Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients: Based on the impact of sex and concomitant valproate on clearance.

WHAT IS KNOWN AND OBJECTIVE: Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated. METHODS: Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters. RESULTS: The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h-1 , 15.4 L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F = 15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10 mg may be sufficient to achieve the therapeutic range of olanzapine. WHAT IS NEW AND CONCLUSION: Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.

A Retrospective Analysis of Steady-State Olanzapine Concentrations in Chinese Patients Using Therapeutic Drug Monitoring: Effects of Valproate and Other Factors.

BACKGROUND: The objective of this study was to investigate the serum concentrations of olanzapine in relation to age, sex, and other factors in Chinese patients aged between 10 and 90 years. METHODS: Data for 884 olanzapine patients, deposited between 2016 and 2017, were retrieved from the therapeutic drug monitoring database of the Affiliated Brain Hospital of Guangzhou Medical University. The effects of covariates on serum olanzapine concentration, dose-normalized concentration (C/D ratio), and normalized concentration (C/D/weight) were investigated. RESULTS: Generally, male patients had lower olanzapine concentration, C/D ratio, and C/D/weight than female patients (P < 0.001). Smoking and drinking reduced olanzapine concentration, C/D ratio, and C/D/weight (P < 0.001). Coadministration with valproate decreased olanzapine concentration, C/D ratio, and C/D/weight by about 16%, 30%, and 40%, respectively (P < 0.001). Patients younger than 60 years had higher olanzapine concentrations (P < 0.05) but lower C/D ratios and C/D/weight (P < 0.001) than patients older than 60 years. Age was correlated with olanzapine concentration (r = -0.082, P < 0.05), C/D ratio (r = 0.196, P < 0.001), and C/D/weight (r = 0.169, P < 0.001). Sample timing after dose and diagnostic factors also contributed to the olanzapine concentrations. Multiple linear regression analysis revealed significant influences of dosage, age, sex, valproate comedication, smoking, postdose interval, and schizophrenia (vs bipolar affective disorders) on serum olanzapine concentrations. CONCLUSIONS: The metabolism of olanzapine may be altered by several factors. Patients characterized with a combination of factors may benefit from therapeutic drug monitoring for the adjustment of olanzapine dose to minimize adverse reactions.

Effect of venlafaxine dosage, valproic acid concentration, sex, and age on steady state dose-corrected concentrations of venlafaxine and O-desmethylvenlafaxine: A retrospective analysis of therapeutic drug monitoring data in a Chinese population.

PURPOSE: This study aimed to investigate the influence of diagnosis, body weight, sex, age, smoking, formulations, and concomitant drugs on steady-state dose-corrected serum concentrations (C/D) of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV). METHODS: A retrospective analysis of therapeutic drug monitoring (TDM) was carried out. Patients' demographic data, therapeutic regimens, and concentrations were collected. RESULTS: We included 91 verified samples from 80 patients. Females had by average 13% smaller body weight, 50% higher C/D of VEN, and VEN + ODV and 25% smaller ODV/VEN than males. Patients >60 years had by average 33-59% higher C/D levels of ODV and VEN + ODV than younger patients. The concomitant use of valproic acid caused an average 51% higher C/D of ODV and a 2.2-fold larger ODV/VEN, while clozapine was related with 40% smaller ratio of ODV/VEN and 38% lower C/D levels of ODV. Positive correlations were detected between valproic acid concentrations and the C/D of VEN and VEN + ODV. In a multiple linear regression analysis, variance in the C/D of VEN + ODV was partly attributed to the daily dose of VEN, sex, age and valproic acid concentration. CONCLUSION: Our results suggested daily dose of VEN, sex, age, and valproic acid as indicators for the C/D of VEN + ODV in Chinese patients. TDM as a valuable tool was suggested in elderly female patients and patients receiving polypharmacy.

Effects of food and grapefruit juice on single-dose pharmacokinetics of blonanserin in healthy Chinese subjects.

