Usefulness of Therapeutic Drug Monitoring and Pharmacogenetics for a Patient Treated with Olanzapine, Buspirone, and Fluvoxamine: A Case Study.

BACKGROUND: A patient, with a mental disorder caused by an intracranial infection, treated with olanzapine, fluvoxamine, and buspirone. The plasma exposure of olanzapine was too high at standard doses, with evidence indicating that it was caused by drug-drug interactions. METHODS: Using pharmacogenomics and therapeutic drug monitoring to guide drug dose adjustment for a patient in clinical practice. RESULTS: The patient underwent pharmacogenetic testing in addition to therapeutic drug monitoring as part of a pharmacist-led comprehensive evaluation of medication therapy management in a clinical setting, resulting in improved clinical efficacy that allowed discharge from a psychiatric hospital. CONCLUSIONS: This case study demonstrates that therapeutic drug monitoring combined with pharmacogenetic-guided dose adjustment can aid in the management of patients receiving complex pharmacological treatments.

Effects of Age, Sex, and Comedication on the Plasma Concentrations of Olanzapine in Chinese Patients With Schizophrenia Based on Therapeutic Drug Monitoring Data.

BACKGROUND: Olanzapine (OLA) is an atypical second-generation antipsychotic that exhibits significant pharmacokinetic variability. We retrospectively investigated the effects of age, sex, and specific comedications on OLA pharmacokinetics in Chinese patients with schizophrenia. METHODS: Data on sex, age, and OLA dosage and steady-state plasma concentrations of 386 patients with schizophrenia (who have received OLA or a comedication of OLA with a psychotherapeutic drug) were collected and analyzed. The combined effects of dosage, age, sex, and comedication on OLA plasma levels were assessed via multiple linear regression analyses. RESULTS: A daily dose of OLA was positively correlated with the drug's plasma concentrations. Overall, the OLA plasma concentrations and concentration-to-dose ratio (C/D) of the studied patients varied by 53.6- and 64.1-fold, achieving median values of 42.7 ng/mL and 2.73 (ng/mL)/(mg/d), respectively. Furthermore, a 1.27-fold higher estimated C/D in patients 60 years or older than in those younger than 60 years was identified. Female patients demonstrated a 33.6% higher C/D than in male patients. When coadministered with mood stabilizers (valproate or lithium), the median OLA C/D was 24.1% to 26.1% lower than that of OLA monotherapy. Interestingly, the OLA plasma concentration and C/D were not significantly affected by a comedication with aripiprazole, haloperidol, amisulpride, risperidone, clozapine, ziprasidone, citalopram, or buspirone. CONCLUSIONS: The administered drug's dose was identified as an important determinant of the achieved OLA plasma concentration, with a positive correlation. The patients' sex and valproate (or lithium) comedication can significantly affect the C/D of OLA. Therapeutic drug monitoring should be routinely applied in cases of OLA-receiving patients with schizophrenia.

Impact of Heat Inactivation of Blood Samples on Therapeutic Drug Monitoring of 5 Second-Generation Antipsychotics and Their Metabolites.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 outbreak has been classified as a pandemic. Because many coronaviruses are heat sensitive, heat inactivation of patient samples at 56°C before testing reduces the risk of transmission. The aim of this study is to assess the impact of heat inactivation of patient blood samples on plasma concentrations of 5 second-generation antipsychotics and their metabolites. METHODS: Blood samples were collected during routine clinical therapeutic drug monitoring examination between April 3, 2021, and April 19, 2021. Samples were divided into 2 groups: group A, noninactivated raw sample, and group B, inactivated samples. Inactivation was performed by a 30-minute incubation at 56°C. The levels of the 5 drugs and their metabolites before and after sample heat inactivation were measured using liquid chromatography-tandem mass spectrometry and compared. Furthermore, correlation and Bland-Altman analyses were conducted. RESULTS: No statistically significant difference was observed between the levels of the 5 drugs and their metabolites (ie, risperidone, 9-OH-risperidone, aripiprazole, dehydroaripiprazole, olanzapine, quetiapine, norquetiapine, clozapine, and norclozapine) in the noninactivated group A and the inactivated group B ( P > 0.05). Each drug's concentration values in inactivated and noninactivated treatments correlated (Spearman rs > 0.98; P < 0.001). The results of the noninactivated treatment methods and samples alone showed good consistency via Bland-Altman analysis. CONCLUSIONS: Blood sample heat inactivation had no significant effect on the therapeutic drug monitoring of 5 second-generation antipsychotics and their metabolites. This inactivated treatment method should be recommended to effectively protect laboratory staff from virus contamination.

