More attention is needed from both researchers and clinicians to demonstrate which drug–drug interactions (DDIs) are clinically relevant in special populations. |
The extent of a DDI may differ if the exposure of the perpetrator changes during pregnancy. DDIs at the level of intestinal transporters do not seem to be different in pregnant women. |
The clinical significance of most DDIs in this review changed during pregnancy when looking at the absolute drug exposure in pregnant women. The combined effects of the DDI and other pregnancy-related physiological changes may lead to a more pronounced reduction in drug exposure, thereby exposing to the risk of therapeutic failure. |
1 Introduction
2 Search Methodology
3 Studied Interactions in Pregnant Women Living with HIV
3.1 Enzyme Inhibition
3.1.1 Boosters and Protease Inhibitors/Elvitegravir
Reference | Population | Outcome measure | Comparison | Ratio pregnant/non-pregnant women of ARV pharmacokinetic parameter | Booster | ||||
---|---|---|---|---|---|---|---|---|---|
AUC | Ctrough | Cmax | AUC | Ctrough | Cmax | ||||
Atazanavir 300 mg QD + ritonavir 100 mg QD | |||||||||
[17] | n = 103, 88% African, sparse sampling, fasted/fed unknown | Self-calculated ratio | 1 T vs PP (intra) | – | 0.65# | – | – | 1.38 | – |
2 T vs PP (intra) | – | 0.69# | – | – | 0.86 | – | |||
3 T vs PP (intra) | – | 0.72# | – | – | 1 | – | |||
[18] | n = 10, 70% white, intensive sampling, fed without concomitant TDF, 1 patient with 400/100 mg | 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) | – | – | – |
[19] | n = 37, mostly Hispanic, intensive sampling, fed without concomitant TDF | Self-calculated ratio | 2 T vs PP (intra) | 0.63# | 0.54# | 0.69# | 0.34* | 0.71 | 0.38* |
[20] | n = 20, 85% black, intensive sampling, fasted/fed unknown | 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) | – | – | – |
3 T vs PP (intra) | 0.79 (0.63–0.99) | 1.01 (0.73–1.39) | 0.73 (0.56–0.96) | – | – | – | |||
[21] | n = 18, 67% black, intensive sampling, fed without concomitant TDF | Self-calculated ratio | 3 T vs PP (intra) | 0.72* | 0.58* | 0.88# | 0.44* | BLOQ | 0.44* |
[22] | n = 25, 52% Caucasian, sparse sampling, fasted/fed unknown | Self-calculated ratio | 1 T vs PP (intra) | – | 0.53 | – | – | 0.43 | – |
2 T vs PP (intra) | – | 0.85* | – | – | 0.35* | – | |||
3 T vs PP (intra) | – | 0.66* | – | – | 0.25* | – | |||
[23] | n = 17, 53% African, intensive sampling, fasted/fed unknown | 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) | – | – | – |
Atazanavir 300 mg QD + cobicistat 150 mg QD | |||||||||
[24] | n = 6, 67% black, intensive sampling, fasted/fed unknown | Self-calculated ratio | 2 T vs PP (intra) | 0.77 | 0.36 | – | – | – | – |
3 T vs PP (intra) | 0.62 | 0.27 | – | – | – | – | |||
Darunavir 600 mg BID + ritonavir 100 mg BID | |||||||||
[25] | n = 6, Europe (66% black), intensive sampling, fed | 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) |
[26] | n = 34, USA (41% Caucasian), intensive sampling, fasted/fed unknown | Self-calculated ratio | 2 T vs PP (intra) | 0.74* | 0.84# | 0.72* | – | – | – |
