Cytochromes P450 and P-Glycoprotein Phenotypic Assessment to Optimize Psychotropic Pharmacotherapy: A Retrospective Analysis of Four Years of Practice in Psychiatry

Abstract

Altered cytochromes P450 enzymes (CYP) and P-glycoprotein transporter (P-gp) activity may explain variabilities in drug response. In this study, we analyzed four years of phenotypic assessments of CYP/P-gp activities to optimize pharmacotherapy in psychiatry. A low-dose probe cocktail was administered to evaluate CYP1A2, 2B6, 2D6, 2C9, 2C19, 3A4, and P-gp activities using the probe/metabolite concentration ratio in blood or the AUC. A therapeutic adjustment was suggested depending on the phenotyping results. From January 2017 to June 2021, we performed 32 phenotypings, 10 for adverse drug reaction, 6 for non-response, and 16 for both reasons. Depending on the CYP/P-gp evaluated, only 23% to 56% of patients had normal activity. Activity was decreased in up to 57% and increased in up to 60% of cases, depending on the CYP/P-gp evaluated. In 11/32 cases (34%), the therapeutic problem was attributable to the patient’s metabolic profile. In 10/32 cases (31%), phenotyping excluded the metabolic profile as the cause of the therapeutic problem. For all ten individuals for which we had follow-up information, phenotyping allowed us to clearly state or clearly exclude the metabolic profile as a possible cause of therapeutic failure. Among them, seven showed a clinical improvement after dosage adaptation, or drug or pharmacological class switching. Our study confirmed the interest of CYP and P-gp phenotyping for therapeutic optimization in psychiatry.

Phenotyping Indices of CYP450 and P-Glycoprotein in Human Volunteers and in Patients Treated with Painkillers or Psychotropic Drugs

“…The phenotypic assessment of metabolic pathways has demonstrated its clinical value [ 25 , 32 , 33 ]. Although it is challenging to make a direct comparison between phenotyping and genotyping regarding clinical outcomes, the high phenoconversion rate [ 34 ] leads us to assert that the phenotypic evaluation of CYP and P-gp activity is a more effective tool than genotyping for personalized medicine [ 35 ].…”

“…Patients were included after giving their written informed consent. The patients and the clinical outcomes of the phenotypic assessments with psychotropics have been described in a previous study [ 25 ].…”

Impact of Pharmacogenetic Testing on Clozapine Treatment Efficacy in Patients with Treatment-Resistant Schizophrenia

“…The suggested therapeutic reference range for a therapeutically effective dose in the treatment of adult patients with schizophrenia is 350–600 ng/mL for CLZ and 100–600 ng/mL for its metabolite [ 30 ]. However, TDM has limits in identifying the origin of the therapeutic failure without being able to explain the cause of some abnormal results in plasma levels or recurrent drug failures [ 31 ]. In these cases, pharmacogenetic analysis of the drug’s pharmacokinetic variables could help to explain the abnormal results obtained.…”