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Persistence of Rilpivirine Following Single Dose of Long-Acting Injection

This study evaluates the persistence of rilpivirine (RPV) in plasma and genital tract fluids after a single dose of long-acting injection. The findings suggest that quantifiable RPV levels can be detected in plasma and female genital tract fluids for more than 18 months, highlighting the need for further characterization of the drug's extended pharmacokinetic profile to avoid potential antiretroviral resistance.

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Persistence of Rilpivirine Following Single Dose of Long-Acting Injection

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  1. Persistence of Rilpivirine Following Single Dose of Long-Acting InjectionIan McGowan MD DPhil FRCPProfessor of Medicine, University of Pittsburghfor the MWRI-01 Team

  2. Disclosure I have no financial relationships with a commercial entity producing, marketing, reselling or distributing healthcare related products and/or services.

  3. Antiretroviral Persistence • Long acting (LA) injectable antiretrovirals (ARV) are being developed for both treatment and prevention indications • The extended half-life associated with LA-ARV is poorly characterized but may increase the risk of ARV resistance in individuals who seroconvert after exposure to LA PrEP

  4. The Pharmacokinetic (PK) Tail Female participant receiving a single 1200 mg dose of rilpivirine (RPV) McGowan I et al. HIVR4P 2014

  5. Resistance after Single 300mg Dose of RPV LA Time after injection (days) Penrose K et al. JID 2016

  6. Methods

  7. MWRI-01 Study • A Phase 1 safety, acceptability, PK/PD evaluation of RPV LA (TMC278) • Single dose phase • Men and women randomized to receive 600 mg or 1200 mg of TMC278 LA • Multiple dose phase • Men and women received 1200 mg of TMC278 LA

  8. Primary Objectives • Primary objective • To evaluate the safety and acceptability of RPV LA given as an intramuscular injection • Primary endpoints • Grade 2 or higher clinical and laboratory adverse events • The proportion of participants who would consider using RPV LA for HIV prevention in the future

  9. Secondary Objectives • Secondary objectives • To determine the plasma, cervical, vaginal, and rectal tissue/secretion PK following single and multiple IM injections of RPV LA • Secondary endpoints • RPV concentrations in plasma, cervical, vaginal, and rectal tissue/secretions

  10. MWRI-01 Design 1200 mg 1A (N=12) N = 5 ♀ 600 mg 2A (N=12) 1200 mg 1200 mg 1200 mg 3A (N=8) 1200 mg 1B (N=6) N = 4 ♂ 600 mg 2A (N=6) 1200 mg 1200 mg 1200 mg 3A (N=4)

  11. PK Analysis (1) • RPV concentrations in all matrices were quantified by validated high-pressure liquid chromatography-mass spectrometry • Matrix lower limit of quantification (LLOQ) • Plasma: 0.5 ng/ml • Fluids: 0.025 ng/sample • Tissue: 0.05 ng/sample Else LJ et al. Bioanalysis. 2014

  12. PK Analysis (2) • Two blanks (extracted drug-free plasma) were included after the upper limit of quantification (400 ng/ml) and after the MQC/HQC • The % carryover after a single blank sample was <20% of the assay LLQ (0.5 ng/ml)

  13. Results

  14. Demographics • Baseline samples were available from 9 participants • 1200 mg: 5 females and 2 males • 600 mg: 2 males

  15. Persistence of RPV • RPV was detectable in 7/7 (100%) of plasma samples collected a mean of 541 days after single dose exposure to 1200 mg of RPV LA • RPV was also detected in endocervical and vaginal fluid • No RPV was found in cervical, vaginal, or rectal tissue or cervicovaginal lavage samples

  16. Baseline PK 4.1 ± 2.4 6.1 ± 4.1 13.2 ± 10.9

  17. Time from RPV LA Exposure All Samples 1200mg Samples

  18. Time from RPV LA Exposure All Samples 1200mg Samples

  19. Conclusions • Quantifiable RPV was found in plasma and female genital tract fluids > 18 months after single dose administration of RPV LA (Mean plasma level 4.1 ng/mL) • Protein-adjusted RPV EC90 is 12 ng/mL • Further characterization of LA PrEP extended PK profile will be critical to better inform management of the PK tail to avoid the potential for ARV resistance

  20. Acknowledgements • University of Pittsburgh Clinical and Stats Support • Ross Cranston • Beatrice Chen • Sharon Achilles • Ron Stall • Patty Peters • Carol Oriss • Carly Mowry • Carol Mitchell • Jonathan Baker • Stacey Edick • KaleabAbebe • Cindy Jacobson • University of Pittsburgh Lab Support • Charlene Dezzutti • Kathy Duffill • Aaron Siegel • Jarret Engstrom • Alexyi Nikorov • University of Pittsburgh Recruitment and Project Management Support • Kathy McCarthy • University of Liverpool • David Back • Saye Khoo • Laura Else • Deidre Egan • Janssen R & D • Peter Williams • Marita Stevens • Joseph Mrus • Alpha StatConsult LLC • Nicola Richardson-Harman • Bill & Melinda Gates Foundation • Lut Van Damme

  21. Funding for the MWRI-01 Study

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