Why even great drugs have serious side effects in some patients

Finding good drugs is hard enough, but even great ones are often laid low by unexpected side effects.  This has to do with the tremendous genetic variation in people, about which, more later.  But first a true story from the past.

Neurologists treat epilepsy.  There was a period of 17 years when I was in practice when not a single new  drug against epilepsy (anticonvulsant) was introduced in the USA.  Each new drug would seem to be the answer for a small group of patients that nothing had helped before.

Felbamate (Felbatol) was one such anticonvulsant.  It helped people that nothing else touched. In the year after introduction some 150,000 people were taking it.   I had several very happy patients using Felbatol in the 90s.   1 year later the bomb dropped.  Ten cases of total bone marrow failure (aplastic anemia) had developed in patients taking the drug, a lethal complication.  Every neurologist (and probably every physician) got an urgent letter from the FDA.

Normally, unless there is an allergic reaction, anticonvulsants are never stopped suddenly.  They are tapered over a week or two.  Why?  Basically all anticonvulsants are sedating.  People adapt to this, and it’s like driving a car with one foot on the brake.  Remove the brake and the car shoots forward.  So neurologists all over the country brought patients into the hospital as the drug was immediately stopped.  We were quite worried that the previously uncontrolled seizures would flare.

I had one such patient.  Her family was quite worried about the possible side effects of suddenly stopping Felbamate.  I managed to control myself (hopefully) as I told them there was no side effect worse than death.  As risky as it is, there are still about 12,000 people taking the drug (after being carefully told about the risks) according to Wikipedia.  That’s how good a drug it is.

Why wasn’t this terrible complication picked up in the phase I, II, III studies of Felbamate — 10 cases in 150,000 people is 1/15,000, and no drug study for epilepsy was that large back then.  The incidence of epilepsy in adults is probably around 1%, meaning that some 1,500,000 people would have to be screened to find those 15,000.  So effectively there is no way to find such a rare complication before the drug was released.

A paper last month in Science (vol. 337 pp. 100 – 104 ’12) showed why this sort of thing is almost certain to happen again and again.

DNA sequencing is getting faster and cheaper all the time, so large numbers of people can have parts of their genomes sequenced.  A recent post https://luysii.wordpress.com/2012/07/31/how-badly-are-thy-genomes-oh-humanity/ discussed a paper that  sequenced roughly three quarters of the genes coding for proteins in some 2,439 people — e.g. 15,585 protein coding genes.

The Science paper was more circumspect.  They sequenced ‘only’ 202 genes coding for proteins in 14,002 people.  These genes were chosen quite carefully out of the 20,000 or so protein coding genes we have.  The 202 genes were known drug targets — say the neurotransmitter uptake proteins targeted by SSRIs and tricyclic antidepressants, the dopamine receptors targeted by antipsychotics.  So were the 14,002 people chosen to have their genes sequenced.  There were two ‘normal’ populations samples with 1,322 and 2,059 people each, and 12 populations chosen from people with particular diseases.  Most of these were European (12,514/14,002).

The findings essentially explain why we’ll always have rare side effects.  The total amount of DNA sequenced in each individual was 864,000 positions.  They found ‘rare’ variants (e.g. found in less than 1/200 people) quite commonly.  In fact in the group as a whole such rare variants occurred once every 21 positions in the Europeans.  The variants are the single nucleotide variants (SNVs).  Here’s a recap of just what a SNV is (for more detail see the link given above).  90% of the rare variants had never been seen before, even in these 202 proteins of great biologic and medical interest.

**** Recall that each nucleotide is one of four possibilities (A, T, G, C), and that each 3 nucleotides therefore has 4^3 = 64 possibilities.  61/64 combinations code for amino acids which, since we have only 20 gives a certain redundancy of the famed genetic code.   The other 3 combinations code for no amino acid (usually) and tell the machinery making proteins to stop.  Although crucial to our existence, these are called nonsense codons.

The genetic code is therefore 3fold degenerate (on average).  However, some amino acids are coded for by just 1 combination of 3 nucleotides while others are coded by as many as 6.  So some single nucleotide variants (SNVs) leave the amino acid coded for the same (these are the synonymous SNVs), while others change the amino acid (nonSynonymous SNVs), and possibly protein function.  *****

Certainly, not all of these variants will cause trouble, and our genomes are incredibly fault tolerant, as most of us carry very impaired genes for at least 35 of the proteins (e.g. they are truncated, so not a full protein is made).  Some almost certainly will cause unexpected reactions or side effects from a given drug.  There are so many SNVs out there.

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