes Fig. 4  Hypothesis of the drug–drug interaction of cobicistat and ten- cistat exposure. c Co-treatment with cobicistat in pregnant women ofovir alafenamide (TAF) in pregnant women explained using three increases the TAF exposure, but this increase is less than in non-preg- situations. The depicted situations are in comparison to TAF expo- nant women with a cobicistat-boosted regimen (situation 4A). indi- sure in non-pregnant women without co-treatment with boosters. a cates a positive effect, \ indicates a negative effect, *, ** and *** Co-treatment with cobicistat increases TAF exposure. b Physiologi- show inter-related effects cal changes by pregnancy decrease TAF exposure, as well as cobi- 3.4 Unknown Mechanism a local interacting effect of TDF on the absorption of ATV. Furthermore, if the DDI is not influenced by physiological 3.4.1 Tenofovir Disoproxil Fumarate and Atazanavir changes in pregnancy, there is probably no competing effect of pregnancy and TFV on ATV absorption (Fig. 5c). Several studies examined the DDI between TDF and ATV in Although the extent of the interaction is similar in non- pregnant women. Most studies observed a ~ 25% decrease in pregnant and pregnant women, the cumulative effect of ATV exposure in non-pregnant patients co-treated with TDF physiological pregnancy changes (Fig. 5c) and the DDI [94–96], but a non-altered ATV exposure was also observed lead to a more clinically significant DDI during pregnancy. in one study [97]. The mechanisms of this DDI is unknown Lower ATV Ctrough is observed in pregnant women with the until today. As tenofovir (TFV) is renally cleared and ATV DDI; a geometric mean (95% CI) of 0.44 (0.31–0.62) mg/ undergoes CYP-mediated metabolism, an interaction at the mL is observed in pregnant women co-treated with ATV and biotransformation level is unlikely. The DDI could possibly TDF vs a geometric mean (95% CI) of 0.89 (0.59–1.32) mg/ occur at the absorption level as a result of induction of intes- mL in non-pregnant women co-treated with ATV and TDF. tinal P-glycoprotein by TFV or owing to a physiochemical Nevertheless, co-treatment with ATV and TDF is not contra- interaction in the gut [94]. indicated during pregnancy because the observed Ctrough is A decrease in ATV exposure has also been confirmed in not lower than the 0.15-mg/L cut-off value considered for pregnant women living with HIV, as shown in Table 2 and therapeutic efficacy [100, 101]. depicted in Fig. 5b [18–21]. The ATV exposure is likely decreased in pregnant women owing to a combination of 3.4.2 Nevirapine and Mefloquine decreased absorption, increased clearance, and reduced booster exposure [19]. Tenofovir exposure is also decreased Haaland et al. examined ARV plasma concentrations in a during pregnancy because of an increased volume of distri- group of pregnant women living with HIV co-treated with bution and increased renal excretion [98, 99]. Three stud- mefloquine, which showed a high rate of mother-to-child ies confirmed that the ATV exposure is lower in pregnant transmission [102]. A significant reduction in median nevi- women treated with a TDF-based regimen compared with rapine concentrations (approximately 25%) was observed in both non-pregnant women co-treated with a TDF-based regi- pregnant women receiving co-treatment with mefloquine, men and pregnant women co-treated with a non TDF-based although the nevirapine concentrations remained above the regimen, see Table 2 and Fig. 5c [18, 19, 21]. previously reported target values to prevent HIV replica- The magnitude of the DDI does not seem to change dur- tion [102]. This reduction was not observed in pregnant ing pregnancy based on our recent data and third-trimester women receiving nevirapine with placebo. The mechanism data from Mirochnick et al. (Table 2) [18, 21]. Interestingly, of this DDI remains unclear, and the DDI may be observed the study of Kreitchmann et al. reports a change in the mag- in pregnant women owing to pregnancy-related physiologi- nitude of DDIs during pregnancy, which seems to relate to cal changes that could amplify the magnitude of the DDI. non-adherence in the non-TDF arm in this study [19]. Thus, This interaction has never been examined in non-pregnant the similar DDI magnitude in pregnant women, despite women, and, therefore, the