Pharmacogenetics-Pharmacogenomics-Personalized Medicine

The latest plot of numbers of publications suing the terms 'Pharmacogenetics', 'Pharmacogenomics', and 'Personalized Medicine'. (see previous plot) Interestingly the term 'Pharmacogenomics' isn't replacing the term 'Pharmacogenetics' at all. This is despite what has often been expressed that the two terms are used interchangeably. Quite obviously the scientific community does make a distinction between the two terms and continue to use them in distinct ways. The number of times the P'genetics term is used still remains greater than that for P'genomics.

Perhaps P'genomics should be considered a subset of P'genetics rather than what has often conversely been suggested.

The brain as a protected efficacy and/or toxicity compartment

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Distribution of selected drug transporters at the BBB. ABC transporters are ATP-driven xenobiotic efflux pumps that can be highly polyspecific (P-glycoprotein is an extreme example), with overlapping substrate specificities that are briefly outlined for each in the boxes. There is considerable controversy over the localization of essentially all ABC transporters in brain capillaries [1,6]. It is likely that species differences in protein expression levels and cellular transporter distribution, as well as differences in detection techniques across laboratories, underlie many of the conflicts that permeate the literature. Nevertheless, when expressed on the luminal plasma membrane, ABC transporters provide an active, structure-sensitive barrier to drugs within the vascular space. Other transporters shown are members of the SLC superfamily and handle primarily organic anions and weak organic acids. Substrates for these transporters include some drugs, such as nonsteroidal anti-inflammatory drugs, as well as drug metabolites and waste products of normal CNS metabolism. They, along with luminal ABC transporters, provide a two-stage system for active and efficient excretion of potentially toxic chemicals and metabolites from the CNS.

(Figure taken from Trends in Pharmacological Sciences Vol.31 No.6)

The brain has for a long time been recognized as a very well protected organ. Chemically, the brain is isolated from the circulation by means of a very tight blood-brain barrier (BBB), first described by Stern in 1921. This BBB consists of very tightly stitched together endothelial junctions which restrict free movement of molecules from the circulation into the interstitial fluid of the brain. The capillaries are themselves encased by a thick basement membrane and the enveloping foot processes of the astrocytes.

It was thought for a long time that this barrier allowed small and lipophilic molecules to passively diffuse across, and that specific transporters mediated essential solutes such as glucose etc. This model however has been challenged by the recognition that few molecules, no matter how small or lipophilic, would diffuse across membranes without the assistance of some transporter protein. Even water required the assistance of aquaporins. The BBB is now recognized as a very sophisticated and metabolically dynamic membrane populated by not only transporter proteins but also CYP450 enzymes.

These functions of the BBB have recently been reviewed and it is worthwhile reading up on these. The following one is a recommended as it discusses also the regulation of transporters at the BBB:
Miller, D. Trends in Pharmacological Sciences 31 (2010) 246–254 (from where the above figure has been borrowed).

The article concludes:
It is now clear from studies with animal models and with patient samples that the expression and activity of P-glycoprotein and other ABC transporters at the BBB can be moving targets, affected by genetics, disease, pharmacotherapy and diet. Indeed, we are rapidly adding to maps of the signals and signaling pathways involved with a view to improving both CNS protection and the delivery of small-molecule drugs to the brain. Thus, an understanding of signaling could provide opportunities to both selectively fine tune barrier function up or down and to begin to identify the barrier-based and external factors that contribute to patient-to-patient variability in response to CNS-acting drugs. Although we are rapidly developing a very detailed picture of signaling to ABC transporters in animal models, it is still not clear to what extent these pathways operate in humans. An understanding of transporter function and regulation at the human BBB is critical before we can determine to what extent signaling can be manipulated to improve drug delivery to the CNS and to enhance neuroprotection.

It should however, also be noted that the BBB is not the only barrier that exists in the brain. It is probably the main barrier for drugs which act on surface receptors on neuronal membranes. But for drugs which act intracellularly, there is yet another barrier which exists at the cell (neurones or astrocytes) membranes. Furthermore, it is far from clear if the BBB is a uniform barrier throughout the brain. It is possible that the population of transporters may have regional differences.

Because of the existence of these barriers to the movement of drug molecules, we must be careful of trying to extrapolate too much from plasma concentrations of drugs acting on the CNS. There is often a significant dichotomy between the plasma pharmacokinetics of drug and what is actually happening not only in the brain but more specifically, intracellular mechanisms in the brain.

Deciphering the efficacy-toxicity profiles of CNS drugs become a complex exercise when efficacy is expected in the CNS while toxicity may be manifest in another tissue protected by a different population of receptors. It becomes even more perplexing when one considers that these populations of transporters in efficacy and toxicity compartments can be modulated differently by environmental and epigenetic mechanisms over time as well as between individuals.

Stress - Nature vs Nurture: Lessons for drug response variability

This has been abstracted from Darlene Francis and Daniela Kaufer's essay in Reading Frames: The Scientist October 2011

Recent advances in neuroscience make a compelling case for finally abandoning the nature vs. nurture debate to focus on understanding the mechanisms through which genes and environments are perpetually entwined throughout an individual’s lifetime. As neurobiologists who study stress, we believe that research in this area will help reframe the study of human nature.

Researchers have historically approached the study of stress from two perspectives: 1) a physiological account of the stress response, which consists of tracking the stress hormone cortisol and its effects on metabolism, immune function, and neural processes; and 2) a psychological/cognitive focus on how the perception and experience of a stressor influences the stress response. These approaches align with the nature vs. nurture debate, pitting nature, represented by the biology of cortisol responses, against nurture, in the form of external experience influencing cognitive processing. Academic researchers typically study stress by adopting one of these perspectives. However, anyone who’s been stuck in rush hour traffic or faced a looming deadline knows that the causes and consequences of stressful experiences do not adhere to these academic divides.

