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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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