Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults

Scott L. Letendre, Anthony Mills, Debbie Hagins, Susan Swindells, Franco Felizarta, Jerome Devente, Christopher Bettacchi, Yu Lou, Susan Ford, Kenneth Sutton, Jafar Sadik Shaik, Herta Crauwels, Ronald D'Amico, Parul Patel

Research output: Contribution to journalArticle

Abstract

Background: Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression. Objectives: To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352). Methods: Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays. Results: Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF. Conclusions: A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.

Original languageEnglish (US)
Pages (from-to)648-655
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume75
Issue number3
DOIs
StatePublished - Mar 1 2020

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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  • Cite this

    Letendre, S. L., Mills, A., Hagins, D., Swindells, S., Felizarta, F., Devente, J., Bettacchi, C., Lou, Y., Ford, S., Sutton, K., Shaik, J. S., Crauwels, H., D'Amico, R., & Patel, P. (2020). Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults. Journal of Antimicrobial Chemotherapy, 75(3), 648-655. https://doi.org/10.1093/jac/dkz504