Pharmacogenomics in dermatology

What is pharmacogenomics?

Pharmacogenomics is the study of how a patient’s whole genome influences their individual response to therapeutics. This field of research combines knowledge from the fields of:

• Pharmacodynamics (the science of a medicine’s mode of action)
• Pharmacokinetics (the study of how medications are absorbed, distributed, metabolised, and excreted in the body)
• The genetic understanding of polymorphisms [1].

Often pharmacogenetics is used interchangeably with pharmacogenomics. However, pharmacogenetics correlates drug efficacy and toxicity with interindividual variations in DNA sequence [1].

Why is pharmacogenomics important?

The interest in pharmacogenomics, pharmacogenetics, and personalised medicine has arisen because of the finding that only about half of the patients given recommended standard doses of many medications will receive the desired therapeutic benefit [2]. Some of this variation in response to medications is attributed to genetic differences in the mechanisms responsible for the pharmacokinetics [3].

Much research has been devoted to the pharmacogenetics of phase 1 metabolism enzymes, particularly the cytochrome P450 (CYP450) system.

• Approximately 50% of drug elimination from the body is due to the CYP450 system [4].
• The CYP450 system is concentrated in the liver with over 57 functional unique enzymes [5].
• Genetic polymorphisms — differences in nucleic acid base sequence — are especially frequent in the CYP1A2, 2C9, 2C19, 2D6 and 3A4/5 enzyme genes; the average CYP enzyme has over 10 nonsynonymous single nucleotide polymorphisms (SNPs) [3].
• Interethnic studies have found that Africans, Asians, and Caucasians have different frequencies of various CYP450 alleles [6].

This variation in the nucleic acid base sequence of genes (the alleles) can alter the action and efficiency of the CYP450 enzymes.

• Extensive metabolisers, individuals with very active CYP450 enzyme variants, rapidly inactivate a drug resulting in subtherapeutic medication levels and treatment failure.
• Poor metabolisers, with absent or reduced CYP450 variants resulting in high drug levels, are at risk of toxicity.
• Normal metabolisers possess the wild type gene and have normal metabolic function [7].

Some medications are prodrugs; their active form is the metabolite of the administered compound. In this case:

• Extensive metabolisers result in excessive production of the active metabolite
• Poor metabolisers may not produce active metabolite [7].

Risks to the patient are heightened for medications with a narrow therapeutic index.

Pharmacogenetic testing to identify variant metabolic genes can:

• Identify individuals who will benefit more from some medicines than others
• Improve the effectiveness of dosing
• Reduce healthcare expenditure [8].

More than half of the drugs that are commonly implicated in adverse effects are major substrates of enzymes that have a mutant form of the gene that poorly metabolises the medication [9].

• Iatrogenic events caused by toxicity or treatment failure lead to greater healthcare costs due to increased patient hospitalisation rates and length of stay [10].
• Adverse events in Australia cause up to 4% of total hospital admissions, increasing to up to 30% in those aged over 75 years, and cost the government an estimated $500 million dollars (AUD) per year [10].
• Adverse events have doubled in the USA hospital system in the period of 1998–2005 and account for approximately 100,000 deaths per year [11].

Pharmacogenetic testing may also help the process of drug discovery if drug interactions and adverse effects can be predicted, limiting the use of a new drug to those who are low risk of such events [12].

Typically, a laboratory may only test a limited number of alleles and enzymes.

How do pharmacogenomics and personalised medicine relate to dermatology?

Drugs with a narrow therapeutic index used in dermatology include immunosuppressants such as tacrolimus, mycophenolate, and ciclosporin. Other examples of the application of pharmacogenomics to dermatology follow.

BRAF inhibitors

Effective targeted therapy of metastatic melanoma using BRAF inhibitors (eg, vemurafenib, dabrafenib) requires molecular pathology demonstrating the specific BRAF V600 mutation. BRAF inhibitors can actually enhance MAPK expression in those with wild type BRAF [13,14].

Methotrexate

The metabolism of methotrexate is complex. Mutations in the key metabolic enzymes for methotrexate, thymidylate synthetase (TS) and methylenetetrahydrofolate reductase (MTHR), are associated with increased toxicity and decreased efficacy in rheumatological indications. Similar issues are likely in the dermatological use of methotrexate [15–17].

Azathioprine

The current standard of care is to test patients for thiopurine methyltransferase (TPMT) activity prior to prescribing azathioprine. This is to evaluate the patient’s capacity to metabolise the drug. There are many alleles that cause low TPMT activity, and patients with low activity are at significantly increased risk for gastrointestinal toxicity or myelosuppression from azathioprine [18].

Ciclosporin/tacrolimus

A polymorphism in the CYP3A5 gene has been associated with increased and decreased bioavailability to ciclosporin and tacrolimus respectively [19,20].

Dapsone

There is an increased risk of haemolytic anaemia and neurotoxicity from dapsone in slow acetylators [21].

Cutaneous adverse drug reactions

The slow-acetylator genotype of NAT2 is a risk factor for sulphonamide-induced toxic epidermal necrolysis/Stevens-Johnson syndrome (TEN/SJS) [22].

Those who are heterozygous or homozygous for HLA-B*1502 and of Chinese or Asian ancestry are at risk of carbamazepine-induced TEN/SJS [23].

The HLA-A*31:01 allele has been associated (although less strongly) with severe cutaneous adverse reactions to carbamazepine in Caucasian populations [23].

The risk of severe cutaneous adverse reactions to allopurinol is greatly increased in Chinese and Thai persons, as well as Koreans with HLA-B*58:01 [24].

Vismodegib

The sonic hedgehog (SHH) pathway inhibitor, vismodegib, is effective for basal cell carcinomas (BCCs) with mutations in the SHH pathway such as PTCH1 and SMO (which occur in 70 and 10–20% of BCCs respectively) [25].

Vitamin D analogues

The A and T alleles of the A-1012G polymorphism of the vitamin D receptor gene are associated with an improved response of psoriasis to topical calcipotriol [26].

Biologics

Individuals with tumour necrosis factor-alpha (TNF-α) receptor or promoter mutations can have either an increased or decreased response to TNF-α inhibitors [27].

HLA-C:06:02 is a marker of the response of psoriasis to ustekinumab, with various interleukin polymorphisms potentially altering the effect of other biologics [28].