Therapeutic Drug Monitoring Service Research Articles

Vancomycin bioanalysis for TDM services by using immunoassay and HPLC: A scoping review

Background: Administration of vancomycin in treating infections caused by Methicillin-resistant Staphylococcus aureus (MRSA) requires therapeutic drug monitoring (TDM). The immunoassay method and high-performance liquid chromatography (HPLC) are the two methods of choice for examining vancomycin levels, with their respective advantages. Objective: This study aims to review the validity of immunoassay and HPLC methods, as well as consider which method is appropriate, effective, and efficient for TDM in the clinical setting. Method: Related articles were searched for using the keywords "immunoassay", "vancomycin", "HPLC", "bioanalysis", and "human" in the PubMed, Google Scholar, and Science Direct databases. Result: A total of 20 publications examined immunoassays, whereas 23 articles covered HPLC. Both the immunoassay and HPLC methods provided acceptable bioanalytical validation values. Conclusion: The immunoassay method is an option for routine sample analysis that requires fast results, but this method is not recommended for patients with high immunoglobulin levels. The HPLC method is a choice because it offers better selectivity and sensitivity.

Rapid Metabolism Underlying Subtherapeutic Serum Levels of Atypical Antipsychotics Preceding Clozapine Treatment: A Retrospective Analysis of Real-World Data.

Adequate antipsychotic treatment intensity is required before diagnosing resistant schizophrenia and initiating clozapine treatment. We aimed to investigate potential rapid drug metabolism underlying low dose-adjusted serum concentration (CD) of non-clozapine atypical antipsychotics preceding clozapine treatment. Patients using non-clozapine, atypical antipsychotics (aripiprazole, risperidone, olanzapine, or quetiapine) within 1 year before starting clozapine were included in this study from a therapeutic drug monitoring service in Oslo, Norway, between 2005 and 2023. Patients were assigned into low CD (LCD) and normal CD (NCD) subgroups. Using a reference sample with 147,964 antipsychotic measurements, LCD was defined as CDs below the 25th percentile, while patients with NCD exhibited CDs between the 25th and 75th percentile of the respective reference measurements. Metabolic ratios, doses, and frequency of subtherapeutic levels of non-clozapine antipsychotics were compared between LCD and NCD groups. Preceding clozapine treatment, 110 out of 272 included patients (40.4%) were identified with LCD. Compared with the NCD group, LCD patients exhibited higher metabolic ratios of olanzapine (1.5-fold; p < 0.001), quetiapine (3.0-fold; p < 0.001), and risperidone (6.0-fold; p < 0.001). Metabolic ratio differences were independent of smoking and CYP2D6 genotype for olanzapine (p = 0.008) and risperidone (p = 0.016), respectively. Despite higher doses of olanzapine (1.25-fold; p = 0.054) and quetiapine (1.6-fold; p = 0.001) in LCD versus NCD patients, faster metabolism among the former was accompanied by higher frequencies of subtherapeutic levels of olanzapine (3.3-fold; p = 0.044) and quetiapine (1.8-fold; p = 0.005). LCD and associated rapid metabolism of non-clozapine antipsychotics is frequent before starting clozapine treatment. For olanzapine and quetiapine, this is associated with significantly increased risk of having subtherapeutic concentrations.

Dose-dependent effect of lamotrigine on quetiapine serum concentration in patients using instant release tablets

PurposeLamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction.MethodsPatients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests.ResultsIn total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06).ConclusionThe effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine.

A cross-sectional study of the current situation with therapeutic drug monitoring in Thailand: Requirements, challenges and the role of educational institutions