PURPOSE: The purpose of this study was to investigate the potential effects of a meal and grapefruit juice on the pharmacokinetics of blonanserin and its metabolite N-desethyl blonanserin in healthy Chinese volunteers. METHODS: This was a single-centre, open-label, fixed-sequence study, where 12 healthy Chinese volunteers received a single dose of 8 mg blonanserin after an overnight fast in period 1 (reference), a high-fat meal during period 2 and with co-administration of 250 mL of grapefruit juice in period 3. The washout period was 7 days. Series of plasma samples were collected after each dose to determine concentrations of blonanserin and its metabolite N-desethyl blonanserin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated by non-compartmental analysis and compared between periods by standard average bioequivalence ANOVA. Adverse events were monitored throughout the study. RESULTS: All subjects completed the study. High-fat meals significantly increased blonanserin exposure (AUCt) 2.58-fold (90% CI 2.21, 3.02), relative to the reference period. Co-administration of blonanserin with grapefruit juice remarkably prolonged elimination half-life of blonanserin (from 9.7 to 21.4 h) and significantly increased exposures to blonanserin and N-desethyl blonanserin by 5.82-fold (90% CI 4.57, 7.42) and 1.81-fold (90% CI 1.65, 1.98), respectively. CONCLUSIONS: These results suggested that blonanserin was largely metabolised in the intestinal tract before becoming systemically available, and both food and grapefruit juice enhanced exposure to blonanserin and N-desethyl blonanserin. Grapefruit juice increased bioavailability and may have reduced systemic clearance of blonanserin. Further intestinal CYP3A4 and hepatic CYP3A4 might be postulated to explain the delayed elimination of blonanserin. Dose adjustment of blonanserin is needed on the basis of co-intake of known strong CYP3A4 inhibitor. Patients taking high-dose blonanserin also need to be cautious about the ingestion of grapefruit juice.

A Simple and Sensitive HPLC-MS/MS Assay for the Quantitation of Blonanserin and N-Desethyl Blonanserin in Rat Plasma and Its Application to Pharmacokinetic Study.

A high-performance liquid chromatographic method coupled with triple quadrupole mass spectrometry (LC-MS/MS) for the analysis of blonanserin and its active metabolite, N-desethyl blonanserin, in rat plasma has been developed and validated. The biological samples were treated by simple direct protein precipitation before separation on an Agilent Eclipse Plus C18 column (4.6 × 100 mm, 3.5 µm) with a column temperature of 35°C at a flow rate of 0.5 mL/min. The mobile phase A is a mixture of methanol and water (75 : 25, v/v, 5 mM ammonium formate), and the mobile phase B is acetonitrile containing 0.1% formic acid. The ratio of mobile phase A to mobile phase B is 15 : 85. Electrospray ionization (ESI) multiple reaction monitoring modes are used for detection, which are m/z 368.10 ⟶ 296.90 (blonanserin), m/z 340.15 ⟶ 297.05(N-desethyl blonanserin), and m/z 348.15⟶ 302.05 (N-desethyl blonanserin-d8). The linear response range was 0.1-100.0 ng/mL for blonanserin and N-desethyl blonanserin. The lower limit of quantification (LLOQ), calibration curves, carryover, and matrix effects were sufficiently accurate and precise according to the National Medical Products Administration (NMPA) guidelines for bioanalytical method validation. This analytical method was successfully applied in a blonanserin-poloxamer thermosensitive gel pharmacokinetic study in rats.

Pharmacokinetics of immediate and sustained-release formulations of paroxetine: Population pharmacokinetic approach to guide paroxetine personalized therapy in chinese psychotic patients.

