May 31, 2022
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
- 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.
- 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.
- 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.
- 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.
- 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!