Pharmacogenomics and precision therapeutics — formative SAQs

SAQ 1 — A TPMT and NUDT15-guided thiopurine plan for a child with Crohn disease (10 marks, 15 minutes)

Stem: A ten-year-old with newly diagnosed moderate Crohn disease is about to start azathioprine. The team asks you to design the precision-prescribing plan, state the tests to order, and defend the action if the child is a poor metaboliser. [1]

Model answer

Tests to order (3 marks). Before the first dose, order thiopurine methyltransferase (TPMT) and NUDT15 genotype together, because either gene can cause thiopurine toxicity and their effects are additive. Pair the genotypes 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 must be recorded in a place the next prescriber finds and flagged on the chart. [1]

Translating the result (3 marks). Translate the genotype into a metaboliser phenotype using the CPIC table. A normal metaboliser uses the standard azathioprine starting dose under gastroenterology guidance. An intermediate metaboliser starts at a reduced dose and is titrated to the full blood count and disease response. A poor metaboliser carries two loss-of-function copies and should not receive a standard dose. [1]

Action if the child is a poor metaboliser (3 marks). A poor metaboliser accumulates active thioguanine nucleotides and is at high risk of severe myelosuppression. The 2018 CPIC update recommends avoiding a standard starting dose and either starting at a greatly reduced dose — about 10 per cent of standard — under intensive full-blood-count monitoring, or choosing an alternative immunosuppressant such as mycophenolate or a biologic. The child still has Crohn disease, so the question is not whether to treat but how to treat safely. [1]

Communication and follow-through (1 mark). Record the genotype, the chosen dose, and the reason permanently on the chart and in the family medicines record, and explain the result to the family in plain language — because the most common and most dangerous failure of pharmacogenomics is the positive result filed and the prescription never changed. [1]

SAQ 2 — HLA-B star 15 colon 02 and CYP2D6 reasoning (10 marks, 15 minutes)

Stem: A six-year-old of Han Chinese background is to start carbamazepine for focal epilepsy, and the ward sister asks whether a four-year-old sent home after adenotonsillectomy can take the codeine prescribed by the referring hospital. Outline the precision-prescribing reasoning for each. [2] [5]

Model answer

The carbamazepine child (5 marks). Before the first dose, 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, as Chung and colleagues first described in 2004. If the result is positive, do not use carbamazepine or oxcarbazepine — choose a non-aromatic alternative such as levetiracetam, valproate, or topiramate, because the child still has epilepsy and still needs treatment. 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. The 2017 CPIC update guides the action, and the screen has reduced the incidence of carbamazepine Stevens-Johnson syndrome in screened Asian populations. [5]

The post-tonsillectomy codeine child (5 marks). Do not let the four-year-old take codeine. 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. The safe alternative is non-opioid multimodal analgesia — paracetamol and a non-steroidal agent where appropriate — with a non-codeine opioid reserved for breakthrough pain in the right setting. Contact the referring hospital to correct the prescription and explain the change to the family in plain language. [2]