Background: Therapeutic drug monitoring (TDM) is a drug dose determination tool for individualised therapy. Objective: This study examined the TDM services provided by hospitals and topics taught in pharmacy schools in Thailand. Methods: TDM service and curriculum questionnaires were sent to 179 hospitals and all 19 pharmacy schools in Thailand. Correlations were tested using Fisher’s exact test. Results: Completed questionnaires were returned by 116 hospitals (64.8%). Forty-three hospitals (37.1%) conducted TDM and most were large hospitals (&gt;500 beds, n=27, 62.8%). Higher numbers of beds and pharmacists positively correlated with conducting TDM (p &lt; 0.001 and p = 0.003, respectively). Phenytoin was the most frequently monitored drug (n=39, 90.7%). All pharmacy schools taught TDM for phenytoin, valproic acid, vancomycin, carbamazepine, and digoxin. The most frequently cited benefit of TDM was to prevent adverse drug reactions (n = 108, 93.1%). The primary reason cited for not conducting TDM was a lack of in-house laboratories (n=78, 67.2%). Conclusion: Despite a positive attitude among respondents and that TDM subjects were being taught in all pharmacy schools in Thailand, less than half of the surveyed hospitals reported conducting TDM. Providing smaller hospitals with access to the TDM laboratories and expertise at large hospitals could increase this proportion.

Novel Identification of Cysteinyl Derivatives of Toxic Clozapine Nitrenium Ions and the Effect of Valproic Acid on Metabolite Formation: A Study Using Reprocessed High-Resolution Mass Spectra of Analyzed Therapeutic Drug Monitoring Samples.

Clozapine (CLZ) use is hampered by the risk of granulocyte toxicity, which is associated with the formation of nitrenium ions and the concurrent use of valproic acid (VPA). These highly reactive nitrenium ions cannot be measured in vivo. Instead, deactivated cysteinyl conjugates may potentially be detected. The aim of this study was to develop a novel method for identifying cysteinylated derivates of CLZ nitrenium ions to investigate the effect of VPA on their formation using therapeutic drug monitoring data. A population comprising 93 VPA comedicated and 162 control patients from a therapeutic drug monitoring (TDM) service in Oslo, Norway, was included. Reprocessing of ultraperformance liquid chromatography high-resolution mass spectra (UHPLC-HR-MS) of previously analyzed TDM samples, combined with the assessment of MS/MS fragmentation patterns, was performed to identify the CLZ cysteinyl conjugates. Smoking, which induces CLZ metabolism, was assessed by detecting cotinine in the reprocessed mass spectra. By reprocessing the UHPLC-HR-MS files of the TDM analyses and reviewing the MS/MS fragment profiles, four cysteinyl conjugates of CLZ were identified. The formations of CLZ cysteinyl (CLZ-Cys 1+ ) and CLZ- N -oxide cysteinyl (CLZ-NOX-Cys 1+ ) were 1.5-fold ( P = 0.038) and 2.1-fold ( P < 0.001) higher in VPA-treated patients than those in the controls. In agreement with previous studies, a 45% reduction in N -desmethylclozapine formation was observed in VPA-treated patients ( P < 0.001). A novel method for detecting cysteinyl conjugates of CLZ was developed. Application of this method indicated that VPA significantly increased the formation of CLZ-Cys 1+ metabolites, which might explain the granulocyte toxicity reported after adding VPA to CLZ treatment. The developed method opens new avenues for investigating CLZ toxicity, e.g. by correlating cysteinyl conjugates and granulocyte counts in patients.

Age of onset for increased dose-adjusted serum concentrations of antidepressants and association with sex and genotype: An observational study of 34,777 individuals.

The aim of this study was to examine the age of onset for increased dose-adjusted serum concentrations (C/D ratio) of common antidepressant drugs and to explore the potential association with sex and CYP2C19/CYP2D6 genotype. Serum concentrations and prescribed daily doses for citalopram, escitalopram, sertraline, venlafaxine and mirtazapine, and CYP genotypes, were obtained from a therapeutic drug monitoring (TDM) service. Segmented linear regression analysis was used to examine the relationship between age and antidepressant log C/D ratio in (i) all individuals, (ii) men and women, and (iii) CYP2D6/CYP2C19 normal metabolizers (NMs) and CYP2D6/CYP2C19 intermediate or poor metabolizers (IMs/PMs). A total of 34,777 individuals were included in the study; CYP genotype was available for 21.3%. An increase in C/D ratio started at 44‒55 years of age. Thereafter, the increase progressed more rapidly for citalopram and escitalopram than for venlafaxine and mirtazapine. A doubled C/D ratio was estimated to occur at 79 (citalopram), 81 (escitalopram), 86 (venlafaxine), and 90 years (mirtazapine). For sertraline, only modest changes in C/D ratio were observed. For escitalopram and venlafaxine, the observed increase in C/D ratio started earlier in women than in men. The results regarding CYP genotype were inconclusive. The age-related increase in C/D ratio starts in middle-aged adults and progresses up to more than twofold higher C/D ratio in the oldest old. Sertraline seems to be less prone to age-related changes in C/D ratio than the other antidepressants.