magnitude of the DDI in the non- the reduced TFV exposure, suggests that this DDI is not pregnant situation is unknown. Despite adequate nevirapine concentration dependent. This supports the hypothesis of trough concentrations, more mother-to-child transmissions Table 2  Overview of reported pharmacokinetic parameters of atazanavir (ATV) in pregnant women compared to non-pregnant women with and without tenofovir disoproxil fumarate (TDF) co- treatment Reference Population Parameter Non-pregnant individuals/postpartum women Pregnant women Without TDF With TDF Self- Without TDF With TDF Self-calcu- calculated lated ratio Drug–Drug Interactions in HIV-Infected Pregnant Women ratio Taburet et al. [94] HIV-infected non-pregnant patients, n = 11, AUC (h*ng/L) 53.8 (35.3) 39.3 (23.0) 0.73 France, intensive sampling after 4 weeks with Cmax (μg/mL) 5.2 (3.0) 3.4 (1.4) 0.66 ATV and 2 weeks co-treatment with TDF, Mean Cmin (μg/mL) 0.86 (0.8) 0.58 (0.4) 0.67 (SD) Colbers et al. [18] HIV-infected pregnant patients, n = 31 (third AUC (h*ng/L) 49.2 (34.7–69.8) 46.1 (36.2–58.6) 0.94 32.08 (21.1–48.7) 28.8 (22.2–37.4) 0.90 trimester), n = 25 (postpartum), 52% black, Cmax (μg/mL) 4.58 (3.31–6.34) 4.17 (3.42–5.08) 0.91 2.93 (1.95–4.40) 2.92 (2.21–3.84) 1.00 intensive sampling, fed, GM (95% CI) Ctrough (μg/mL) 0.90 (0.47–1.71) 0.89 (0.59–1.32) 0.99 0.58 (0.32–1.05) 0.44 (0.31–0.62) 0.76 Kreitchmann et al. [19] HIV-infected pregnant patients, n = 31 (second AUC (h*ng/L) 48.8 (34.9–67.5) 58.7 (41.4–80.5) 1.20 30.6 (19.9–39.0) 26.2 (19.9–38.4) 0.86 trimester), n = 68 (postpartum), 44% Hispanic, Cmax (μg/mL) 4.52 (2.31–5.61) 5.43 (3.81–6.80) 1.20 3.11 (1.95–4.06) 2.73 (1.65–4.02) 0.88 intensive sampling, fed, Median (IQ) Ctrough (μg/mL) 0.90 (0.39–1.33) 1.26 (0.69–1.95) 1.40 0.71 (0.47–1.00) 0.44 (0.28–0.59) 0.62 Mirochnick et al. [21] HIV-infected pregnant patients, n = 38 (third tri- AUC (h*ng/L) 57.9 (47.1–64.8) 39.6 (21–54.9) 0.68 41.9 (27.4–60.8) 28.8 (15.4–34.5) 0.69 mester), n = 32 (postpartum), fed, Median (IQ) Cmax (μg/mL) 4.1 (3–5.8) 4.1 (1.7–4.5) 1.00 3.6 (2.8–5.1) 2.5 (1.6–3) 0.69 Ctrough (μg/mL) 1.2 (1.1–2) 0.8 (0.6–1.2) 0.67 0.7 (0.5–1.1) 0.5 (0.4–0.7) 0.71 AUC​area under the curve, CI confidence interval, Cmax maximum concentration, Cmin minimum concentration, Ctrough trough concentration, GM geometric mean, HIV human immunodeficiency virus, IA interaction, IQ interquartile range, SD standard deviation, self-calculated ratio ratio of published mean values calculated by the authors 1229 1230 V. E. Bukkems et al. A. Only interaction B. Only pregnancy C. Pregnancy + interaction ? Absorption ATV ↓ ? ? Exposure to Pregnancy ATV ↓ Other physiological TDF / ? changes TFV ↓ * *Absorption ATV ↓ ? ? ? Exposure to ? TDF Absorption ATV ↓ ? Exposure to ATV ↓ *** ATV ↓↓ Pregnancy Exposure to Other physiological Pregnancy Physiological changes TFV ↓ changes Fig. 5  Hypothesis of the drug–drug interaction of tenofovir diso- women decreases the ATV exposure even more than in non-pregnant proxil fumarate (TDF) and atazanavir (ATV) in pregnant women women because of the joined effects of the physiological changes in explained using three situations. The depicted situations are in com- pregnancy and the interaction. The degree of interaction does not parison to ATV exposure in non-pregnant women without tenofovir seem to change. indicates a positive effect, \ indicates a negative (TFV) co-administration. a Co-treatment with TDF decreases ATV effect, --- indicates likely negligible effect, *, ** and *** show inter- exposure. b Physiological changes by pregnancy decrease ATV expo- related effects sure, as well as TFV exposure. c Co-treatment with TDF in pregnant were observed, making this DDI likely of clinical relevance pregnancy because gastrointestinal motility is decreased in for HIV and malaria co-infected pregnant women. pregnant women [14]. The limited decrease of raltegravir and dolutegravir (DTG) exposure in pregnant women is not considered to be of clinical significance [111–113], but 4 Common Unstudied Interactions may become of clinical significance in pregnant women co- in Pregnant Women Living with HIV treated with iron. Furthermore, the common DDI between gastric acid- Other commonly used drugs in pregnancy that can interact neutralizing drugs and ATV or rilpivirine (RPV) is yet with ARV include: proton pump inhibitors, iron and min- unstudied in pregnant women living with HIV. The absorp- eral supplements, antacids, domperidone, and macrolide tion of RPV/ATV decreases with increasing gastric pH, thus antibiotics [103, 104]. Drug–drug interactions with these co-administration with proton pump inhibitors is contra- co-medications have not been studied in pregnant women, indicated in non-pregnant women and it is recommended to while having the potential for clinically relevant interactions. stagger administration with histamine ­H2 antagonists (cime- They also illustrate possibly altered interaction mechanisms tidine, famotidine, ranitidine) [96, 114]. However, a different during pregnancy at the level of distribution, absorption, and recommendation might be needed in pregnant women as non-CYP metabolism. pregnancy-related physiological changes include a possible For instance, caution is needed when interpreting serum increase in gastric pH that will also result in a decrease in concentrations of highly protein-bound ARVs (such as PIs RPV/ATV exposure [13, 115–117]. Thus, it is possible that and INSTIs) in pregnancy, especially when co-administered the absorption of ATV/RPV is worse in pregnant women with other highly protein-bound drugs. A DDI at the level treated with an H­ 2 antagonist because of the additive effect of distribution can theoretically change in pregnant women of the drug- and pregnancy-related physiological changes because the amount of plasma proteins decreases during on the gastric pH. Research is needed to show if a contra- pregnancy [14]. Competition for plasma proteins with a indication for ATV/RPV and ­H2 antagonists is required in highly protein-bound concomitant drug and a decrease in pregnant women. plasma proteins can co-exist, resulting in even lower total Hepatic DDIs concerning non-CYP enzymes can be ARV concentrations. potentially altered during pregnancy as well. A common Another common DDI mechanism involves the chelation example is the DDI between rifampicin and DTG, as the of INSTIs with divalent cations such as iron, requiring stag- prevalence of HIV-tuberculosis co-infection is high in gered administration [8, 105–110]. The magnitude of the third-world countries and DTG-containing regimens are physiochemical interaction in the gut is not affected by phys- preferred according to the World Health Organization iological changes in pregnancy. However, this DDI is likely guidelines [118]. Glucuronidation to the main metabolite to be more clinically relevant in pregnant women because of DTG is catalyzed by UGT1A1, which can be induced by of the additive effects of chelation and pregnancy-related rifampicin. A dose increase to 50 mg of DTG twice daily is physiological changes potentially leading to a lower abso- needed in non-pregnant individuals when co-administered lute INSTI exposure. Additionally, the time between INSTI with rifampicin [118, 119]. In pregnant women, DTG expo- and iron administration may need to be increased during sure is modestly decreased and UGT1A1 induction and Drug–Drug Interactions in HIV-Infected Pregnant Women 1231 decreased plasma proteins have been suggested as causes medicine, DDIs cannot be ignored and are an opportunity [111, 120, 121]. It is still uncertain if UGT1A1 is induced for a more effective and individualized drug treatment. More during pregnancy [14], as some studies suggested UGT1A1 attention is needed from both researchers and clinicians to induction during pregnancy [122, 123], but an increased demonstrate which DDIs are clinically relevant in special metabolic ratio of DTG-glucuronide/DTG could not be dem- populations. onstrated in a small pharmacokinetic study with pregnant women using DTG [120]. In pregnant women co-treated with DTG and rifampicin, the effect of physiological preg- 6 Conclusions nancy alterations and rifampicin UGT1A1 induction could increase, leading to a larger decrease in DTG exposure than Drug–drug interactions in pregnant women remain a com- in pregnant women without rifampicin. A larger DTG dose plex situation because the extent and clinical significance increase may be needed in pregnant women co-treated with of a DDI can change during pregnancy. Only a few studies rifampicin and DTG, but a pharmacokinetic