Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long-Acting Intramuscular Injection in Real-World People with HIV.
Paul Thoueille, Susana Alves Saldanha, Fabian Schaller, Eva Choong, François Veuve, Aline Munting, Matthias Cavassini, Dominique Braun, Huldrych F Günthard, Jessy J Duran Ramirez, Bernard Surial, Hansjakob Furrer, Andri Rauch, Pilar Ustero, Alexandra Calmy, Marcel Stöckle, Caroline Di Benedetto, Enos Bernasconi, Patrick Schmid, Catia Marzolini, François R Girardin, Thierry Buclin, Laurent A Decosterd, Monia Guidi, Swiss HIV Cohort Study
Author Information
Paul Thoueille: Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ORCID
Susana Alves Saldanha: Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Fabian Schaller: Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Eva Choong: Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ORCID
François Veuve: Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Aline Munting: Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ORCID
Matthias Cavassini: Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ORCID
Dominique Braun: Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland. ORCID
Huldrych F Günthard: Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland. ORCID
Jessy J Duran Ramirez: Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland. ORCID
Bernard Surial: Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. ORCID
Hansjakob Furrer: Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. ORCID
Andri Rauch: Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. ORCID
Pilar Ustero: Division of Infectious Diseases, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland. ORCID
Alexandra Calmy: Division of Infectious Diseases, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland. ORCID
Marcel Stöckle: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Basel, Switzerland.
Caroline Di Benedetto: Division of Infectious Diseases, Ente Ospedaliero Cantonale, Lugano, Switzerland.
Enos Bernasconi: Division of Infectious Diseases, Ente Ospedaliero Cantonale, Lugano, University of Geneva, and University of Southern Switzerland, Lugano, Switzerland. ORCID
Patrick Schmid: Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
Catia Marzolini: Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ORCID
François R Girardin: Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ORCID
Thierry Buclin: Service of Clinical Pharmacology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ORCID
Laurent A Decosterd: Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ORCID
Monia Guidi: Service of Clinical Pharmacology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ORCID
Long-actingcabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real-world reference percentile curves of cabotegravir concentrations, accounting for patient-related factors that may affect cabotegravir exposure. The second objective is to simulate whether dosing interval adjustments of cabotegravir could be considered in specific subpopulations. Overall, 238 PWH contributed to 1,038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). cabotegravir pharmacokinetics was best described using a one-compartment model with distinct first order-absorption for oral and intramuscular administrations, and identical volume and clearance. Our model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady-state of 8 months and an elimination half-life of 4.6 weeks for Long-actingcabotegravir. Sex and body mass index significantly influenced absorption, and bodyweight affected clearance. Model-based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4-fold protein-adjusted 90% inhibitory target concentration.
References
Trezza, C., Ford, S.L., Spreen, W., Pan, R. & Piscitelli, S. Formulation and pharmacology of long‐acting cabotegravir. Curr. Opin. HIV AIDS 10, 239–245 (2015).
U.S. Food and Drug Administration. Cabenuva product label . Accessed February 2023.
European Medicines Agency (EMA). Vocabria Product Information . Accessed February 2023.
Hodge, D., Back, D.J., Gibbons, S., Khoo, S.H. & Marzolini, C. Pharmacokinetics and drug–drug interactions of long‐acting intramuscular Cabotegravir and Rilpivirine. Clin. Pharmacokinet. 60, 835–853 (2021).
European Medicines Agency (EMA). Rekambys Product Information . Accessed February 2023.
Delany‐Moretlwe, S. et al. Cabotegravir for the prevention of HIV‐1 in women: results from HPTN 084, a phase 3, randomised clinical trial. Lancet (London, England) 399, 1779–1789 (2022).
Landovitz, R.J. et al. Cabotegravir for HIV prevention in cisgender men and transgender women. N. Engl. J. Med. 385, 595–608 (2021).
U.S. Food and Drug Administration. Apretude product label . Accessed March 2023.
