Sex, Drugs, and Rats

Show Notes for Episode Twenty-Two of seX & whY: Sex, Drugs, and Rats

Host: Jeannette Wolfe
Guest: Dr Irv Zucker, Faculty at UC Berkley since 1966. Interests include behavioral endocrinology, chronobiology, and sex differences in pharmacology

General discussion

Many times, the worlds of basic science and human clinical trials do not overlap to the degree that they should. Greater coordination between the two silos, especially as it comes to the examination of sex differences, would likely produce more robust, higher quality science that would benefit a greater number of patients. 

• In a good deal of drug research, the amount of basic science research done on a particular drug prior to market release is often quite limited. As significant drug side effects may only be identified after the drug’s release, using established animal models that match up well to conditions similarly experienced in humans, may help identify potential problems earlier in the drug development pipeline. Dr Zucker believes that this is particularly important when trying to evaluate for specific behavioral side effects in the offspring of pregnant or lactating females using certain drugs (see his paper here). As these side effects in humans may take 10-15 years to be identified, leveraging the shorter natural life cycles of lab animals could help flag potentially deleterious effects years before they might otherwise be identified by traditional post-release surveillance data.
• There are two big governmental National Institute of Health policies that shifted research to become more inclusive of sex/gender.

      1993 NIH Revitalization Act. To get NIH funding for human clinical trials researchers needed to include or explain why they were not including, both men and women in clinical trials

       2016 Sex as a Biological Variable. Applied above rules to basic science lab work. Irv and his team’s work were instrumental in triggering this policy change. 

Sampling of Dr Zucker's Research

This paper surveyed prominent journals from 10 different areas of basic science research and highlighted that the consideration of the existence of sex differences was rarely considered by pre-clinical researchers. Most studies included only male animals with less than 25% including both sexes.  Some concerning numbers in specific fields were totally lop-sided. For example, in neuroscience there was a 5:1 male to female animal ratio

Follow up research  reexamined these numbers after the 2016 guideline change and showed:  

• Almost 50% included both sexes in research but…..
• 1/3 of researchers didn’t give breakdown of how many males and females they included in study. (Meaning researchers could have included 10, 50 or 70 percent of animals from one sex.)
• Some fields like pharmacology still were underrepresented (less than 30% of research included both sexes)
• When both sexes were included only about 40% broke down their outcome data by sex

Here is the paper we discussed that busted the myths surrounding female animal variability and numbers needed to study: Female mice liberated for inclusion in neuroscience and biomedical research. 

• This is a meta-analysis of almost 300 different articles examining behavioral, physiological, and molecular trials in female and male mice without regards to estrous cycle and found that female animals were no more variable and at times even less variable than males. This was doubly surprising because the dogma had been that male hormonal variability was insignificant. Interesting both males and female animals became much more variable when housed with other animals.  

Next, we talked about pharmacokinetics: Sex differences in pharmacokinetics predict adverse drug reactions in women. They evaluated 86 drugs in which they could find published information about pharmacokinetics broken down by biological sex (for example, if the drug was absorbed, distributed, metabolized and excreted similarly or differently in male and female bodies) and then compared these findings with a data base that evaluated for adverse side effects. 

• Of 86 drugs with available information (of note in the vast majority of currently used medications this information is NOT readily available) they found 76 of drugs had greater levels in women with an 88% correlation of higher levels being associated with adverse drug reactions in women

Bottom line - when giving a drug to a female start at the lowest dose possible and review other scripts they are taking to avoid potential drug/drug cross-reaction.

Also here is the amazing story of Dr Frances Kelsey who stood tall against the tremendous pressure by the manufacturers of  thalidomide to approve the drug in the United States. Her request to not approve the drug without additional data ultimately saved the lives and physical disabilities of countless babies. 

Take home points from podcast

1. Historically the vast amount of basic science research was done only on male animals thereby potentially missing important findings that may be unique to a specific sex.
2. The inclusion of female animals in and by themselves do not produce greatly variability in basic science research results. In fact,  in many cases, using male animals may produce significant variability suggesting that male hormones may not be as consistent as once believed. The bottom line is, it depends on what you are studying and there are easy to apply scientific methods that can allow you to determine if hormonal variation may be playing a part in outcome results without using excessive amounts of animals.
3. Pharmacokinetics of how a drug is absorbed, distributed, metabolized and excreted are often influenced by biological sex, yet very few drugs that are currently on the market have adequate and accessible data on pharmacokinetics broken down by biological sex.
4. Drugs that have greater concentrations in a female body correlate to the chance of an increased likelihood of an adverse reaction. If you prescribe medications, it is a good rule of thumb to start at the lowest possible dose in a female and to ensure you review their med list to avoid predictably adverse cross reactions.
5. The ethics around studying drugs in pregnant and lactating females are challenging especially as many of these drugs may have side effects that will not be apparent for decades. One way to help fill this gap is to run parallel basic science studies that examine long term behavior changes in animals after drug exposure.  

Thanks for listening!