3 T vs PP (intra) | 0.74* | 0.88# | 0.71* | – | – | – | |||
[27] | n = 16, USA and Puerto Rico (63% black), intensive sampling, fasted/fed unknown | LSM ratio (90%CI) or self-calculated ratio | 2 T vs PP (intra) | Total: 0.76 (0.63–0.90) Unbound: 0.92 (0.66–1.30) | Total: 0.71 Unbound: 0.98 | Total: 0.72 (0.61–0.86) Unbound: 0.78 (0.52–1.18) | 0.72 (0.44–1.17) | 0.57 | 0.66 (0.41–1.08) |
3 T vs PP (intra) | Total: 0.83 (0.72–0.97) Unbound: 0.93 (0.69–1.24) | Total: 0.88 Unbound: 1.18 | Total: 0.81 (0.69–0.96) Unbound: 0.82 (0.57–1.16) | 0.67 (0.43–1.04) | 0.58 | 0.63 (0.40–0.98) | |||
Darunavir 800 mg QD + ritonavir 100 mg QD | |||||||||
[28] | n = 16, USA and Puerto Rico (41% white), intensive sampling, fasted/fed unknown | LSM ratio (90% CI) or self-calculated ratio | 2 T vs PP (intra) | Total: 0.66 (0.60–0.74) Unbound: 0.76 (0.67–0.85) | Total: 0.70 Unbound: 0.91 | Total: 0.66 (0.59–0.75) Unbound: 0.75 (0.65–0.87) | 54.71 (46.72–62.82) | 0.58 | 54.16 (44.08–66.54) |
3 T vs PP (intra) | Total: 0.65 (0.57–0.74) Unbound: 0.80 (0.71–0.89) | Total: 0.67 Unbound: 0.88 | Total: 0.69 (0.63–0.77) Unbound: 0.84 (0.74–0.96) | 53.44 (43.47–65.70) | 0.61 | 50.85 (41.34–62.54) | |||
[25] | n = 18, European (50% Caucasian), intensive sampling, fed | 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) |
[26] | n = 32, USA (53% black), intensive sampling, fasted/fed unknown | Self-calculated ratio | 2 T vs PP (intra) | 0.62* | 0.36* | 0.83* | – | – | – |
3 T vs PP (intra) | 0.61* | 0.42* | 0.71* | – | – | – | |||
[29] | n = 20, 60% black sparse sampling, fasted/fed unknown | Self-calculated ratio | 2 T vs PP (intra) | – | 0.55# | – | – | – | – |
3 T vs PP (intra) | 0.47* | ||||||||
[30] | n = 5, Spain (50% Caucasian), intensive sampling, fed | GMR (90% CI) | 3 T vs PP (intra) | Total: 0.69 (0.35–1.35) Unbound: 0.76 (0.44–1.32) | Total: 0.53 (0.19–1.52) Unbound: 0.76 (0.26–2.25) | Total: 0.73 (0.41–1.32) Unbound: 0.71 (0.44–1.16) | – | – | – |
[31] | n = 33, 67% black, sparse sampling, fed | Self-calculated ratio | 1 T vs PP (intra) | 1.08 | |||||
2 T vs PP (intra) | 0.51* | ||||||||
3 T vs PP (intra) | 0.46* | ||||||||
Darunavir 800 mg BID + ritonavir 100 mg BID | |||||||||
[32] | n = 24, 50% black, intensive sampling, fasted/fed unknown | 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)# |
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 (0.54–0.83)* | |||
Darunavir 800 mg QD + cobicistat 150 mg QD | |||||||||
[33] | n = 7, 71% black, intensive sampling, fed | LSM (90% CI) | 2 T vs PP (intra) | Total: 0.44 (0.24–0.80) Unbound: 0.55 (0.28–1.06) | Total: 0.08 (0.01–0.50) Unbound: 0.08 (0.02–0.42) | Total: 0.51 (0.30–0.86) Unbound: 0.59 (0.34–1.02) | 0.37 (0.17–0.79) | 0.17 (0.05–0.61) | 0.50 (0.28–0.91) |
3 T vs PP (intra) | Total: 0.50 (0.37–0.66) Unbound: 0.60 (0.44–0.83) | Total: 0.11 (0.04–0.30) Unbound: 0.12 (0.05–0.27) | Total: 0.63 (0.50–0.79) Unbound: 0.77 (0.59–1.00) | 0.51 (0.33–0.80) | 0.17 (0.04–0.74) | 0.73 (0.52–1.02) | |||
[34] | n = 29, USA (62% black), fasted/fed unknown | 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) | – | – | – |