Paroxetine is one of the most potent selective serotonin reuptake inhibitors (SSRIs) approved for treating depression, panic disorder, and obsessive-compulsive disorder. There is evidence linking genetic polymorphisms and nonlinear metabolism to the Paroxetine's pharmacokinetic (PK) variability. The purpose of the present study was to develop a population PK (PPK) model of paroxetine in Chinese patients, which was used to define the paroxetine's PK parameters and quantify the effect of clinical and baseline demographic factors on these PK characteristics. The study included 184 inpatients with psychosis (103 females and 81 males), with a total of 372 serum concentrations of paroxetine for PPK analyses. The total daily dosage ranged from 20 to 75 mg. One compartment model could fit the PKs characterize of paroxetine. Covariate analysis revealed that dose, formulation, and sex had a significant effect on the PK parameters of paroxetine; however, there was no evident genetic influence of CYP2D6 enzymes on paroxetine concentrations in Chinese patients. The study determined that the population's apparent distribution volume (V/F) and apparent clearance (CL/F), respectively, were 8850 and 21.2 L/h. The CL/F decreased 1-2-fold for each 10 mg dose increase, whereas the different formulations caused a decrease in V/F of 66.6%. Sex was found to affect bioavailability (F), which decreased F by 47.5%. Females had higher F values than males. This PPK model described data from patients with psychosis who received paroxetine immediate-release tablets (IR-T) and/or sustained-release tablets (SR-T). Paroxetine trough concentrations and relative bioavailability were different between formulations and sex. The altered serum concentrations of paroxetine resulting from individual variants and additive effects need to be considered, to optimize the dosage regimen for individual patients.

Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy.

Lamotrigine (LTG) is a second-generation anti-epileptic drug widely used for focal and generalized seizures in adults and children, and as a first-line medication in pregnant women and women of childbearing age. However, LTG pharmacokinetics shows high inter-individual variability, thus potentially leading to therapeutic failure or side effects in patients. This prospective study aimed to establish a population pharmacokinetics model for LTG in Chinese patients with epilepsy and to investigate the effects of genetic variants in uridine diphosphate glucuronosyltransferase (UGT) 1A4, UGT2B7, MDR1, ABCG2, ABCC2, and SLC22A1, as well as non-genetic factors, on LTG pharmacokinetics. The study population consisted of 89 patients with epilepsy, with 419 concentrations of LTG. A nonlinear mixed effects model was implemented in NONMEM software. A one-compartment model with first-order input and first-order elimination was found to adequately characterize LTG concentration. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. The use of valproic acid decreased CL/F by 38.5%, whereas the co-administration of rifampicin caused an increase in CL/F of 64.7%. The CL/F decreased by 52.5% in SLC22A1-1222AA carriers. Patients with the ABCG2-34AA genotype had a 42.0% decrease in V/F, whereas patients with the MDR1-2677TT and C3435TT genotypes had a 136% increase in V/F. No obvious genetic effect of UGT enzymes was found relative to the concentrations of LTG in Chinese patients. Recommended dose regimens for patients with different gene polymorphisms and comedications were estimated on the basis of Monte Carlo simulations and the established model. These findings should be valuable for developing individualized dosage regimens in adult and adolescent Chinese patients 13-65 years of age.

Simultaneous analysis of olanzapine, fluoxetine, and norfluoxetine in human plasma using liquid chromatography-mass spectrometry and its application to a pharmacokinetic study.

Adjunctive therapy with olanzapine and fluoxetine has been shown to be beneficial in treatment-resistant depression and the depressive phase of bipolar disorder. Consensus guidelines issued by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie strongly recommend that patients taking olanzapine undergo therapeutic drug monitoring (TDM), and suggest that TDM is useful for patients taking fluoxetine. The aim of the current study was to develop and validate a sensitive, practical, and robust liquid chromatography-tandem mass spectrometry method (LC-MS/MS) for simultaneous determination of olanzapine, fluoxetine, and norfluoxetine in human plasma for routine TDM. Simple liquid-liquid extraction using ethyl acetate was used to extract olanzapine, fluoxetine, and norfluoxetine from 200 µL of pre-basified human plasma. Analytes were separated on an Agilent Eclipse Plus C18 column (4.6 × 100 mm, 5 µm) eluted with a mobile phase consisting of methanol:20 mM ammonium formate buffer (82.5:17.5, v/v), and then quantified using an electrospray ionization source operated in positive ion multiple reaction monitoring mode. The linear range for the analytes was 0.2-25 ng/mL, covering the vast majority of levels encountered in real-life samples. A weighting factor of 1/x2 best fit the calibration curves. The mean internal standard-normalized matrix effects for all analytes were 99.5%-110%. The extraction recoveries were 75%-85% for olanzapine and olanzapine­d3, and 58%-69% for fluoxetine, norfluoxetine, and their deuterated internal standards. Accuracy and precision values also met the acceptance criteria. The stability assessments showed that QC samples containing the three analytes were stable for at least 1 d at room temperature, 21 d at -70 °C, and through three freeze-thaw cycles. Post-preparation storage for 2 d in the autosampler did not cause obvious degradation of the investigated compounds. This validated high performance LC-MS/MS method was successfully applied to a pharmacokinetic study in healthy male volunteers.