Therapeutic drug monitoring of perospirone: The lowest effective plasma concentration in patients with schizophrenia.

OBJECTIVES: This study investigated the effects of demographic factors such as age, sex and comedications on the plasma concentrations of perospirone in individuals diagnosed with schizophrenia. Additionally, the relationship between these plasma levels and the clinical efficacy of the medication was explored. METHODS: Data regarding the plasma concentration of perospirone in patients with schizophrenia were obtained from the Xi'an Mental Health Center and were retrospectively analysed. RESULTS: The study results revealed a range of 0.50-1.59 ng/mL for the 25th-75th percentile of perospirone concentration in the plasma, which ranged from 0.07 to 6.0 ng/mL. The plasma concentration of perospirone increased with the daily oral dose (r = 0.283, P < 0.05). Furthermore, patients with higher plasma perospirone concentrations and concentration-to-dose ratios (C/D) tended to be older or were women. Notably, the coadministration of valproate significantly reduced perospirone concentration and the C/D ratio by 54.7% and 35.3%, respectively (P < 0.01). Receiver operating characteristics curve analyses revealed that patients exhibited a good clinical response when their plasma perospirone concentrations were ≥ 1.17 ng/mL. CONCLUSION: The findings suggest that therapeutic drug monitoring of perospirone and adjustments to achieve steady-state concentrations of ≥ 1.17 ng/mL can be beneficial for optimising treatment for patients with schizophrenia.

A novel and robust analytical method for the quantification of perospirone in human plasma using an LC-MS/MS system with self-internal standard calibration.

OBJECTIVES: This study aims to establish a novel method for measuring perospirone in human plasma for therapeutic drug monitoring (TDM) by liquid chromatography-mass spectrometry (LC-MS) coupled with an automatic liquid chromatograph mass spectrometer coupler 9500 (LC-MS/MS-Mate 9500), which has been equipped with self-internal standard (SIS) calibration technology. DESIGN & METHODS: A novel and attractive analytical calibration method designed for perospirone, calibration with SIS, was reported. After protein precipitation with acetonitrile-cyclopentanol (9:1, v/v) containing 1% NH3·H2O, LC-MS quantification of perospirone was performed by multiple reaction monitoring in the positive mode with quantitative and qualitative analysis of the ion pairs m/z 427.30 â†’ 177.15 and 427.30 â†’ 166.15 for perospirone and SIS. Chromatographic separation was accomplished in < 2.0 min on an Hypersil GOLDTM C18 column (2.1 mm × 50 mm, 3.0 µm) using a mobile methanol phase and 0.1% formic acid in water. RESULTS: This method showed good selectivity because no interfering peaks were observed in the plasma samples during the 2.0-min run time. The calibration curve range was 0.05-20 ng/mL, with a correlation coefficient of ≥ 0.9995. Intraday and interday accuracies were 98.3%-107.9%, respectively, with precision relative standard deviation values of < 10%. The matrix effects ranged from 92.7% to 96.1%, and extraction recoveries were between 97.3% and 108.8%. Finally, this method was successfully applied to routine clinical TDM for 142 patients. The perospirone plasma concentrations of the patients ranged between 0.07 and 10.96 ng/mL. CONCLUSIONS: This bioanalytical method can be used for the quantification of perospirone in human plasma by LC-MS/MS-Mate 9500 using perospirone itself as the SIS.