3 T vs PP (intra) | 0.52 (0.37–0.74) | 0.25 (0.13–0.49) | 0.64 (0.50–0.82) | – | – | – | |||
Elvitegravir 150 mg QD + cobicistat 150 mg QD | |||||||||
[35] | n = 30, USA (67% black), intensive sampling, fed | 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) |
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) | |||
[36] | n = 1, intensive sampling, fed | Self-calculated ratio | 3 T vs PP (intra) | Total: 0.93 Unbound: 1.28 | Total: 0.30 Unbound: BLOQ | Total: 0.94 Unbound: 1.45 | 0.76 | 0.67 | |
[37] | n = 1, black, intensive sampling, fasted/fed unknown | Self-calculated ratio | 3 T vs PP (intra) | 1.07 | 0.4 | 1.09 | 0.57 | BLOQ | |
[38] | n = 14, European (71% black), intensive sampling, fed | 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) | – | – | |
Fosamprenavir 700 mg BID + ritonavir 100 mg BID | |||||||||
[39] | n = 10, 50% black, 50% Hispanic, intensive sampling, fasted/fed unknown | 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) |
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) | |||
[40] | n = 29, 52% Hispanic, intensive sampling, fasted/fed unknown | 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) |
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) | |||
Indinavir 400 mg BID + ritonavir 100 mg BID | |||||||||
[41] | n = 26, Thailand, intensive sampling, fasted and fed | Self-calculated ratio | 2 T vs PP (intra) | 0.55 | 0.46 | 0.72 | 0.40 | 0.44 | 0.37 |
3 T vs PP (intra) | 0.59 | 0.46 | 0.67 | 0.41 | 0.50 | 0.32 | |||
Lopinavir 400 mg BID + ritonavir 100 mg BID | |||||||||
[42] | n = 27, Brazil tablet, intensive sampling, fasted/fed unknown | Self-calculated ratio | 2 T vs PP (intra) | 0.72 | 0.74 | 0.75 | 0.57 | 0.47 | 0.62 |
3 T vs PP (intra) | 0.71 | 0.71 | 0.76 | 0.60 | 0.56 | 0.59 | |||
[43] | n = 33, 61% Hispanic, tablet, intensive sampling, fed | Self-calculated ratio | 2 T vs PP (intra) | 0.54* | 0.51* | 0.58* | 0.61 | 0.74 | 0.53 |
[44] | n = 42, 70% black, tablet or soft-gel, sparse sampling, fasted/fed unknown | Self-calculated ratio | 1 T vs PP (intra) | Total: 0.88 Unbound: 1.09 | Total: 0.69* Unbound: 0.79# | – | – | – | – |
2 T vs PP (intra) | Total: 0.73 Unbound: 0.85# | Total: 0.68* Unbound: 0.79# | – | – | – | – | |||
3 T vs PP (intra) | Total: 0.74 Unbound: 0.74# | Total: 0.69* Unbound: 0.79# | – | – | – | – | |||
[45] | n = 41, 83% Caucasian, tablet, sparse sampling, fed | GMR (95% CI) | 3 T vs non-pregnant (inter) | - | 0.87 (0.62–1.32) | – | – | – | – |
[46] | n = 12, 75% black, tablet, intensive sampling, fed | Self-calculated ratio | 2 T vs PP (intra) | Total: 0.63 Unbound: 0.62 | Total: 0.72 Unbound: 0.62 | Total: 0.77 Unbound: 0.64 | 0.48 | 0.43 | 0.56 |
3 T vs PP (intra) | Total: 0.71 Unbound: 0.69 | Total: 0.68 Unbound: 0.69 | Total: 0.85 Unbound: 0.86 | 0.46 | 0.54 | 0.58 | |||
[47] | n = 10, 50% black, soft-gel, 4 samples, fed | GMR (95% CI) | 3 T vs PP (intra) | 0.60 (0.25–1.43) | 0.36 (0.14–0.92) | ||||
[48] | n = 17, 41% black, 41% Hispanic, soft-gel, intensive sampling, fed | 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) |