assessment is examined this complex situation; therefore, the management needed for confirmation. of DDIs in pregnant women is mostly based on theoretical assumptions. This makes decisions regarding the optimal dose and ARV regimen very difficult, and places pregnant 5 Future Perspectives women living with HIV and their newborns at risk. The extent of a DDI can change during pregnancy, More research on DDIs in pregnant women is needed, but the although it is very challenging, if not impossible, to distin- study design remains challenging. Pregnancy pharmacology guish the influence of individual processes. The extent of a studies lend themselves to investigate DDIs, as well as the DDI may differ if the exposure of the perpetrator changes systematic collection of therapeutic drug monitoring sam- during pregnancy as suggested for concentration-dependent ples. In both cases, accurate registration of co-medication, DDIs such as the DDI between cobicistat and PIs/EVG (inhi- dose, and time of intake make it possible to determine the bition of metabolism). Drug–drug interactions at the level of absolute exposure of ARVs in pregnant women with DDIs, intestinal transporters do not seem to be different in pregnant but a sufficient sample size is crucial for the interpretation. women (i.e., TAF co-administered with cobicistat). Observational pharmacology studies in pregnancy generally More importantly, the clinical significance of most DDIs focus on the exposure to the ARV; however, in the presence in this review changed during pregnancy when looking at the of potential DDIs with non-ARVs, the plasma concentration absolute drug exposure in pregnant women. The combined of these agents should be systematically determined. Physi- effects of the DDI and other pregnancy-related physiologi- ologically based pharmacokinetic (PBPK) models have been cal changes may lead to a more pronounced reduction in applied to predict drug exposure in special populations and drug exposure, thereby exposing to the risk of therapeutic to simulate DDIs. The validity of pregnancy PBPK models failure. Only the DDI between cobicistat and PIs/EVG in has improved tremendously during the recent years owing pregnancy has led to a change in drug labels; currently, to the increased interest in these models [124]. Although the use of cobicistat-boosted regimens in pregnancy is no more in vitro and clinical studies are needed to fill knowl- longer recommended [16]. There are not enough data for edge gaps, for example on UGT and drug transporter activ- the other reviewed DDIs to change the official recommenda- ity, the models are already widely used to understand and tions, although some DDIs resulted in drug concentrations predict pharmacokinetic changes during pregnancy [124]. below the target values in a large proportion of the pregnant The knowledge from DDI and pregnancy PBPK models can women. be combined to improve our understanding of this complex situation. In particular, DDIs on the level of placental drug Compliance with Ethical Standards transport are difficult to investigate in clinical studies as only sampling from the umbilical cord during delivery is consid- Funding No specific funding was received for the preparation of this article. ered to be ethical. Knowledge on pregnancy PBPK models including the placenta and the fetus is gained rapidly and a combination of these models can offer a solution for predict- Conflict of interest DMB has received research grants to his institution from Merck, BMS, Janssen/Tibotec, ViiV Healthcare, and Gilead, has ing placental drug transporter DDIs [125]. received educational grants from Merck, was a speaker for a symposia Clinically relevant DDIs apply to pregnant women, but for Merck, and is a member of the advisory boards of ViiV Healthcare are also a factor of consideration for other special patient and Merck. VEB, AC, CM, and JM have no conflicts of interest that are population such as the elderly, children, and patients with directly relevant to the content of this article. hepatic impairment. The management of DDIs has to be conducted on an individual basis. In the era of precision 1232 V. E. Bukkems et al. Open Access This article is licensed under a Creative Commons Attri- 13. 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