Development, validation and clinical implementation of a UPLC-MS/MS bioanalytical method for simultaneous quantification of cabotegravir and rilpivirine E-isomer in human plasma

A reversed phase ultra-high performance liquid chromatography method was developed for the simultaneous quantification of cabotegravir (CAB) and the E-isomer of rilpivirine (RPV) in human EDTA plasma, also considering RPV E-isomer instability. Because of the instability of RPV (and CAB) in all light conditions, the (RPV Z-isomer/total RPV)-isomer ratio of RPV was determined for each stock, calibration curve standard, quality control sample and patient sample. [2H3]-CAB and [13C6]-RPV were used as internal standard. Sample preparation involved protein precipitation of plasma using methanol. An HSS T3 column with a guard column (set at 40 °C) was used for analyte separation. The mobile phase components were 65 % 0.1 % formic acid in water (A) and 35 % 0.1 % formic acid in acetonitrile (B) and the flow rate was 0.5 mL/min. Detection was performed with tandem mass spectrometry (MS/MS) in a total runtime of 3.0 min. The assay was validated over the concentration range of 0.0500 – 10.0 mg/L for CAB and 0.00300 – 3.00 mg/L for RPV. The average within-day and between-day accuracies for the assay in plasma were 101 % and 101 % for CAB and 97.6 % and 98.5 % voor RPV, respectively. Within-day and between-day precision in coefficients of variations (CV) were 5.0 %. Extraction recovery was 99 % and 102 % for CAB and its internal standard and 95 % and 97 % for RPV and its internal standard. As our aim was that the (Z-isomer RPV/total RPV) response ratio in patient samples had to be less than 10 % to give reliable results, the (Z-isomer RPV/total RPV) response ratio in stocks, calibration curve standards and internal quality control samples were also taken into account being maximal 0.9 % and 2.3 % respectively. This assay has been successfully used in our Therapeutic Drug Monitoring (TDM) service for people living with HIV on long-acting injectable therapy with CAB/RPV and will also be used in future pharmacokinetic studies.

Effect of CYP2D6 genotype on duloxetine serum concentration.

Duloxetine is metabolized by cytochrome P450 (CYP)1A2 and CYP2D6. The aim of this study was to investigate the effect of the CYP2D6 genotype on duloxetine serum concentration adjusting for age and sex. Patients were included retrospectively from a therapeutic drug monitoring service. Multiple linear regression analysis was used to investigate the effect of CYP2D6 genotype, age and sex on the duloxetine concentration-to-dose (C/D) ratio. In total, 269 patients were included and assigned to the following genotype-predicted phenotype subgroups: CYP2D6 poor metabolizers (PMs, n= 23), intermediate metabolizers (IMs, n= 121), normal metabolizers (NMs, n= 120) and ultrarapid metabolizers (UMs, n= 5). Multiple linear regression analysis revealed a 95% higher duloxetine C/D ratio in PMs compared with NMs (p= 0.009). Patients ≥65 years had a 56% higher C/D ratio than younger patients (p= 0.01), while women had a 46% higher C/D ratio than men (p= 0.04). In conclusion, the CYP2D6 PM phenotype is associated with a twofold higher concentration at recommended dosing compared with the NM phenotype. CYP2D6 PM females above 65 years are at particular risk of high duloxetine levels as they may obtain a threefold higher C/D ratio compared with younger, male NMs.

Assessing Adherence to Clozapine: Practical Considerations.

