When I use a word . . . The languages of medicines—generics and bioavailability

Gnosis

One of the most prolific, possibly the most prolific, of all IndoEuropean word roots is the one that is perhaps best represented simply as GN.

In his monumental two-volume dictionary, Indogermanisches etymologisches Wörterbuch,1 in which he listed German words that are derived from Proto-IndoEuropean roots, the Austro-Czech linguist Julius Pokorny (1887–1970) listed four different basic forms of the GN root, with connotations of either knowing or begetting: ĝen-, ĝenɘ, ĝnē-, and ĝnō-. Many English words are also derived from this root. The basic connection between its two principal meanings can be seen in the mindful connection between knowing and conceiving. This is also reflected in the biblical formula, Adam knew his wife, Eve, and she conceived, a fitting quote from Chapter 4 of the book of … Genesis, of course.

Some linguists split their discussion of the GN root into two groups: GEN and GENƎ, to beget, and GNŌ, to know, and that certainly helps to navigate the many derivatives they generate.

GEN and GENƎ gave Greek and Latin words such as γένος, race or offspring, and genus, race or kind. These in turn gave us allogeneic, androgenous, congener, degenerate, engender, gender, gene, genealogy, general, generate, generation, generous, genocide, genotype, genre, genuine, genus, heterogeneous, homogeneous and homogenous (don’t confuse them2), homogenise, indigenous, ingenious, ingenuous, miscegenation, regenerate, and syngeneic. Not forgetting genesis and all of its many derivatives, from abiogenesis and angiogenesis, via embryogenesis and epigenesis, metagenesis and mutagenesis, organogenesis and osteogenesis, to tumorigenesis and xenogenesis. And, of course, all the adjectival derivatives ending in –genetic.

The Latin noun ingenium, natural talent, gives us engine and engineer, genius and ingenious.

The lectum genialis was the nuptial bed, a place to be companionable, giving us genial and congenial.

From the Latin noun gens, a race, we get gendarme, genteel, gentile, gentle, gentry, and jaunty.

The idea of chemical begetting gives us words with –gen as a suffix, such as halogen, hydrogen, nitrogen, and oxygen, androgen, carcinogen, hallucinogen, oestrogen, mitogen, mutagen, oncogen, pepsinogen, and progestogen.

Then there are o-grade forms, GON and GONƎ, which give us words such as archegonium, carpogonium, epigone, and gonad. The Sanskrit loan word yoni also comes from GON. From Greek variants of γένος—γόνος and γονή, offspring, race, generation, or seed—we get a swathe of words beginning gono-: gonoblast, gonoblastidium, gonocalyx, gonocheme, gonochorism, gonococcus, gonocyte, gonoduct, gonomere, gonophore, gonoplasm, gonopore, gonorrhoea, gonosome, gonosphere, gonotheca, gonotocont, gonotome, and gonozooid.

GN, the zero-grade form of the root, when suffixed, gave the Latin verb impregnare, from which we get pregnant and impregnate, and the adjectives benignus and malignus, giving us benign and malign. In Germanic languages GN became KN, giving the German word for a child, Kind, and the English loan words kindergarten and wunderkind.

Reduplication gave the Latin verb gignere, to beget, yielding congenital, genital, genitive, genitor, geniture, gent, genteel, primogenitor, primogeniture, progenitor, and progeny.

From the GN/GNŌ branch, to know, came the Greek noun γνώμη, thought, judgment, or opinion, and so a gnome is a wise saying and a gnomon on a sundial gives you knowledge of the time of day. Physiognomy is the study of facial features, taken to reflect what is in one’s mind. As Lady Macbeth says to her husband, “Your face, my thane, is as a book, where men may read strange matters.”

From the Greek reduplicated verb γιγνώσκειν, to know, we get know, knowledge, and acknowledge, cognition and cognisance, ignore and ignorant, incognito and recognise, and, less obviously, can and canny, con and cunning, reconnaissance and reconnoitre.

And gnosis gives us diagnosis and prognosis.

Generic

So, “generic” comes from GEN, via the Latin noun genus, a class or type, by addition of the adjectival suffix –ic to the derivatising root gener–. As an adjective, “generic” is defined in the Oxford English Dictionary (OED) as “Characteristic of or relating to a class or type of objects, phenomena, etc.; applicable to a large group or class, or any member of it; not specific, general. Also: characteristic of or relating to the use of language, as generic name, term, word, etc.”3 The earliest citation, from 1658, refers to a generic body, and the first instance of which I am aware in which “generic” is used to refer to the name of something is from only a few years later, in 1665, in a book review in which the anonymous reviewer of Christopher Merret's Pinax (i.e. Pharmacopoeia4) writes that “... as to Vegetables, he reckons up about 410 sorts; and gives their Latine [sic] and English Names, and the Places and Times of their growth: reducing them afterwards to certain Classes, hitherto used by Botanick Writers in their Histories of Plants: Adding the Etymology of their Generick Names, and a compendious Register of the Time, when and how long the English Plants do shoot and flourish.”5

However, it was not until 1949 that the adjective “generic” was used in a modern sense to describe pharmaceutical products, defined in the OED as, “Of the name of a drug: specially given in order that it may be freely used without legal restriction (e.g. in pharmacopoeias), in contrast to a brand name assigned by a particular manufacturer.” Here is the earliest recorded example, from JAMA6: “In general, the Council does not recognize names that suggest therapeutic use and prefers names, both protected and common or generic, that indicate the potent element or constituent of the product. The Council's Committee on Nomenclature, which is charged with preliminary consideration of names, works in close collaboration with other groups, scientific and governmental, interested in rational drug terminology. Fundamental, of course, is the provision of a single ‘generic’ name for each drug.” The inverted commas show how new the usage was.

