Steady‐State Pharmacokinetics of Etravirine and Lopinavir/Ritonavir Melt Extrusion Formulation, Alone and in Combination, in Healthy HIV‐Negative Volunteers

Schöller-Gyüre, Monika; Kakuda, Thomas N.; Witek, James; Akuma, Sophie H.; Smedt, Goedele De; Spittaels, Kurt; Vyncke, Veerle; Hoetelmans, Richard M. W.

doi:10.1177/0091270012445205

Cited by 11 publications

(14 citation statements)

References 19 publications

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“…9 No clinically relevant effects on the pharmacokinetics of ritonavir-boosted darunavir, lopinavir (soft gel or meltrex formulations), or saquinavir were observed when coadministered with etravirine. 9,20,21 Coadministration of etravirine significantly decreased maraviroc AUC 0-12h by 53% compared with maraviroc alone, 8,22 but had no significant effect on elvitegravir pharmacokinetic parameters. 9 Rifabutin, clarithromycin, sildenafil, and atorvastatin AUCs have also been shown to significantly decrease in the presence of etravirine, that is, the LSM ratios (90% CIs) 0.83 (0.75, 0.94), 0.61 (0.53, 0.69), 0.43 (0.36, 0.51), and 0.63 (0.58, 0.68), respectively.…”

Section: Discussionmentioning

confidence: 93%

“…Etravirine can be coadministered with some ritonavir‐boosted protease inhibitors such as darunavir, lopinavir, or saquinavir . No clinically relevant effects on the pharmacokinetics of ritonavir‐boosted darunavir, lopinavir (soft gel or meltrex formulations), or saquinavir were observed when coadministered with etravirine . Coadministration of etravirine significantly decreased maraviroc AUC 0–12h by 53% compared with maraviroc alone, but had no significant effect on elvitegravir pharmacokinetic parameters .…”

Section: Discussionmentioning

confidence: 99%

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The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects

Kakuda

Solingen-Ristea

Onkelinx

et al. 2013

The Journal of Clinical Pharmacology

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The effect of etravirine on cytochrome P450 (CYP) enzymes and P-glycoprotein were evaluated in two randomized, crossover trials in healthy subjects. A modified Cooperstown 5 + 1 cocktail was utilized to determine the effects of etravirine on single-dose pharmacokinetics of model CYP probes. The cocktail was administered alone, then, after a 14-day washout, etravirine 200 mg twice daily (bid) was given for 14 days with cocktail on days 1 and 14. In a separate study, digoxin (0.5 mg) was administered alone, then, after a 14-day washout, etravirine 200 mg bid was administered for 12 days with digoxin on day 8. In the cocktail study, the AUClast least squares mean (LSM) ratios (90% confidence intervals [CIs]) for cocktail + etravirine versus cocktail were 0.93 (0.88, 0.99; paraxanthine), 0.58 (0.44, 0.75; 7-OH-S-warfarin), 0.43 (0.20, 0.96; 5-OH-omeprazole), 0.85 (0.78, 0.94; dextrorphan), and 0.69 (0.64, 0.74; midazolam). Digoxin AUC0-8h was slightly increased with etravirine coadministration (LSM ratio 1.18 [0.90, 1.56]). These data suggest that etravirine is a weak CYP3A isozyme inducer and minimally inhibits CYP2C9, 2C19, and P-glycoprotein activity.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects

Kakuda

Solingen-Ristea

Onkelinx

et al. 2013

The Journal of Clinical Pharmacology

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“…Concomitant DRV/r significantly increases etravirine apparent oral clearance by 40% in the non-pregnant adult population (Schöller-Gyüre et al, 2007 ; Kakuda et al, 2010 ; Lubomirov et al, 2013 ). Two studies have also analyzed concomitant use of etravirine with boosted lopinavir (LPV/r; Lubomirov et al, 2013 ; Schöller-Gyüre et al, 2013 ). Concomitant LPV/r also increases etravirine apparent oral clearance in the non-pregnant adult population but not significantly (Lubomirov et al, 2013 ; Kakuda et al, 2010 ; Schöller-Gyüre et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Etravirine Pharmacokinetics in HIV-Infected Pregnant Women

et al. 2016

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Background: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women.Methods: IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL).Results: Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0–12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19–4.25) and no perinatal transmission occurred.Conclusion: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available.Clinical Trial registration: The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929.

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“…Simulated results were visually inspected by overlaying clinical plasma concentration-time profiles (extracted using WebPlotDigitizer, San Francisco, CA) with model predictions. 2,[22][23][24][25][26][27][28] Thereafter, the PBPK models were validated using a twofold criterion to compare the clinically observed and model predicted PK parameters, such as the maximum plasma concentration (C max ), area under the plasma concentration-time profile (AUC 0-t ), time needed to reach C max (T max ), oral clearance (CL/F), terminal half-life, and minimum plasma concentration at steady-state (C min ).…”

Section: Model Validationmentioning

confidence: 99%

Physiologically‐Based Pharmacokinetic Modeling to Predict the Clinical Efficacy of the Coadministration of Lopinavir and Ritonavir against SARS‐CoV‐2

Thakur

Tan

Chan

2020

Clin Pharma and Therapeutics

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Lopinavir/ritonavir, originally developed for treating HIV, is currently undergoing clinical studies for treating the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although recent reports suggest that lopinavir exhibits in vitro efficacy against SARS-CoV-2, it is a highly protein-bound drug and it remains unknown if it reaches adequate in vivo unbound (free) concentrations in lung tissue. We built a physiologically-based pharmacokinetic model of lopinavir/ritonavir in white and Chinese populations. Our aim was to perform pharmacokinetic/pharmacodynamic correlations by comparing simulated free plasma and lung concentration values achieved using different dosing regimens of lopinavir/ritonavir with unbound half-maximal effective concentration (EC 50,unbound) and unbound effective concentration 90% values of lopinavir against SARS-CoV-2. The model was validated against multiple observed clinical datasets for single and repeated dosing of lopinavir/ritonavir. Predicted pharmacokinetic parameters, such as the maximum plasma concentration, area under the plasma concentration-time profile, oral clearance, half-life, and minimum plasma concentration at steady-state were within twofold of clinical values for both populations. Using the current lopinavir/ritonavir regimen of 400/100 mg twice daily, lopinavir does not achieve sufficient free lung concentrations for efficacy against SARS-CoV-2. Although the Chinese population reaches greater plasma and lung concentrations as compared with whites, our simulations suggest that a significant dose increase from the current clinically used dosing regimen is necessary to reach the EC 50,unbound value for both populations. Based on safety data, higher doses would likely lead to QT prolongation and gastrointestinal disorders (nausea, vomiting, and diarrhea), thus, any dose adjustment must be carefully weighed alongside these safety concerns.

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Steady‐State Pharmacokinetics of Etravirine and Lopinavir/Ritonavir Melt Extrusion Formulation, Alone and in Combination, in Healthy HIV‐Negative Volunteers

Abstract: Lopinavir/ritonavir induced etravirine metabolism to a similar extent as most other boosted HIV protease inhibitors. The short-term coadministration of etravirine and lopinavir/ritonavir was well tolerated and did not lead to increased incidences of adverse events.

Cited by 11 publications

References 19 publications

The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects

The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects

Etravirine Pharmacokinetics in HIV-Infected Pregnant Women

Physiologically‐Based Pharmacokinetic Modeling to Predict the Clinical Efficacy of the Coadministration of Lopinavir and Ritonavir against SARS‐CoV‐2

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