Lopinavir soft-gel 533 mg BID + ritonavir 133 mg BID | |||||||||
[49] | n = 26, 42% black, intensive sampling, fed | Self-calculated ratio | 3 T vs PP (intra) | 0.58* | 0.53* | 0.58* | |||
Lopinavir tablet 600 mg BID + ritonavir 150 mg BID | |||||||||
[42] | n = 26, Brazil, tablet, intensive sampling, fasted/fed unknown | Self-calculated ratio | 2 T vs PP (intra) | 0.91 | 0.87 | 0.95 | 0.90 | 0.85 | 0.98 |
3 T vs PP (intra) | 0.85 | 0.76 | 0.93 | 0.83 | 0.76 | 1.01 | |||
Saquinavir 1000 mg BID + ritonavir 100 mg BID | |||||||||
[50] | n = 14, 71% white, intensive sampling, fed | Self-calculated ratio | 2 T vs PP (intra) | 0.86 | 1.08 | 1.19 | 0.47 | 0.34 | 0.63 |
3 T vs PP (intra) | 0.44 | 0.30 | 0.82 | 0.36 | 0.34 | 0.61 | |||
[51] | n = 28, Germany, intensive sampling, fed | GMR (90% CI) | 3 T vs non-pregnant (inter) | 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) |
[52] | n = 37, 38% black, intensive sampling, fed | Self-calculated ratio | 2 T vs PP (intra) | 0.94 | 1.05 | 0.92 | 0.74 | 0.90 | 0.79 |
3 T vs PP (intra) | 0.95 | 1.08 | 0.94 | 0.64 | 0.94 | 0.61 | |||
Tenofovir alafenamide 10 mg QD + cobicistat 150 mg QD | |||||||||
[53] | n = 27, USA (52% Hispanic), intensive sampling, fasted/fed unknown | GMR (90% CI) | 2 T vs PP (intra) | 0.79 (0.50–1.27) | – | – | – | – | – |
3 T vs PP (intra) | 0.86 (0.66–1.12) | – | – | – | – | – | |||
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) | – | – | – | – | – |
3.2 Enzyme Induction
3.2.1 Efavirenz and Lumefantrine
3.2.2 Efavirenz plus an Anti-Tuberculosis Drug: Additional Influence of Genotype
3.3 Transporter Inhibition
3.3.1 Etravirine and Tenofovir Disoproxil Fumarate: An Additional Compartment
3.3.2 Cobicistat and Tenofovir Alafenamide
3.4 Unknown Mechanism
3.4.1 Tenofovir Disoproxil Fumarate and Atazanavir
Reference | Population | Parameter | Non-pregnant individuals/postpartum women | Pregnant women | ||||
---|---|---|---|---|---|---|---|---|
Without TDF | With TDF | Self-calculated ratio | Without TDF | With TDF | Self-calculated ratio | |||
Taburet et al. [94] | HIV-infected non-pregnant patients, n = 11, France, intensive sampling after 4 weeks with ATV and 2 weeks co-treatment with TDF, Mean (SD) | AUC (h*ng/L) | 53.8 (35.3) | 39.3 (23.0) | 0.73 | |||
Cmax (μg/mL) | 5.2 (3.0) | 3.4 (1.4) | 0.66 | |||||
Cmin (μg/mL) | 0.86 (0.8) | 0.58 (0.4) | 0.67 | |||||
Colbers et al. [18] | HIV-infected pregnant patients, n = 31 (third trimester), n = 25 (postpartum), 52% black, intensive sampling, fed, GM (95% CI) | 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 |
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 | ||
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 trimester), n = 68 (postpartum), 44% Hispanic, intensive sampling, fed, Median (IQ) | 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 |
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 | ||
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 trimester), n = 32 (postpartum), fed, Median (IQ) | 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 |
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 |