In Silico Pharmacokinetics Evaluation of Forgiveness for Doravirine and Rilpivirine.
Journal
Therapeutic drug monitoring
ISSN: 1536-3694
Titre abrégé: Ther Drug Monit
Pays: United States
ID NLM: 7909660
Informations de publication
Date de publication:
26 Dec 2023
26 Dec 2023
Historique:
received:
15
06
2023
accepted:
29
08
2023
medline:
2
1
2024
pubmed:
2
1
2024
entrez:
30
12
2023
Statut:
aheadofprint
Résumé
This study aimed to evaluate the concentrations of rilpivirine (RLP) and doravirine (DOR) after 3 days-off using simulations from population pharmacokinetics models. The authors conducted a series of 500 sets of 10,000 Monte Carlo simulations to examine the steady-state conditions for 2 common dosage levels: 25 mg/d for RLP and 100 mg/d for DOR. These simulations were conducted under 2 scenarios: 1 without drug cessation and another after a 3-day break. The validity of the implementation was established through a comparison of median trough concentrations (C24h) with previously reported data. Subsequently, the proportion of simulated patients with C24h and C72h after 3 days-off (C72h/3do) that exceeded the inhibitory concentration 50 (IC50), 5.2 mcg/L for DOR and 20.5 mcg/L for RLP respectively, was calculated. The inhibitory quotient (IQ) was also computed, which was 6 times IC50 for DOR and 4.5 times IC50 for RLP. Finally, nomograms were constructed to estimate the probability of having C72h/3do > IC50 or > IQ for different ranges of C24h. Simulated C24h median ± SD for RLP were 61.8 ± 0.4 mcg/L and for DOR 397 ± 0 mcg/L. For RLP, 99.3 ± 0.1% exceeded IC50 at C24h, 16.4 ± 0.4% at C72h/3do, and none surpassed the IQ threshold. In contrast, DOR had 100% ± 0% above IC50 at C24h, 93.6 ± 0.2% at C72h/3do, and 58.6 ± 0.5% exceeded the IQ. These findings suggest that treatment with DOR may offer a more forgiving therapeutic profile than RLP, given the larger proportion of patients achieving effective drug exposure with DOR. However, it is important to acknowledge a significant limitation of this study, namely, the assumption that drug concentration is a perfect surrogate for drug effectiveness.
Sections du résumé
BACKGROUND
BACKGROUND
This study aimed to evaluate the concentrations of rilpivirine (RLP) and doravirine (DOR) after 3 days-off using simulations from population pharmacokinetics models.
METHODS
METHODS
The authors conducted a series of 500 sets of 10,000 Monte Carlo simulations to examine the steady-state conditions for 2 common dosage levels: 25 mg/d for RLP and 100 mg/d for DOR. These simulations were conducted under 2 scenarios: 1 without drug cessation and another after a 3-day break. The validity of the implementation was established through a comparison of median trough concentrations (C24h) with previously reported data. Subsequently, the proportion of simulated patients with C24h and C72h after 3 days-off (C72h/3do) that exceeded the inhibitory concentration 50 (IC50), 5.2 mcg/L for DOR and 20.5 mcg/L for RLP respectively, was calculated. The inhibitory quotient (IQ) was also computed, which was 6 times IC50 for DOR and 4.5 times IC50 for RLP. Finally, nomograms were constructed to estimate the probability of having C72h/3do > IC50 or > IQ for different ranges of C24h.
RESULTS
RESULTS
Simulated C24h median ± SD for RLP were 61.8 ± 0.4 mcg/L and for DOR 397 ± 0 mcg/L. For RLP, 99.3 ± 0.1% exceeded IC50 at C24h, 16.4 ± 0.4% at C72h/3do, and none surpassed the IQ threshold. In contrast, DOR had 100% ± 0% above IC50 at C24h, 93.6 ± 0.2% at C72h/3do, and 58.6 ± 0.5% exceeded the IQ.
CONCLUSIONS
CONCLUSIONS
These findings suggest that treatment with DOR may offer a more forgiving therapeutic profile than RLP, given the larger proportion of patients achieving effective drug exposure with DOR. However, it is important to acknowledge a significant limitation of this study, namely, the assumption that drug concentration is a perfect surrogate for drug effectiveness.
Identifiants
pubmed: 38158596
doi: 10.1097/FTD.0000000000001169
pii: 00007691-990000000-00175
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
Références
EACS Guidelines. EACSociety. Available at: https://www.eacsociety.org/guidelines/eacs-guidelines/. Accessed September 6, 2022.
EMA. Edurant. European Medicines Agency. Published September 17, 2018. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/edurant. Accessed April 13, 2023.
Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients. J Int AIDS Soc. 2014;17:19532.
EMA. Pifeltro. European Medicines Agency. Published September 24, 2018. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/pifeltro. Accessed August 24, 2022.
Landman R, de Truchis P, Assoumou L, et al. A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial. Lancet HIV. 2022;9:e79–e90.
Palich R, Saliba S, Landowski S, et al. Intermittent doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintains a high level of viral suppression in virologically suppressed people living with HIV. Infect Dis Now. 2023;53:104736.
