Helloooo GFPs! Thank you for all your lovely messages following last week's newsletter, as always, they are so appreciated. I'm so lucky to have you lovely lot as readers. Like, I'm biased, but I'm pretty sure you're the best newsletter subscriber list in the whole d*mn world 🥰Anyway, I'm rewarding you with a newsletter that will infuriate you, YOU'RE WELCOME xoxoxoOh, just one thing before we dive in! I have been trying, without success, to find the journal that announced a couple of years ago -- I think it might have been about a year after IW was published -- that it was going to require all submissions to have sex disaggregated data. It wasn't one of the huge hitters like the Lancet or BMJ or Nature or anything like that, it was a specific speciality journal.Does ANYONE remember what this journal was? Please help! 😍
[caption align="alignnone" width="980"]
[/caption]
Gender data gap of the week
Following on from last week's exposé of the major sex difference in adverse reactions to various kinds of cancer treatments, this week we're broadening our scope a bit, thanks to an analysis by Irving Zucker and Brian J. Prendergast. Why am I writing out their full names? Because, GFPs, Irving Zucker and I have history -- not that he knows it, and that is my tragedy 😭
Nevertheless, we do, and the truth is that had I not read Zucker's 2011 paper on the failure to include female animals in research Invisible Women might never have existed. Here's abstract for that paper:
[caption align="alignnone" width="980"]
ENDLESS SCREAMING[/caption]
Over a decade on, his recommendations have not been systematically adopted -- but they did make a woman living in North London extremely cross. Cross enough to end up writing a whole book, in fact.
Anyway, the result is that when a Zucker paper crosses my desktop, I pay attention. And this latest one I've come across does not disappoint. I mean, Zucker does not disappoint. The findings however...well, let's have a look at them shall we?
The paper looks at the sex differences in pharmacokinetics (basically, the time a drug takes to be metabolised and excreted by the body) and the relation of these sex differences to the fact that women have "a nearly 2-fold greater risk than men for exhibiting ADRs [adverse drug reactions] across all drug classes and are significantly more likely to be hospitalized secondary to an ADR."
The question Zucker sets out to answer is: are sex differences in pharmacokinetics (PKs) and sex differences in ADRs connected, and if so should we therefore abandon our one-dose-fits-men approach to prescribing?
Naturally, our ability to answer this question is impeded by a data gap.
The existing knowledge base for sex-aware prescribing lacks information on sex differences for one-third of all drugs [9, 10]. Pharmaceutical companies responsible for generating pre-approval data often fail to include information on sex differences in NDA documents, and the FDA has previously failed to enforce its own requirements before approving new drugs [11]. Consequently, potential sex differences in PK [pharmacokinetic] measures and their relation to unwanted side effects often remain unknown. Most of the data submitted to the FDA by drug companies are not publicly available and not subject to peer-review by the broader scientific community [9].
This is, of course, fine.
[caption align="alignnone" width="980"]
I don't know how this picture got here[/caption]
Still, from the drugs that do have publicly available PK data, we know enough to know that we have a problem: in this analysis, 86 drugs were identified that have "substantial" PK sex differences, and the correspondence of these sex differences with sex differences in ADRs, was "striking".
among patients administered a standard drug dose, females are exposed to higher blood drug concentrations and longer drug elimination times than males. This likely contributes to the near doubling of adverse drug reactions in female patients, raising the possibility that women are routinely overmedicated.
I like to imagine the authors pausing at this point, peering over the top of their glasses, and then delivering this following line:
Whether this relation also holds for the thousands of drugs for which sex-stratified PK data are not publicly available remains to be investigated.
[caption align="alignnone" width="980"]
[/caption]
This paper does not set out to prove why women tend to experience higher PKs than men, although it does suggest some ideas most of which will be familiar to readers of Invisible Women (sex differences in metabolic enzymes, glomerular filtration rates, gastric emptying time, gastric pH, plasma volume, average organ blood flow, total body water and, of course, body size).
That said, Zucker et al. do spend some time specifically dealing with the seemingly obvious explanation for all this, which is that that men are simply bigger than women, so naturally a dose set for an average male body will be too high for an average female body DUH:
Some have argued that what we ascribe to sex differences in the genesis of ADRs is causally related to differences in body weight. In reference to the sex difference in ADRs among patients taking zolpidem, Richardson et al. [57] stated “body weight, not sex, is the culprit.” They contend that body weight eliminates the statistical significance of sex as a variable in clearance of zolpidem, referencing a study by Greenblatt et al. [58]. However, the cited paper makes no such claim, instead stating that “AUC averaged 40% to 50% higher in females than in males receiving the same dose, and the sex effect was incompletely explained by body weight”. In a more recent review, Greenblatt et al. [59] note that women had on average 35% lower apparent clearance of zolpidem than men and that this difference was not explained by body weight. They conclude instead that the pharmacodynamic effects of zolpidem are greater in women due to a combination of higher plasma concentrations and greater intrinsic sensitivity [58]. The present analysis indicates that many sex differences in ADRs persist after corrections for body weight are made.
In conclusion, they write, "the sex disparity in ADRs does not merely reflect body mass masquerading as an effect of sex," and so while administering drugs on a milligram/kilogram basis might be an improvement on the current default male dosing regimen, it wouldn't fix the overall problem.