Scientists and laymen alike still spend too much time and effort trying to quantify the relative importance of nature and nurture.
In the past decade, researchers have made great strides in understanding the cellular, molecular, genetic, and epigenetic processes involved in the regulation of the stress response. Surprisingly, as stress research elucidated this molecular dimension, it shed light on the powerful role of environment and experience in remodeling our molecular makeup. It became clear that the environmental effects (nurture) are modulated by genetic polymorphism and epigenetic programming of gene expression (nature) to shape development. So, as the molecular underpinnings are elucidated, the need to study the interaction between environment and our genome is highlighted, and the divide seems less relevant.

Bridging the efficacy–effectiveness gap

Bridging the efficacy–effectiveness gap: a regulator's perspective on addressing variability of drug response
Hans-Georg Eichler, Eric Abadie, Alasdair Breckenridge, Bruno Flamion, Lars L. Gustafsson, Hubert Leufkens, Malcolm Rowland, Christian K. Schneider & Brigitte Bloechl-Daum

Abstract

Drug regulatory agencies should ensure that the benefits of drugs outweigh their risks, but licensed medicines sometimes do not perform as expected in everyday clinical practice. Failure may relate to lower than anticipated efficacy or a higher than anticipated incidence or severity of adverse effects. Here we show that the problem of benefit–risk is to a considerable degree a problem of variability in drug response. We describe biological and behavioural sources of variability and how these contribute to the long-known efficacy–effectiveness gap. In this context, efficacy describes how a drug performs under conditions of clinical trials, whereas effectiveness describes how it performs under conditions of everyday clinical practice. We argue that a broad range of pre- and post-licensing technologies will need to be harnessed to bridge the efficacy–effectiveness gap. Successful approaches will not be limited to the current notion of pharmacogenomics-based personalized medicines, but will also entail the wider use of electronic health-care tools to improve drug prescribing and patient adherence.

Nature Reviews Drug Discovery 10, 495-506 (July 2011)

Looking at PK data #2

Here is a parallel set of data comparing young healthy adults and patients with cirrhosis. Again, this set of data is not meant to prove changes which happen in cirrhosis but more as an exercise to explore and understand PK effects.

As in the previous post, the first thing that strikes you is the massive changes in AUC seen in cirrhotics. The AUC for cirrhotics is 1.85 times that of the young. By the same logic as in the previous post this AUC increase is inversely related to a decrease in clearance and/or bioavailability. Since there is no way to assess bioavailability in this set of data, we shall leave it out of the discussion for the time being. It is not that the cirrhosis did not result in a change of bioavailability, it is just that the experimental design does not allow us to examine bioavailability effects.

Unlike the situation with the elderly, the reduction in clearance in cirrhotics is not accompanied by a fall in the unbound fraction. Instead, the unbound fraction is elevated from 3.5 to 5.3%. Changes in protein binding is not uncommon in liver cirrhosis. Often serum albumin is reduced. Here the protein binding is decreased with a corresponding increase in the free fraction. In fact the increase in free fraction has the effect of actually increasing metabolic clearance.The reduction in clearance is therefore not a result of a decrease free fraction, but primarily due to loss of enzyme activity. One can in addition, expect that the extent of degradation of enzyme activity is even greater than indicated by the extent of decrease of clearance because part of this effect is mitigated by an increased clearance caused by the increase in free fraction.

The increase in elimination halflife and corresponding fall in Kel is related to the reduction in clearance. The magnitude of the change in halflife is however larger than the fall in clearance and suggests that perhaps the Vd may have increased as well. This is expected because of the increase in free fraction.

Looking at PK data #1

Here is a set of data, adapted from published information comparing pk data of orally administered Drug X between young subjects and elderly subjects. The data here just provides an opportunity to qualitatively discuss PK effects, and it is not the intention here to 'prove' any PK changes in the elderly.

In this case the most apparent difference is rather large and significant difference in AUC between young and elderly. The AUC in elderly is about 1.84 times greater than that for the young. This is not an unexpected finding. The question is what is the cause of the reduced AUC?

We know from theory that AUC is determined primarily by bioavailability and clearance. However, since we have no way to assess bioavailability here, we shall concentrate on clearance effects instead. The increase in AUC is consistent with a reduction in clearance in the elderly. Again from theory, assuming this is primarily metabolic clearance, we expect that metabolic clearance of an orally administered drug is dependent on protein binding and enzyme activity.

When we inspect the protein binding data we find that the protein binding in elderly is actually increased with the unbound fraction falling from 4.3 to 3.4%. But this magnitude of change is relatively small compared to the estimated change in clearance. Hence it is possible the the total change in clearance reflects both a reduction in unbound fraction as well as a degradation of enzyme activity.

The fall in the unbound fraction potentially also affects the Vd. We have no direct way of assessing the Vd changes here but the Cmax provides indirect (though inaccurate) look at possible Vd changes. The Cmax for the elderly is higher than in the young but marginally less (probably insignificantly less) than the magnitude of change for AUC, so the Vd effect is uncertain.

The halflife changes in the elderly are consistent with the reduction in metabolic clearance.

The uncertainty in this case study is how much any bioavailability changes play in affecting the PK data. The magnitude of halflife change is quite comparable to the magnitude of AUC and clearance changes. This suggests that if there are bioavailability effects it is probably minimal.