Microbicide Safety

The development of topical microbicides represents a new and exciting field in the prevention of sexually transmitted diseases, and it is especially important that candidate products undergo rigorous preclinical safety and efficacy testing before advancing to clinical trials.


The physico-chemical and biological properties of active pharmaceutical ingredients (APIs) and their formulations are the foundation of safe, efficacious and acceptable microbicides. Hence, the initial selection of the API and its primary formulation is crucial. Certain undesirable properties of an API can be compensated or masked by an appropriate formulation. However, there is a risk in proceeding with inadequate APIs or formulations, as they may fail later in development, costing more time and money. 

It is important to have a set of criteria that inform Go/No Go decisions prior to entering in clinical trials. This set of criteria is based on API and formulation parameters derived from a comprehensive evaluation of their in vitro P/C properties, drug release rates, specific activity, and cell and tissue toxicity, which in turn represent the base for animal studies focused on organ toxicity/safety, pharmacokinetics (PK), and pharmacodynamics (PD) and efficacy.

A solid preclinical foundation will help navigate clinical testing successfully, ultimately leading to a safe and effective microbicide. In addition to the more classical IND-enabling studies, new models, assays and biomarkers have been developed and adapted to the evaluation of genital and rectal microbicides.

Experience with previous microbicide candidates has led to the inclusion of assays evaluating the impact of genital environmental factors such as low pH, seminal plasma, CV secretions and microflora on microbicide safety and efficacy. Microbicide-induced inflammatory mediators and alteration of innate immunity have also been recently incorporated to the standard testing.

Given the need of antiretroviral compounds, in particular reverse transcriptase inhibitors, to enter target tissues and cells and, in some cases be activated inside them, PK/PD evaluations are now essential components of preclinical and early clinical microbicide evaluation.

Testing safety and acceptability
Although initial trials of safety and acceptability focus on women, they must also include evaluation of male partners. Acceptable, practical, and standardised methods are needed for assessing toxicity to the vaginal mucosa by the naked eye and colposcopy, such as those proposed by the International Working Group on Microbicides. Risks to participants in trials must be minimised by protection from pregnancy and screening to exclude sexually transmitted infections and HIV.

Microbicides are likely to be most effective at population level if they both protect uninfected women against HIV infection and reduce the infectiousness of women already infected. Trials therefore also need to check safety of microbicides in infected women; they could also study effects on levels of HIV RNA in vaginal swabs as a proxy for infectiousness. Because epidemiological and cultural conditions vary so greatly, studies of safety and acceptability are needed in all likely target populations. Other factors that need to be assessed before an efficacy trial are the distribution and retention of microbicide in the vagina.