Pharmacokinetic and Pharmacodynamic Evaluation following Vaginal Application of IQB3002, a Dual-Chamber Microbicide Gel Containing the Nonnucleoside Reverse Transcriptase Inhibitor IQP-0528 in Rhesus Macaques

Lara E. Pereira, Pedro M M Mesquita, Anthony Ham, Tyana Singletary, Frank Deyounks, Amy Martin, Janet McNicholl, Karen W. Buckheit, Robert W. Buckheit, James M. Smith

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

We evaluated the in vivo pharmacokinetics and used a complementary ex vivo coculture assay to determine the pharmacodynamics of IQB3002 gel containing 1% IQP-0528, a nonnucleoside reverse transcriptase inhibitor (NNRTI), in rhesus macaques (RM). The gel (1.5 ml) was applied vaginally to 6 simian-human immunodeficiency (SHIV)-positive female RM. Blood, vaginal fluids, and rectal fluids were collected at 0, 1, 2, and 4 h. RM were euthanized at 4 h, and vaginal, cervical, rectal, and regional lymph node tissues were harvested. Anti-human immunodeficiency virus (HIV) activity was evaluated ex vivo by coculturing fresh or frozen vaginal tissues with activated human peripheral blood mononuclear cells (PBMCs) and measuring the p24 levels for 10 days after an HIV-1Ba-L challenge. The median levels of IQP-0528, determined using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methods, were between 104 and 105 ng/g in vaginal and cervical tissue, between 103 and 104 ng/g in rectal tissues, and between 105 and 107 ng/ml in vaginal fluids over the 4-h period. The vaginal tissues protected the cocultured PBMCs from HIV-1 infection ex vivo, with a viral inhibition range of 81 to 100% in fresh and frozen tissues that were proximal, medial, and distal relative to the cervix. No viral inhibition was detected in untreated baseline tissues. Collectively, the median drug levels observed were 5 to 7 logs higher than the in vitro 50% effective concentration (EC50) range (0.21 ng/ml to 1.29 ng/ml), suggesting that 1.5 ml of the gel delivers IQP-0528 throughout the RM vaginal compartment at levels that are highly inhibitory to HIV-1. Importantly, antiviral activity was observed in both fresh and frozen vaginal tissues, broadening the scope of the ex vivo coculture model for future NNRTI efficacy studies.

Original languageEnglish (US)
Pages (from-to)1393-1400
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number3
DOIs
StatePublished - Mar 1 2016

Fingerprint

Reverse Transcriptase Inhibitors
Anti-Infective Agents
Macaca mulatta
Pharmacokinetics
Gels
Coculture Techniques
HIV-1
Blood Cells
HIV
IQP-0528
Virus Diseases
Cervix Uteri
Liquid Chromatography
Antiviral Agents
Mass Spectrometry
Lymph Nodes

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Pharmacokinetic and Pharmacodynamic Evaluation following Vaginal Application of IQB3002, a Dual-Chamber Microbicide Gel Containing the Nonnucleoside Reverse Transcriptase Inhibitor IQP-0528 in Rhesus Macaques. / Pereira, Lara E.; Mesquita, Pedro M M; Ham, Anthony; Singletary, Tyana; Deyounks, Frank; Martin, Amy; McNicholl, Janet; Buckheit, Karen W.; Buckheit, Robert W.; Smith, James M.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 3, 01.03.2016, p. 1393-1400.

Research output: Contribution to journalArticle

Pereira, Lara E. ; Mesquita, Pedro M M ; Ham, Anthony ; Singletary, Tyana ; Deyounks, Frank ; Martin, Amy ; McNicholl, Janet ; Buckheit, Karen W. ; Buckheit, Robert W. ; Smith, James M. / Pharmacokinetic and Pharmacodynamic Evaluation following Vaginal Application of IQB3002, a Dual-Chamber Microbicide Gel Containing the Nonnucleoside Reverse Transcriptase Inhibitor IQP-0528 in Rhesus Macaques. In: Antimicrobial Agents and Chemotherapy. 2016 ; Vol. 60, No. 3. pp. 1393-1400.
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abstract = "We evaluated the in vivo pharmacokinetics and used a complementary ex vivo coculture assay to determine the pharmacodynamics of IQB3002 gel containing 1{\%} IQP-0528, a nonnucleoside reverse transcriptase inhibitor (NNRTI), in rhesus macaques (RM). The gel (1.5 ml) was applied vaginally to 6 simian-human immunodeficiency (SHIV)-positive female RM. Blood, vaginal fluids, and rectal fluids were collected at 0, 1, 2, and 4 h. RM were euthanized at 4 h, and vaginal, cervical, rectal, and regional lymph node tissues were harvested. Anti-human immunodeficiency virus (HIV) activity was evaluated ex vivo by coculturing fresh or frozen vaginal tissues with activated human peripheral blood mononuclear cells (PBMCs) and measuring the p24 levels for 10 days after an HIV-1Ba-L challenge. The median levels of IQP-0528, determined using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methods, were between 104 and 105 ng/g in vaginal and cervical tissue, between 103 and 104 ng/g in rectal tissues, and between 105 and 107 ng/ml in vaginal fluids over the 4-h period. The vaginal tissues protected the cocultured PBMCs from HIV-1 infection ex vivo, with a viral inhibition range of 81 to 100{\%} in fresh and frozen tissues that were proximal, medial, and distal relative to the cervix. No viral inhibition was detected in untreated baseline tissues. Collectively, the median drug levels observed were 5 to 7 logs higher than the in vitro 50{\%} effective concentration (EC50) range (0.21 ng/ml to 1.29 ng/ml), suggesting that 1.5 ml of the gel delivers IQP-0528 throughout the RM vaginal compartment at levels that are highly inhibitory to HIV-1. Importantly, antiviral activity was observed in both fresh and frozen vaginal tissues, broadening the scope of the ex vivo coculture model for future NNRTI efficacy studies.",
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