Han, K. et al. Population pharmacokinetics of cabotegravir following administration of oral tablet and long‐acting intramuscular injection in adult HIV‐1‐infected and uninfected subjects. Br. J. Clin. Pharmacol. 88, 4607–4622 (2022).
Yu, Y. et al. A population pharmacokinetic model based on HPTN 077 of long‐acting injectable cabotegravir for HIV PrEP. Br. J. Clin. Pharmacol. 88, 4623–4632 (2022).
Margolis, D.A. et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral‐naive adults with HIV‐1 infection (LATTE): a randomised, phase 2b, dose‐ranging trial. Lancet Infect. Dis. 15, 1145–1155 (2015).
Landovitz, R.J. et al. Tail‐phase safety, tolerability, and pharmacokinetics of long‐acting injectable cabotegravir in HIV‐uninfected adults: a secondary analysis of the HPTN 077 trial. Lancet HIV 7, e472–e481 (2020).
Han, K., Baker, M., Margolis, D. et al. Impact of UGT induction by rifampin and Rifabutin on Cabotegravir long‐acting pharmacokinetics for HIV pre‐exposure prophylaxis (PrEP) using population pharmacokinetic modeling and simulation. HIVR4P 27–28 January & 3–4 February (2021).
Orkin, C. et al. Initiation of long‐acting cabotegravir plus rilpivirine as direct‐to‐injection or with an oral lead‐in in adults with HIV‐1 infection: week 124 results of the open‐label phase 3 FLAIR study. Lancet HIV 8, e668–e678 (2021).
Thoueille, P., et al. Real‐world trough concentrations and effectiveness of long‐acting cabotegravir and rilpivirine: a multicenter prospective observational study in Switzerland. Lancet Regional Health Europe 36, 100793 (2023). https://doi.org/10.1016/j.lanepe.2023.100793
Thoueille, P. et al. Guidance for the interpretation of long‐acting cabotegravir and rilpivirine concentrations based on real‐world Therapeutic Drug Monitoring data and documented failures. Open Forum Infect. Dis. 11, ofae023 (2024). https://doi.org/10.1093/ofid/ofae023
Scherrer, A.U. et al. Cohort profile update: the Swiss HIV cohort study (SHCS). Int. J. Epidemiol. 51, 33–34j (2022).
Courlet, P. et al. Development and validation of a multiplex UHPLC‐MS/MS assay with stable isotopic internal standards for the monitoring of the plasma concentrations of the antiretroviral drugs bictegravir, cabotegravir, doravirine, and rilpivirine in people living with HIV. J Mass Spectrometry 55, e4506 (2020).
Cabotegravir (Oral) PK Fact Sheet. University of Liverpool. Produced February (2021).
Cabotegravir (IM) PK Fact Sheet. University of Liverpool. Produced February (2021).
Overton, E.T. et al. Long‐acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV‐1 infection: 152‐week results from ATLAS‐2M, a randomized, open‐label, phase 3b, noninferiority study. Clin. Infect. Dis. 76, 1646–1654 (2023).
Ahn, J.E., Karlsson, M.O., Dunne, A. & Ludden, T.M. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J. Pharmacokinet. Pharmacodyn. 35, 401–421 (2008).
Levey, A.S. et al. A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 150, 604–612 (2009).
Child, C.G. & Turcotte, J.G. Surgery and portal hypertension. Major Probl. Clin. Surg. 1, 1–85 (1964).
Bettonte, S., Berton, M., Stader, F., Battegay, M. & Marzolini, C. Management of drug‐drug interactions between long‐acting cabotegravir and rilpivirine and comedications with inducing properties: a modelling study. Clin. Infect. Dis. 76, 1225–1236 (2022).
Lindbom, L., Pihlgren, P. & Jonsson, E.N. PsN‐toolkit – a collection of computer intensive statistical methods for non‐linear mixed effect modeling using NONMEM. Comput. Methods Prog. Biomed. 79, 241–257 (2005).
