The most promising candidate drugs and formulations IPM selects for further development during the prioritization process undergo rigorous preclinical studies to establish their key attributes and safety profile.
If results of that research, which can take several years, are favorable, a compound may be advanced through a series of clinical trials in human volunteers.
Preclinical Activities at IPM
Preclinical work at IPM falls into two main categories:
- Research: Conducting laboratory studies including developing models to address gaps and advance microbicide-related science.
- Development: Establishing strategies and conducting studies to select the most promising microbicide candidates to progress into clinical trials and, ultimately, to facilitate licensure of and access to products.
IPM’s Research Activities:
- in vitro and in vivo models of safety and efficacy
- imaging techniques for tracking drug distribution
- pharmacokinetic/pharmacodynamic relationship models
This work is conducted in partnership with academic institutions and external research organizations.
IPM’s Preclinical Development:
- virology studies
- pharmacology studies
- pharmacokinetic studies
- toxicology studies
IPM’s preclinical development of a microbicide candidate involves a complex series of tests to determine the virological, pharmacological, pharmacokinetic and toxicological properties of the compound.
These studies are conducted at academic institutions and contract research organizations.
Virology studies: These include a variety of in vitro assays, or test-tube experiments, to evaluate the activity of the compound:
- against lab-adapted strains of HIV-1
- against cell-free and cell-associated HIV-1 isolates
- against HIV-1 in primary cells
- against primary HIV-1 strains across clades (groups of related HIV-1 strains)
- in relevant physiological fluids, such as semen, and fluids from the cervix and vagina and across pH levels
- against HIV-1 uptake by dendritic cells
- against drug-resistant HIV-1 strains
Tests are also conducted to evaluate the potential for HIV to develop drug-resistant mutations in the presence of the compound, which may potentially reduce the effectiveness of the microbicide in individuals exposed to virus with those mutations.
Another test, developed by researchers outside IPM, is an ex vivo model in which cervical tissue collected from women undergoing routine surgical procedures is exposed to a microbicide and then to HIV in order to evaluate whether the microbicide will protect the tissue from infection with HIV.
Pharmacology studies: A battery of safety pharmacology studies are performed on candidate microbicides to evaluate possible adverse effects on the central and autonomic nervous systems, cardiovascular system and gastrointestinal tract.
Additional studies are also conducted to assess the effect of microbicides on normal vaginal bacteria and sperm.
Pharmacokinetic investigations: These are performed to establish that a drug gets to the tissues and cells where it needs to be in order to be effective. The studies of absorption, distribution, metabolism and excretion, commonly known as ADME, for microbicides may be less extensive than for other drugs because vaginal delivery is associated with less systemic exposure than oral therapy.
They also establish whether the animal models used in toxicity studies metabolize a drug in a way similar to what would be expected in humans.
Toxicology studies: These are performed to evaluate the potential adverse effects of a microbicide, including:
- single-dose toxicity
- repeat-dose toxicity
- genotoxicity (potential to damage cellular DNA)
- reproductive toxicity (adverse effects on fertility and reproductive function, embryofetal development and prenatal and postnatal development)
- carcinogenicity (potential to cause cancer)
- other toxicities, such as sensitization, vaginal irritation and other endpoints (or outcomes) related to a specific microbicide candidate
These studies are important in evaluating potential adverse effects of microbicides in organs and tissues. IPM’s toxicology studies are performed in a variety of species, as dictated by the principles of good laboratory practice (GLP) and international regulatory guidelines.
For a list of abstracts and scientific publications related to IPM’s preclinical research, visit our Publications & Media page.