Pharmacogenomics and precision therapeutics — branching viva

Opening — the azathioprine start in Crohn disease

Examiner: A ten-year-old is about to start azathioprine for moderate Crohn disease. What tests do you order, and why together? [1]

Candidate (model): Before the first dose I order thiopurine methyltransferase, TPMT, and NUDT15 genotype together, because either gene can cause thiopurine toxicity and their effects are additive. I pair them with a baseline full blood count and liver enzymes so the monitoring curve starts from a known point. The genotype is a once-in-a-lifetime result, so it is recorded in a place the next prescriber finds and flagged on the chart. [1]

Branch 1 — the result is a poor metaboliser

Examiner: The TPMT result comes back as a poor metaboliser. Walk me through the action. [1]

Candidate (model): A poor metaboliser carries two loss-of-function copies and clears the active thioguanine nucleotides slowly, so they accumulate and suppress the marrow. The 2018 CPIC update recommends avoiding a standard starting dose. My options are to start at a greatly reduced dose — about 10 per cent of standard — under intensive full-blood-count monitoring, or to choose an alternative immunosuppressant such as mycophenolate or a biologic with the gastroenterology team. The child still has Crohn disease, so the question is how to treat safely, not whether to treat. [1]

Branch 2 — the HLA-B star 15 colon 02 child opens

Examiner: Now a different child: a six-year-old of Han Chinese background needs carbamazepine for focal epilepsy. What do you do before the first dose, and why? [5]

Candidate (model): Before the first dose I screen for HLA-B star 15 colon 02, because the allele is carried by roughly 10 to 15 per cent of Han Chinese and Southeast Asian people and is strongly associated with carbamazepine Stevens-Johnson syndrome, which Chung and colleagues first described in 2004. If the result is positive, I do not use carbamazepine or oxcarbazepine — I choose a non-aromatic alternative such as levetiracetam, valproate, or topiramate. If the result is negative, carbamazepine can be used with the usual monitoring, but a negative result does not give total protection, because HLA-B star 15 colon 02 accounts for most but not all cases of carbamazepine Stevens-Johnson syndrome. [5]

Branch 3 — the post-tonsillectomy codeine trap

Examiner: The ward sister asks whether a four-year-old sent home after adenotonsillectomy can take the codeine the referring hospital prescribed. What do you say? [2]

Candidate (model): No. Codeine is a weak analgesic that must be converted by CYP2D6 into morphine to work, and a CYP2D6 ultrarapid metaboliser — who inherits extra functional copies of the gene — converts a therapeutic codeine dose into a morphine overdose, with fatal respiratory depression reported in tonsillectomised children. Because you cannot tell at the bedside who is an ultrarapid metaboliser, codeine and tramadol are avoided in all children under twelve years, in breastfeeding mothers, and in all children under eighteen after tonsillectomy or adenoidectomy. I would contact the referring hospital to correct the prescription, start non-opioid multimodal analgesia — paracetamol and a non-steroidal agent where appropriate — and explain the change to the family in plain language. [2]

Branch 4 — explaining a result to a family

Examiner: How would you explain the HLA result to this family in plain language? [5]

Candidate (model): I would say that your child has a gene that many people carry safely, but it can cause a serious skin reaction to one specific medicine — the one we were going to start. So we are going to use a different medicine that works just as well and does not carry that risk for your child. This result is permanent and will be useful for any future prescriptions, so we will write it down in your child's record and give you a copy. The principle is to match the medicine to the child's own genes, not to a standard chart. [5]

Closing — the one-liners examiners reward

Examiner: Give me the three principles you would want every registrar to remember. [1] [5]

Candidate (model): First, recognise the four paediatric gene-drug pairs — TPMT and NUDT15 with thiopurines, CYP2D6 with codeine, HLA-B star 15 colon 02 with carbamazepine, and HLA-B star 57 colon 01 with abacavir — and order the test before the first dose. Second, translate the genotype into a phenotype and change the prescription per the CPIC rule, because the child still has the disease and still needs treatment. Third, never let a positive result sit in the chart while the original prescription carries on — when I order the genotype, I own the follow-through. [1] [5]