Drug metabolism and precision prescribing
A patient's response to a drug depends on more than the drug and its dose, and many of the factors that affect it act through metabolism. The best-understood metabolic pathways are those of the cytochrome P450 enzymes, such as CYP3A4. Inhibiting one of those pathways can cause serious harm or can itself be the treatment, and doctors need clinical practice guidelines to make practical decisions from information about these factors.
Personalised and precision medicine
Medicine has historically followed a one-size-fits-all approach: a doctor prescribed a drug, the patient took it, and the two discussed its benefit and decided whether to switch medications based on the patient's reactions. Under that approach some patients benefited, some did not and some had adverse reactions. As of 2020, precision medicine was an emerging approach to prescribing, and it builds on the prescribing approach known as personalised medicine. Doctors often assess several factors that may affect a patient's response to a drug, among them disease subtype, risk profile, demographics, genetics, the concentration of biomarkers in the blood, comorbidities, especially kidney and liver disease, and other medications.
The goal of precision medicine is to give each patient only medications that will benefit them. It can draw on genetic information, medical records, demographic information, biomarker analysis and companion diagnostics, among other techniques that help identify the most beneficial treatment for a disease, and in this way doctors can see an exact profile of each patient. As of 2020, many new medications were being approved alongside a companion diagnostic that lets doctors identify and treat the patient population that will benefit from the medication.
Metabolism and the cytochrome P450 enzymes
To prescribe only to patients who will benefit, doctors must understand both the cause of the disease and the drug's mechanism of action. Metabolism is often the best-understood aspect of that mechanism, and many of the factors that affect an individual's response to a drug do so through their effect on metabolism.
The best-elucidated metabolic pathways are those of the cytochrome P450 enzymes. CYP3A4 metabolises many common drugs, among them statins and selective serotonin reuptake inhibitors. Grapefruit juice can inhibit CYP3A4 and slow the metabolism of these drugs, and drinking it while taking certain classes of medication can greatly increase their potency and cause very serious side effects. Such interactions show the need for a better understanding of the mechanisms of action and metabolic pathways of the medications in use.
Enzyme inhibition as treatment
Enzyme inhibition sometimes has positive outcomes. Some drugs are metabolised by CYP3A4 too quickly to produce the intended benefit, but combining lopinavir with ritonavir, which like grapefruit juice inhibits CYP3A4, led to a first-line treatment for HIV infection. Ritonavir can likewise be combined with ombitasvir and paritaprevir in a therapy that cures more than 95% of all patients with hepatitis C genotypes 1 and 4. The interactions of grapefruit juice and ritonavir with CYP3A4 are a few examples of the many interactions, genetic and environmental, that affect the effectiveness and safety of drugs.
Clinical practice guidelines
Doctors need more information to improve personalised and precision medicine, but information alone is not enough: they need clinical practice guidelines to make practical clinical decisions from it. The Clinical Pharmacogenetics Implementation Consortium publishes guidelines for using genetic information to help doctors prescribe appropriate medications for each patient's genetic profile.
As of 2020, prescribing practice was expected to keep evolving as understanding grew of the factors that influence an individual's response to medication. Precision medicine was expected to grow as more clinical information became available and as physicians and patients became more aware of the effects of pharmacogenetics, drug metabolism and the other factors that bear on the precision approach. Once that knowledge was translated into published clinical practice guidelines, it was expected to help the adoption of precision approaches to treatment.