Sandra Grañana-Castillo (1), Maiara Montanha-Camotti (1), Fazila Bunglawala (1), Nicolas Cottura (1), Hannah Kinvig (1), Andy Lloyd (1), Saye Khoo (1), Rachel Bearon (1), Marco Siccardi (1)
(1) Department of Pharmacology & Therapeutics, University of Liverpool, United Kingdom
Introduction: Tuberculosis remains the primary cause of death among people living with HIV [1]. First-line treatment for tuberculosis often includes rifampicin and isoniazid. However, rifampicin is a strong drug metabolising enzyme inducer, potentially jeopardizing HIV treatment. Alternatives to rifampicin are rifabutin and rifapentine, which have a less potent induction effect on drug metabolising enzymes. Recently, intramuscular (IM) formulations of long-acting (LA) cabotegravir and rilpivirine have been approved for the treatment of HIV, providing an alternative to traditional oral daily tablets with monthly administration regimens. Cabotegravir is primarily metabolised by UGT1A1 and to a lesser extent by UGT1A9, whereas rilpivirine is mainly metabolised by CYP3A4 [2]. Rifabutin is an inducer of CYP3A4 and UGT1A1 [3], with the DDI between oral formulations resulting in a 21% and 42% decrease in the AUC for cabotegravir 30 mg and rilpivirine 25 mg, respectively [4, 5]. Current target minimum concentrations for cabotegravir are 0.664 mg/L (4x protein adjusted IC90), and 0.050 mg/L for rilpivirine [6, 7]. However, the DDI between rifabutin and LA IM cabotegravir and rilpivirine have yet to be investigated. Physiologically based pharmacokinetic (PBPK) modelling is an effective tool for the virtual exploration of clinical DDI scenarios, enabling the prediction of DDI magnitude.
Objectives: In this in silico study, we aimed to simulate the DDI magnitude between daily oral rifabutin 300 mg with IM LA cabotegravir 400 mg monthly or 600 mg bimonthly, and IM LA rilpivirine 600 mg monthly or 900 mg bimonthly.
Methods: A whole-body PBPK model was built in Simbiology (Matlab R2018a) to simulate 100 adult individuals. Due to the limited available in vitro data, UGT1A1 induction was represented as a 1.75-fold increase on the UGT1A1-mediated intrinsic clearance [8]. CYP3A4 induction was applied using an in vitro Emax of 4.75-fold and EC50 value of 0.3 μM [9]. The PBPK model was verified against reported clinical data for oral rifabutin, rilpivirine and cabotegravir, IM LA rilpivirine and cabotegravir, and oral DDIs between rifabutin with either cabotegravir or rilpivirine. The model was assumed to be verified if the simulated values were within 2-fold of the reported clinical values and if the absolute average-fold error (AAFE) was below 2.
Results: The model was successfully qualified with a 1.21 (1.00-1.84) average (min-max) AAFE. Four virtual clinical scenarios were simulated, each treated with oral rifabutin 300 mg with either: A) IM LA cabotegravir 400 mg monthly, B) IM LA cabotegravir 600 mg bimonthly, C) IM LA rilpivirine 600 mg monthly, or D) IM LA rilpivirine 900 mg bimonthly. At steady state, the decrease in AUC, Cmax and Ctrough were the following: 32%, 31%, 31% (scenario A), 32%, 34%, 30% (scenario B), 43%, 42% and 39% (scenario C), and 42%, 41% and 38% (scenario D) with a simulated Ctrough of 2.62 mg/L, 1.67 mg/L, 0.060 mg/L, and 0.032 mg/L, respectively.
Conclusions: The DDIs between IM LA cabotegravir and rilpivirine with oral rifabutin were simulated in healthy adults using a whole-body PBPK model. The predictions suggest a significant decrease of key pharmacokinetic parameters, with the mean Ctrough for rilpivirine 900 mg bimonthly being decreased below the minimum target concentration. Therefore, a clinical evaluation of this potential interaction, especially regimens involving rilpivirine, might be required to fully evaluate the safety of concomitant use with moderate enzymatic inducers.
References:
[1] World Health Organisation (WHO). HIV and Tuberculosis. Available from: https://www.who.int/westernpacific/health-topics/hiv-aids/hiv-and-tuberculosis.
[2] Hodge, D., D. J. Back, S. Gibbons, S. H. Khoo and C. Marzolini. Pharmacokinetics and Drug-Drug Interactions of Long-Acting Intramuscular Cabotegravir and Rilpivirine. Clin Pharmacokinet, 2021. 60(7): p. 835-853.
[3] Yapa, H.M., M. Boffito, and A. Pozniak. Critical Review: What Dose of Rifabutin Is Recommended With Antiretroviral Therapy? J Acquir Immune Defic Syndr, 2016. 72(2): p. 138-52.
[4] Ford, S. L., Y. Lou, N. Lewis, M. Kostapanos, R. D’Amico, W. Spreen and P. Patel. Effect of rifabutin on the pharmacokinetics of oral cabotegravir in healthy subjects. Antivir Ther, 2019. 24(4): p. 301-308.
[5] Electronic Medicines Compendium (EMC). SmPC: EDURANT (rilpivirine) 25mg film-coated tablets. Available from: https://www.medicines.org.uk/emc/product/4968/smpc.
[6] Trezza, C., S. L. Ford, W. Spreen, R. Pan and S. Piscitelli. Formulation and pharmacology of long-acting cabotegravir. Curr Opin HIV AIDS, 2015. 10(4): p. 239-45.
[7] Néant, N., M. P. Lê, N. Bouazza, F. Gattacceca, Y. Yazdanpanah, C. Dhiver, S. Bregigeon, S. Mokhtari, G. Peytavin, C. Tamalet, D. Descamps, B. Lacarelle and C. Solas. 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(12): p. 2404-2413.
[8] Brainard, D. M., K. Kassahun, L. A. Wenning, A. S. Petry, C. Liu, J. Lunceford, N. Hariparsad, R. Eisenhandler, A. Norcross, E. P. DeNoia, J. A. Stone, J. A. Wagner and M. Iwamoto. Lack of a clinically meaningful pharmacokinetic effect of rifabutin on raltegravir: in vitro/in vivo correlation. J Clin Pharmacol, 2011. 51(6): p. 943-50.
[9] McGinnity, D. F., G. Zhang, J. R. Kenny, G. A. Hamilton, S. Otmani, K. R. Stams, S. Haney, P. Brassil, D. M. Stresser and R. J. Riley. Evaluation of multiple in vitro systems for assessment of CYP3A4 induction in drug discovery: human hepatocytes, pregnane X receptor reporter gene, and Fa2N-4 and HepaRG cells. Drug Metab Dispos, 2009. 37(6): p. 1259-68.
Reference: PAGE 30 (2022) Abstr 10041 [www.page-meeting.org/?abstract=10041]
Poster: Drug/Disease Modelling - Infection