There's something in their tone here that makes me suspect that the authors have got a bit bored of having to go over this ground. Or maybe it's just that I personally am bored of having this debate. I find it both bizarre and disheartening that some people -- and we're often talking smart people here -- remain invested, in the face of all the evidence, in insisting that all sex differences can be boiled down to men being on average bigger than women. Or maybe it's not so bizarre since if all that we need to do is adjust the default male research by size and weight, nothing much needs to change and we can carry on merrily default male-ing to our heart's content. After all, scaling down the default male dummy has worked so well for car safety hasn't it...
Still, I suppose we should look on the bright side: at least these people are not pretending there are no differences at all and that we should continue to give women the "standard" for which read default male dose.
The same cannot be said for the FDA:
One survey of clinical pharmacology data for 300 new drug applications (NDAs) evaluated by the FDA between 1994 and 2000 [10] indicated that 31% of studies showed a possible sex effect based on pharmacokinetic (PK) sex differences greater than 20%. In the same report, 11 drugs showed a > 40% difference between males and females in PK measures, yet no dosing recommendations to consider sex were issued, implicitly based on the unsubstantiated grounds that these differences were not clinically relevant.
*looks over glasses at the FDA*
This, Zucker et al. point out, is daft:
In many cases, [sex-based dosing recommendations] can be implemented at little cost. As demonstrated below, the data required to implement these procedures already exist for a number of drugs but have been ignored.
The paper closes with some excellent recommendations including that the FDA should publish the data it has on PKs, so that we can do the same analysis for the thousands of drugs for which PK data is not currently publicly available.
[caption align="alignnone" width="980"]
[/caption]
Similarly, the FDA "should require all empirical [new drug application] data to be accompanied by documentation of statistical analyses which should meet requirements for publication in a peer-reviewed journal. Experiments reported in NDAs are less likely to be subjected to replication attempts by the scientific community, and therefore methodological or interpretive errors are less likely to be rapidly corrected by the iterative scientific process." I mean, I can't quite believe this doesn't already happen and I had thought myself pretty unshockable at this point.
They also recommend that pharma companies should be thinking about sex from the *beginning* of the process as opposed to an add-on at the end.
If, during the early stages of pre-clinical development, a compound is titrated or optimized specifically in male cells or in male mice, then any sex biases inherent in such models may be passed forward into later stages of drug development. The disproportionate expression of increased PKs and ADRs in women may be one result of this continued neglect.
To all of which I can only say
[caption align="alignnone" width="980"]
[/caption]
srsly tho if I never hear another researcher tell me that if they find anything interesting in males they'll add females at a later date IT WILL BE FAR TOO SOON.
I am also a massive fan of the recommendations that "credible evidence of sex differences in PKs should be made available in drug labels" and on "popular websites directed at the public either by drug companies, or by sites such as WebMDm," and that "an appropriate understanding of the clinical relevance of sex-differences in drug treatment should be part of the board certification process for healthcare providers and reinforced in continuing medical education courses."
These are all excellent recommendations that should be implemented across the board immediately
Naturally therefore,
[caption align="alignnone" width="980"]
[/caption] [caption align="alignnone" width="980"]
I don't know why these pictures keep appearing in this section [/caption] [caption align="alignnone" width="980"]
[/caption]
Default male of the week
Sticking with default male drugs, this week the ultimate default male drug: V**gra! [I'm asterisking that because last time I included anuything about the p3n15 in my newsletter Gmail completely freaked out and basically no one got the email]
Anyway, loyal readers may V**gra's cameo appearance in Invisible Women where it featured in a period pain study that ran out of funding and was never repeated (thanks NIH! Women feel so cherished by you 🥰). Anyway, you can therefore understand that my interest was piqued when I saw this headline:
I take V**gra every day – I’m proof that women need it too | The Independent — www.independent.co.uk
V**gra – and alternatives like T*****fil – have wider applications than just treating ***c**le dysfunction and are used by women too
Wider applications, you say...
This woman was, however, not using v**gra to treat her period pain (please do not try this at home, ladies, it has not been through full clinical trials), but instead to treat high blood pressure in her lungs. She has been taking it for six years. And throughout those six years she has been confronted with this message on the information leaflet included with her prescription medication:
Tadalafil is not intended for use by women.
Very reassuring.
If you are enjoying this newsletter, consider becoming a member! Members get access to member-only events, a members-only area, plus the warm glow that comes from supporting the work that goes into producing this weekly blast 😍
Product of the week
On and off over the years, GFPs have been telling me to look into Lucy and Yak and this week I finally got round it, tipped over the edge by GFP Izzy who wrote the following:
I wanted to point out lucy and yak! I bought some of their Dana Jean's and holy hell the pockets are massive. I can fit a 500ml metal water bottle in them. I mean I wouldn't carry it in there as it wasnt very comfortable but when i wear the Jean's I can now go bag less!
GFP Izzy clearly knows the way to my heart.
Anyway, off I trotted to their website to read all about them and, ok, I was impressed. The pockets, they are indeed bounteous and bountiful. I didn't actually find bottoms that *didn't* have pockets, which is always a pretty good sign that I am among GFPs.
They also seem like a company that is trying very hard to do the right thing when it comes to their employees and the environment, and despite this don't charge a fortune, which is refreshing.
Anyway, I'm not currently in the market for a new pair of jeans or dungarees, so other GFPs will have to do the honours there and let the rest of us know how that goes, but I spotted these completely mad trousers on sale and decided to buy a pair for reasons that are currently unclear to me.
I will report back!
Poppy pic of the week
[caption align="alignnone" width="980"]
these are MINE, ALL MINE! [/caption]
That's it! Until next time, my dear GFPs...xoxoxo