Pharmacokinetic considerations in the treatment of hypertension in risperidone-medicated patients – thinking of clinically relevant CYP2D6 interactions

Abstract

Background: Treatment of arterial hypertension in patients with severe mental illnesses often results in polypharmacy, potentially leading to drug-drug interactions. The objective of the study was to analyse the in vivo inhibitory potential of two antihypertensive drugs, amlodipine and metoprolol on CYP2D6 catalysed 9-hydroxylation of risperidone (RIS). Methods: A therapeutic drug monitoring database with plasma concentrations of RIS and 9-hydroxyrisperidone (9-OH-RIS) of 1584 patients was analysed. Three groups were considered; a group of patients receiving RIS without a potentially cytochrome influencing co-medication (control group, R 0 , n=852), a group co-medicated with amlodipine (R A , n=27) and a group, co-medicated with metoprolol (R M , n=41). Plasma concentrations, concentration-to-dose ratios (C/Ds) of RIS, 9-OH-RIS and the active moiety (AM), as well as the metabolic ratios were computed and compared using the Kruskal-Wallis test, the Mann-Whitney U test and the Jonckheere-Terpstra test to determine the means and different patterns of distribution of plasma concentrations as well as the concentration-to-dose ratios. Results: The median daily dosage of RIS did not differ between the groups (p=0.708). No differences were found in median plasma concentrations of RIS, 9-OH-RIS and AM. However, concentration-to-dose ratios for RIS, 9-OH-RIS and AM were significantly higher in the amlodipine group (p=0.025, p=0.048 and p=0.005). In the metoprolol group, the concentration-to-dose ratio for RIS was significantly higher than in the control group (p=0.017), while the C/D for 9-OH-RIS and AM was not. Conclusions and limitations:Our data show a potential pharmacokinetic interaction, most likely via CYP3A4 between amlodipine and RIS, reflected in significantly different C/Ds for RIS, 9-OH-RIS and AM. Although the interaction did not result in significantly higher plasma levels, changes in C/Ds and their distribution with regard to the median concentrations were observed.

Cytochrome P450‐mediated interaction between perazine and risperidone: implications for antipsychotic polypharmacy

“…However, this need remains unmet for various widely prescribed psychotropic (e.g. perazine) and nonpsychotropic drugs .…”

“…Moreover, data regarding the efficacy and safety of combined treatment regimens are occasionally conflicting, and tailored strategies lack evidence from clinical studies . Antipsychotic polypharmacy has been linked to an increased prescription of anticholinergic agents, which may be reflected in the enhanced prevalence of adverse reactions , and combined treatment strategies may also give rise to pharmacokinetic drug–drug interactions (DDIs) . From a clinical perspective, data highlight the unmet need for a better understanding of both pharmacodynamic and pharmacokinetic DDIs.…”

“…Therapeutic drug monitoring databases are a valuable source for promoting the safety and tolerability of pharmacotherapy in a clinical setting. Furthermore, the evaluation of databases of drug concentrations allows many interesting pharmacokinetic and/or clinical issues to be addressed, such as DDIs , the effect of smoking on drug concentrations , adverse drug reactions and clinical topics such as treatment responses in correlation with pharmacokinetic patterns of drug concentrations in patients' blood . As data on the pharmacokinetics of perazine (e.g.…”

Lack of Smoking Effects on Pharmacokinetics of Oral Paliperidone-analysis of a Naturalistic Therapeutic Drug Monitoring Sample

“…Using TDM is more likely to provide a comprehensive overview rather than using guidelines of dosage equivalents extrapolated from dopamine D 2 -receptor occupancy [42]. This is because of the large inter-individual variability in risperidone's pharmacokinetic parameters [43], as well as the low amount of variance of the brain dopamine blockade explained by risperidone TDM [24].…”

Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment

“…The TDM databases are a valuable source to promote the safety and tolerability of pharmacotherapy in a clinical setting. 47,48 In the case of multiple available plasma concentrations for 1 single patient, only the most recent value was included in the analysis. After adjusting the database for multiple values, and after excluding patients with depot formulations, RIS and 9-OH-RIS plasma concentrations were available for 1,584 adult inpatients and outpatients who had been treated with RIS for different reasons.…”