Novel biomarkers for dose individualization and monitoring of antipsychotic drugs

Recommended doses of drugs are generally fitted to the ‘average patient’. However, due to extensive individual variability in pharmacokinetic processes, the actual biological exposure (‘dose’) differ plenty-fold between patients using similar dosages. Generally, metabolism is the most important process facilitating excretion of drugs, including psychotropic agents. Individual variability in metabolic phenotypes in the liver and gastrointestinal tract is therefore a crucial source behind interpatient differences in clinical response to drug treatment. Enzymes of the cytochrome P450 (CYP) superfamily are the most important ones in drug metabolism. These enzymes catalyze oxidative reactions on drug molecules to make them more hydrophilic and/or reactive towards conjugation reactions (phase II metabolism), which facilitate renal or biliary excretion. To enable penetration into the central nervous system (CNS), most psychotropic drugs are very lipophilic and subjected to metabolism via CYP enzymes before excretion from the body. Individual differences in CYP metabolism will therefore largely determine each patient’s ability eliminate psychotropic agents. The enzyme CYP3A4 in involved in the metabolism of about 30% of all clinically used drugs, where many are frequently prescribed in patients suffering of psychosis. The endogenous agent 4β-hydroxycholesterol is formed by CYP3A4-mediated metabolism of cholesterol. CYP3A4 is highly expressed in both the liver and intestinal wall restricting entry of drugs into the systemic circulation, as well as facilitating the subsequent elimination. The current PhD project has substantially increased the knowledge on the application of 4β-hydroxycholesterol for personalized drugs dosing in terms of novel findings published in multiple international papers (cf. attached publication list). Some of the main findings are as follows: - 4β-hydroxycholesterol could be measured in serum samples from patients by ultra-performance liquid chromatography (UPLC) tandem mass spectrometry (MS/MS) as shown by a novel method developed in the project (paper 1, Br J Clinical Pharmacol 2016) - 4β-hydroxycholesterol is highly and dose-dependently increasing when patients are using enzyme inducers, e.g. anti-infective and antiepileptic drugs, which could be compensated by precise dose increases according to 4β-hydroxycholesterol concentration in serum (paper 1, Br J Clinical Pharmacol 2016) - 4β-hydroxycholesterol is closely correlated with the serum concentration of quetiapine and could be applied as an individual dosing biomarker of the latter (paper 2, Br J Clinical Pharmacol 2017) - 4β-hydroxycholesterol is both formed by CYP3A4 in the liver and intestine, as shown in an interaction study on healthy volunteers (paper 3, submitted manuscript January 2019) Several other papers related to the project have also been published during the funding period, but the PhD candidate, Caroline Gjestad, will include the three papers above, where she is the first author, in her thesis. Due to a 1-year maternity leave, Gjestad has had a similar delay in the progression of her PhD education. This has previously been reported to the research administration of Helse Sør-Øst. The thesis of Gjestad will soon be submitted for evaluation by an external committee, and the subsequent disputation is planned in May/June 2019. Thus, this is regarded as the ‘end report’ of the PhD project. The overall goal of the PhD project is/was to determine if endogenous agents may serve as novel biomarkers for individualized dosing and monitoring of antipsychotic drugs. In particular, the project has focused on 4β-hydroxycholesterol as biomarker for CYP3A4 metabolism, as this is a key elimination route of many antipsychotics. The overall results of the project, which is now in its finishing part, where writing of the PhD thesis and acceptance of the last paper are remaining, provide strong evidence that 4β-hydroxycholesterol could be implemented in clinical routine as a blood-based biomarker for dose individualization of commonly used antipsychotics, such as quetiapine, which according to the prescription registry (www.reseptregisteret.no) is administered annually to more than 55 000 Norwegian inhabitants.