Punyawudho B, Singkham N, Thammajaruk N, et al. Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients. Expert Rev Clin Pharmacol. 2016;9:1583–1595.
Aouri M, Barcelo C, Guidi M, et al. Population pharmacokinetics and pharmacogenetics analysis of rilpivirine in HIV-1-infected Individuals. Antimicrob Agents Chemother. 2017;61:008999-16.
Yee KL, Ouerdani A, Claussen A, et al. Population pharmacokinetics of doravirine and exposure-response analysis in individuals with HIV-1. Antimicrob Agents Chemother. 2019;63:e02502-18.
Néant N, Lê MP, Bouazza N, et al. Usefulness of therapeutic drug monitoring of rilpivirine and its relationship with virologic response and resistance in a cohort of naive and pretreated HIV-infected patients. Br J Clin Pharmacol. 2020;86:2404–2413.
Morse GD, Catanzaro LM, Acosta EP. Clinical pharmacodynamics of HIV-1 protease inhibitors: use of inhibitory quotients to optimise pharmacotherapy. Lancet Infect Dis. 2006;6:215–225.
Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacometrics Syst Pharmacol. 2012;1:e6.
Guidi M, Csajka C, Buclin T. Parametric approaches in population pharmacokinetics. J Clin Pharmacol. 2022;62:125–141.
Elmokadem A, Riggs MM, Baron KT. Quantitative systems pharmacology and physiologically-based pharmacokinetic modeling with mrgsolve: a Hands-On Tutorial. CPT Pharmacometrics Syst Pharmacol. 2019;8:883–893.
Labriffe M, Woillard JB, Debord J, et al. Machine learning algorithms to estimate everolimus exposure trained on simulated and patient pharmacokinetic profiles. CPT Pharmacometrics Syst Pharmacol. 2022;11:1018–1028.
Feng M, Sachs NA, Xu M, et al. Doravirine suppresses common nonnucleoside reverse transcriptase inhibitor-associated mutants at clinically relevant concentrations. Antimicrob Agents Chemother. 2016;60:2241–2247.
Wang X, Milinkovic A, Pereira B, et al. Pharmacokinetics of once-daily doravirine over 72 h following drug cessation. J Antimicrob Chemother. 2020;75:1658–1660.
Anderson MS, Gilmartin J, Cilissen C, et al. Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects. Antivir Ther. 2015;20:397–405.
Yee KL, Sanchez RI, Auger P, et al. Evaluation of doravirine pharmacokinetics when switching from efavirenz to doravirine in healthy subjects. Antimicrob Agents Chemother. 2017;61:e01757-16.
Khalilieh S, Yee KL, Sanchez R, et al. Clinical pharmacokinetics of the novel HIV-1 non-nucleoside reverse transcriptase inhibitor doravirine: an assessment of the effect of patient characteristics and drug-drug interactions. Clin Drug Investig. 2020;40:927–946.
Boyle A, Moss CE, Marzolini C, et al. Clinical pharmacodynamics, pharmacokinetics, and drug interaction profile of doravirine. Clin Pharmacokinet. 2019;58:1553–1565.
Hoetelmans R, Van Heeswijk R, Kestens D, et al. Effect of food and multiple-dose pharmacokinetics of TMC278 as an oral tablet formulation: healthy volunteers. Poster presented at: IAS; July 24, 2005; Rio de Janeiro, Brazil. Available at: https://www.natap.org/2005/ias/ias_12.htm. Accessed April 13, 2023.
Dickinson L, Yapa HM, Jackson A, et al. Plasma tenofovir, emtricitabine, and rilpivirine and intracellular tenofovir diphosphate and emtricitabine triphosphate pharmacokinetics following drug intake cessation. Antimicrob Agents Chemother. 2015;59:6080–6086.
Goebel F, Yakovlev A, Pozniak AL, et al. Short-term antiviral activity of TMC278−a novel NNRTI−in treatment-naive HIV-1-infected subjects. AIDS. 2006;20:1721–1726.
Turkova A, Moore CL, Butler K, et al. Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents and young adults (BREATHER): Extended follow-up results of a randomised, open-label, non-inferiority trial. PLoS One. 2018;13:e0196239.
Pozniak AL, Morales-Ramirez J, Katabira E, et al. Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial. AIDS. 2010;24:55–65.
Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Doravirine dose selection and 96-week safety and efficacy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial. Antivir Ther. 2019;24:425–435.
Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011;25:1737–1745.
Cottrell ML, Hadzic T, Kashuba ADM. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet. 2013;52:981–994.
Rizzardini G, Overton ET, Orkin C, et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J Acquir Immune Defic Syndr. 2020;85:498–506.
Patel P, Ford SL, Crauwels H, et al. 2495. Pharmacokinetics of cabotegravir (CAB) and rilpivirine (RPV) long-acting (LA) injectables in HIV-infected individuals through 48 weeks in the FLAIR and ATLAS phase 3 studies. Open Forum Infect Dis. 2019;6(suppl 2):S865–S866.
Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS. 2021;35:1333–1342.
Lai MT, Feng M, Falgueyret JP, et al. In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother. 2014;58:1652–1663.