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. 2024 Jun 1;46(3):391-396.
doi: 10.1097/FTD.0000000000001169. Epub 2023 Dec 26.

In Silico Pharmacokinetics Evaluation of Forgiveness for Doravirine and Rilpivirine

Yeleen Fromage  1 , Najwa Jamal  1 , Cyrielle Codde  1 , Caroline Monchaud  1 , Marc Labriffe  1 , Laure Ponthier, Pierre Marquet  1 , Jean François Faucher, Jean-Baptiste Woillard  1
Affiliations

In Silico Pharmacokinetics Evaluation of Forgiveness for Doravirine and Rilpivirine

Yeleen Fromage et al. Ther Drug Monit. .

Abstract

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: 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: 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: 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.

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Conflict of interest statement

The authors declare no conflict of interest.

References

    1. EACS Guidelines. EACSociety. Available at: https://www.eacsociety.org/guidelines/eacs-guidelines/ . Accessed September 6, 2022.
    1. 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.
    1. 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.
    1. 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.
    1. 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.