Furthermore, the council required that generic names should appear on the labels of accepted formulations marketed under trademarked names, and that the generic name should be given “at least half the display value of the protected name.” This is reminiscent of the rules about British Approved Names that the UK’s Pharmacopoeia Commission had laid down in 1944.7

It took longer still before the adjective turned into a noun, meaning a generic drug or product. And again the earliest instance is American, from a headline in the Science News Letter in 1967: “Senate backing of low cost generics could cut retail prices and open new competition between drugs.” A little later the compound adjective “no-name” was introduced as a synonym for “generic” although it has rarely if ever been used to describe generic medicines.

Generics versus branded products

The phenomenon of bioavailability, better called “systemic availability,” lies at the root of difficulties with the use of generic formulations. When a medicinal product is given parenterally, the medicine in the formulation has to find its way past several barriers before it can reach the systemic circulation and then the pharmacological target on which it is intended to act. For example, after peroral administration a drug has to escape inactivation by gastric acid and enzymes in the lumen of the gut, it has to be absorbed across the gastrointestinal mucosa, and to escape metabolism by oxidative enzymes in the wall of the gut and excretion by transporters. Then it has to escape metabolism in the liver before it can finally reach the bloodstream. The extent to which it escapes elimination by any of these mechanisms is called its bioavailability, expressed as a fraction or percentage of the administered dose.

In the 1970s problems were reported with some drug formulations. For example, the bioavailability of digoxin changed when it was marketed in a new formulation,8 as was that of phenytoin in a similar case.9 Since each of these was a medicine with a low therapeutic index, i.e. one for which small changes in dose can causes large changes in effects, cases of undertreatment and toxicity were reported.

The problem with varying bioavailability was associated with the in vivo dissolution rate of the formulation, which could be tested in vitro. Dissolution tests had been included in the US Pharmacopeia since the 1960s, and in vitro dissolution rate testing was soon introduced elsewhere for all new formulations.

It was not surprising therefore that a similar problem arose with modified-release formulations, prepared so that the medicine they contained could be released very slowly, so that they looked as if they were being given by slow intravenous administration. However, different formulations of the same medicines could yield different rates of release.101112 I recall being consulted on the case of a woman who was being given oral lithium in a modified-release formulation, under supervision in a hospital ward, but in whom no lithium could be detected in the blood. Her physicians were surprised when I suggested changing the formulation to one that they were not accustomed to using, but very soon the difference became apparent, when lithium started to appear in her blood in therapeutic concentrations.

Observations of this sort led to recommendations that for a few drugs whose bioavailability depended on the type of formulation, prescribers should specify such medicines by their brand names when writing prescriptions.

Generics companies

Generics companies started to develop rapidly in the 1970s. An excellent example is that of Teva, one of the largest pharmaceutical companies in the world and currently the largest generics company. Teva began in 1901 in Jerusalem as a wholesale drugs firm and expanded its business in the 1930s and 1940s, at a time when other companies were also being formed.13 In 1976, Teva merged with two other such companies, Assia and Zori, and built up its generics trade.

In 1984, when few generic products were coming on to the market, President Reagan signed the Hatch–Waxman Act (the Drug Price Competition and Patent Term Restoration Act) into US law.14 The main purpose of the act was to make it easier for generics manufacturers to enter abbreviated new drug applications (ANDAs) on behalf of their products, while still requiring them to fulfil the criteria of strength and pharmaceutical quality of their products, and therefore efficacy and safety. The act amended the 1938 Federal Food, Drug, and Cosmetic Act to make this possible. It was also hoped that innovators would find it more difficult to obstruct the emergence of generic products, although this does not seem to have happened—innovators can be innovative in this respect too.15

Soon after the passage of the Hatch–Waxman Act, Teva acquired Lemmon, a small generics manufacturer, as its US distributor, and its generics business took off.

Bioavailability standards

Generic products are typically cheaper than branded products,16 and governments in many countries have therefore encouraged prescribers to use the generic names of drugs, except in a few cases, as discussed above.

However, an important criterion when authorising a manufacturer to market a generic product is that it must have bioavailability comparable to that of the originator product. Companies are therefore required to submit evidence to regulators showing that any new formulation that they hope to market provides adequate bioavailability.17

The European definition of a generic medicinal product is “a product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.”18 The European Medicines Agency also considers different salts, esters, ethers, isomers, mixtures of isomers, complexes, or derivatives of an active substance to be the same active substance, “unless they differ significantly in properties with regard to safety and/or efficacy.”

This standardisation generally guarantees that generic formulations afford comparable bioavailability to the corresponding branded formulations. However, the fact that a generic formulation has acceptably similar bioavailability to a branded one is usually determined in studies in healthy volunteers under standard conditions. In practice, various factors, such as age, may affect bioavailability, as may the conditions under which it is studied (e.g. fasting or fed).

Thus, occasionally a patient may find that their response to therapy is not as would be expected were the generic product identical or at least closely similar to the branded product. When it is not, the outcomes of treatment may alter when they change from one formulation to another. In that case, think about altered bioavailability as a possible cause.