Bergstrand, M., Hooker, A.C., Wallin, J.E. & Karlsson, M.O. Prediction‐corrected visual predictive checks for diagnosing nonlinear mixed‐effects models. AAPS J. 13, 143–151 (2011).
Jonsson, E.N. & Karlsson, M.O. Xpose – an S‐PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput. Methods Prog. Biomed. 58, 51–64 (1999).
Sheiner, L.B. & Beal, S.L. Some suggestions for measuring predictive performance. J. Pharmacokinet. Biopharm. 9, 503–512 (1981).
Savic, R.M. & Karlsson, M.O. Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J. 11, 558–569 (2009).
Jucker, B.M. et al. Multiparametric magnetic resonance imaging to characterize cabotegravir long‐acting formulation depot kinetics in healthy adult volunteers. Br. J. Clin. Pharmacol. 88, 1655–1666 (2021).
Glenmark, B., Nilsson, M., Gao, H., Gustafsson, J.‐Å., Dahlman‐Wright, K. & Westerblad, H. Difference in skeletal muscle function in males vs. females: role of estrogen receptor‐β. Am J Physiol‐Endocrinol Metabol 287, E1125–E1131 (2004).
Cutrell, A.G. et al. Exploring predictors of HIV‐1 virologic failure to long‐acting cabotegravir and rilpivirine: a multivariable analysis. AIDS 35, 1333–1342 (2021).
Orkin, C. et al. Expanded multivariable models to assist patient selection for long‐acting Cabotegravir + Rilpivirine treatment: clinical utility of a combination of patient, drug concentration, and viral factors associated with Virologic failure. Clin. Infect. Dis. 77, 1423–1431 (2023).
Elliot, E. et al. Efficacy, safety, and pharmacokinetics by BMI category in phase 3/3b cabotegravir + rilpivirine long‐acting trials. J. Infect. Dis. (2023). https://doi.org/10.1093/infdis/jiad580
Bettonte, S., Berton, M., Stader, F., Battegay, M. & Marzolini, C. Effect of obesity on the exposure of long‐acting cabotegravir and rilpivirine: a modelling study. Clin. Infect. Dis. (2024). https://doi.org/10.1093/cid/ciae060
Marzinke, M.A. et al. Cabotegravir pharmacology in the background of delayed injections in HPTN 084. Oral Abstract Session‐08. Conference on Retroviruses and Opportunistic Infections (CROI), February 19–22‐ Seattle, WA, USA (2023).
Hazra, A., Landovitz, R.J., Marzinke, M.A., Quinby, C. & Creticos, C. Breakthrough HIV‐1 infection in setting of cabotegravir for HIV pre‐exposure prophylaxis. AIDS 37, 1711–1714 (2023).
Han, K. et al. Pharmacokinetics and tolerability of cabotegravir and rilpivirine long‐acting intramuscular injections to the vastus lateralis (lateral thigh) muscles of healthy adult participants. Antimicrob. Agents Chemother. 68, e0078123 (2024). https://doi.org/10.1128/aac.00781‐23
Felizarta, F. et al. Thigh injections of Cabotegravir + Rilpivirine in virally suppressed adults with HIV‐1. Conference on Retroviruses and Opportunistic Infections (CROI), February 19–22‐Seattle, WA, USA (2023).
Ullah Nayan, M. et al. Advances in long‐acting slow effective release antiretroviral therapies for treatment and prevention of HIV infection. Adv. Drug Deliv. Rev. 115009, 115009 (2023).
Young, I.C. et al. Dose‐ranging plasma and genital tissue pharmacokinetics and biodegradation of ultra‐long‐acting Cabotegravir in situ forming implant. Pharmaceutics 15, 1487 (2023). https://doi.org/10.3390/pharmaceutics15051487