[Effects and Mechanisms of In-situ Cement Solidification/Stabilization on a Pb-, Zn-, and Cd-Contaminated Site at Baiyin, China].

In order to evaluate the effects and mechanism of in-situ cement solidification/stabilization (S/S) on heavy metal contaminated soils, leaching tests, speciation analysis, and microscopic analysis were conducted after cement treatment of a Pb, Zn, and Cd contaminated site in Baiyin, China. The leaching test results showed that cement could effectively stabilize Cd and Zn, which could reduce 99.5%-100% and 96.6%-98.8% of H2SO4-HNO3 extractable Cd and Zn, respectively. However, the leaching concentration of Pb was 2.6-5.8 times higher than that before 5% cement treatment. After adding 8% cement, H2SO4-HNO3 extractable Cd and Zn were reduced by 99.6%-100% and 94.4%-97.9% respectively. Similarly, the leaching concentration of Pb was 1.9-12.5 times higher than that before 8% cement treatment. The results of sequential extraction test proposed by the European Community Bureau of Reference (BCR) showed that cement could transform acid extractable Cd and Zn to residual form and transform reducible fractions of Pb to oxidizable and residual form, increasing the stability of heavy metals in soil. The microscopic analysis results showed that Pb2+, Zn2+, and Cd2+ could participate in the process of cement hydration and form silicate minerals and hydroxides. In conclusion, cement could be an effective S/S agent to remediate heavy metal contaminated soils, and site characteristics and environmental conditions should also be considered during the construction process.

A Simple HPLC-MS/MS Method for Determination of Tryptophan, Kynurenine and Kynurenic Acid in Human Serum and its Potential for Monitoring Antidepressant Therapy.

The kynurenine pathway, in which tryptophan is metabolized to kynurenine and kynurenic acid, has been linked to depression. A rapid and highly reproducible liquid-chromatography-tandem mass spectrometry (LC-MS/MS) method were established for determining tryptophan, kynurenine and kynurenic acid in human serum. Biological samples were precipitated with methanol before separation on an Agilent Eclipse XDB-C18. The stable-isotope-labeled internal standards (kynurenine-13C415N and kynurenic acid-d5) were used for quantification. Detection was performed using multiple reaction monitoring in electrospray ionization mode at m/z 205.1→188.1 for tryptophan, m/z 209.1→146.1 for kynurenine, m/z 190.1→144.1 for kynurenic acid. Good linearity of analyte to internal standard peak area ratios was seen in the concentration range 1,000-50,000 ng/mL for tryptophan, 100-5,000 ng/mL for kynurenine and 1-60 ng/mL for kynurenic acid. Pooled drug-free human serum was purified using activated charcoal and the method was shown to be linear, with validation parameters within acceptable limits. The newly developed method was successfully used to determine concentrations of tryptophan, kynurenine and kynurenic acid in serum from 26 healthy volunteers and 54 patients with depression. Concentrations of tryptophan and kynurenine were lower in serum from depressed individuals than from healthy individuals.

Development and validation of an HILIC-MS/MS method by one-step precipitation for chloroquine in miniature pig plasma.

BACKGROUND: Quantification of polar compounds such as chloroquine by revered-phase LC is a challenge because of poor retention and silanol interactions with stationary phase. Strong ion-pairing reagents added to mobile phases to improve reversed-phase retention and improve peak shape can be harmful for MS. RESULTS: This new approach provides a rapid and sensitive method for the detection of chloroquine using hydrophilic interaction LC coupled to MS/MS (HILIC-MS/MS). Ammonium formate and formic acid were added to mobile phase to attain good peak shapes and the salified chloroquine as well retained in an HILIC column. Linearity, intra- and inter-day precision, accuracy, recovery, matrix effect and stability were evaluated during the validation process. CONCLUSION: The validated method has been successfully used in a PK study in miniature pigs, and paves way for future development.

Pharmacokinetic Properties of Peramivir After Single and Multiple Intravenous Infusions in Healthy Chinese Volunteers.

BACKGROUND AND OBJECTIVES: Peramivir, an antiviral agent for intravenous administration, is used to treat progressive influenza in patients with serious complications. The present study was designed to determine the pharmacokinetics of single and multiple intravenous infusions of peramivir in healthy Chinese subjects. METHODS: Single (150, 300 and 600 mg) and multiple (600 mg) doses of peramivir were intravenously administered to 12 healthy Chinese subjects. There was a 7-day washout period between dosing periods. Blood samples were collected in heparinized tubes at various times. Plasma peramivir and urine peramivir concentrations were measured using a high-performance liquid chromatography-tandem mass spectrometry method. RESULTS: Following single doses of peramivir (150, 300 and 600 mg), the maximum concentration (C max) values were 12,416 ± 3078, 23,147 ± 3668 and 44,113 ± 3787 µg/L, respectively, and the area under the plasma concentration-time curve (AUC) from 0 h to infinity post-dose (AUC∞) values were 24.68 ± 6.48, 47.33 ± 9.22 and 92.43 ± 12.72 mg·h/L, respectively. C max, AUC from 0 to 36 h (AUC0-36) and AUC∞ of peramivir increased proportionally with the dose, and no trend towards accumulation after multiple doses was observed. About 65 % of the peramivir was excreted unchanged in the urine within the first 24 h. CONCLUSIONS: Peramivir pharmacokinetics were dose proportional with increasing doses, with no accumulation after multiple dosing. Peramivir was generally well tolerated, and no serious adverse events occurred.

Plasma pharmacokinetics and lung distribution of tetrahydropalmatine after topical application of cold asthma recipe extract: Feishu (BL 13) versus Non-Feishu acupoint.

ETHNOPHARMACOLOGICAL RELEVANCE: Acupoint application of cold asthma recipe (CAR) was a traditional Chinese medicine (TCM) method, widely used as an alternative medicine for clinical prevention of the common winter diseases of asthma and bronchitis. Tetrahydropalmatine (THP) was a main active ingredient of CAR extract. The aim of this study is to compare plasma pharmacokinetics and lung distribution of THP between Feishu (FS) acupoint (BL 13) and Non-Feishu (NFS) acupoint application of CAR extract by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). MATERIALS AND METHODS: The extract of CAR was topically administrated in FS and NFS acupoint of rats for plasma pharmacokinetics, and topically administrated in FS and NFS acupoint of mice for lung distribution. The plasma and lung homogenates were pretreated by protein precipitation with acetonitrile. Chromatographic separation was performed on an ACQUITY UPLC BEH C18 column with a mobile phase consisted of 0.1% formic acid in acetonitrile and 0.1% formic acid in water. The detection was accomplished by multiple-reaction monitoring (MRM) scanning in the positive electrospray ionization (ESI(+)) mode. All pharmacokinetic parameters were estimated by non-compartmental analysis. RESULTS: A sensitive, accurate and precise UPLC-MS/MS method was successfully established for determination of THP in 100 µL plasma and lung homogenate. The lower limit of quantification (LLOQ) of THP was 0.05 ng/mL and 0.072 ng/mL, respectively. The pharmacokinetic results manifested that THP was absorbed and eliminated slowly in plasma. Additionally, it was found that there was significantly higher amount of THP absorbed into blood and lung after FS acupoint application compared to NFS acupoint application. CONCLUSIONS: Both of the rat plasma pharmacokinetics and mice lung distribution of THP could support that FS acupoint application of CAR extract has greater advantages of absorption into the blood circulation and distribution in target tissue over NFS acupoint application. The results might be helpful in providing a rational explanation for why the TCM chose the acupoint application and elucidating the underlying mechanism of this treatment.