The clinical assessment of adherence to clozapine may prove difficult. We studied the incidence of nonadherence (plasma clozapine <0.01 mg L -1 ) in samples submitted to a clozapine therapeutic drug monitoring (TDM) service, 1993-2017. Clozapine was not detected in 2865 samples from men (2214 patients, 1.1% of all samples from men) and 1068 samples from women (822 patients, 1.0% of all samples from women). Information on the prescribed dose was supplied for 1623 of these samples from men and 492 of these samples from women. Prescribed doses ranged up to 1200 mg d -1 , although most were in the range 100 to 600 mg d -1 . Norclozapine was detected in 260 (9.1%) and 67 (6.3%) of the samples from men and from women, respectively, that did not contain clozapine. While an assay was requested to confirm either a patient history of nonadherence, or to establish that clozapine had been cleared from the circulation after overdosage, for example, in at least 38 instances, in the vast majority of cases the absence of clozapine from the sample was unexpected. While adherence to clozapine may be good in general, tolerance to its potentially fatal cardiovascular effects is easily lost. Moreover, in treatment-resistant schizophrenia, the risk of self-harm increases if the drug is not taken regularly. In addition to presently available TDM services, the advent of a clozapine immunoassay for laboratory use should make it easy to institute at least monthly clozapine TDM at minimal extra cost.

Impact of age, sex and cytochrome P450 genotype on quetiapine and N-desalkylquetiapine serum concentrations: A study based on real-world data from 8118 patients.

To investigate the effect of aging, sex and cytochrome P450 (CYP) genotypes on the exposure of quetiapine (QUE) and the pharmacologically active metabolite N-desalkylquetiapine (NDQ). Patients with serum concentrations of QUE and NDQ were included retrospectively from a therapeutic drug monitoring service. The outcome measures were concentration:dose (C:D) ratios of QUE and NDQ, and NDQ:QUE metabolic ratio. Linear mixed model analyses were used to evaluate the effects of age, sex and, subsequently, CYP2D6/3A genotypes. The average age of the included population (n= 8118 patients) was 44 years (13.5% ≥65 years). The C:D ratio of QUE and NDQ gradually increased in patients aged >50 years compared to those aged 18-30 years, with 28 and 29% increase, respectively, for patients aged >70 years (P< .001). Compared to males, females had 15% lower QUE C:D ratio and 10% higher C:D ratio of NDQ (both P< .001). The NDQ:QUE metabolic ratio was 30% higher in females than in males (P< .001). For females ≥65 years, the NDQ C:D ratio was 36% higher compared to males <65 years (P< .001). A significantly higher NDQ C:D ratio was observed for CYP2D6 intermediate (+7%, P= .012) and poor (+17%, P= .001) compared to normal metabolizers. No effects of CYP3A4*22 and CYP3A5*1 allele variants were observed. This study shows an increase of the QUE and NDQ exposures during aging. Old age, female sex and CYP2D6 allele variants encoding reduced activity are factors associated with high NDQ exposure. Therefore, females ≥65 years carrying CYP2D6 allele variants encoding reduced activity have the highest risk of dose-dependent side effects of NDQ during QUE treatment.

From "wet" matrices to "dry" blood spot sampling strategy: a versatile LC-MS/MS assay for simultaneous monitoring caffeine and its three primary metabolites in preterm infants.

To update traditional "wet" matrices to dried blood spot (DBS) sampling, based on the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) technique, and develop a method for simultaneous analyzing caffeine and its three primary metabolites (theobromine, paraxanthine, and theophylline), supporting routine therapeutic drug monitoring (TDM) for preterm infants. DBS samples were prepared by a two-step quantitative sampling method, i.e.,volumetric sampling of a quantitative 10 μL volume of peripheral blood and an 8 mm diameter whole punch extraction by a methanol/water (80/20, v/v) mixture containing 125 mM formic acid. Four paired stable isotope labeled internal standards and a collision energy defect strategy were applied for the method optimization. The method was fully validated following international guidelines and industrial recommendations on DBS analysis. Cross validation with previously developed plasma method was also proceeded. The validated method was then implemented on the TDM for preterm infants. The two-step quantitative sampling strategy and ahigh recovery extraction method were developed and optimized. The method validation results were all within the acceptable criteria. Satisfactory parallelism, concordance, and correlation were observed between DBS and plasma concentrations of the four analytes. The method was applied to provide routine TDM services to 20 preterm infants. A versatile LC-MS/MS platform for simultaneous monitoring caffeine and its three primary metabolites was developed, fully validated, and successfully applied into the routine clinical TDM practices. Sampling method switching from "wet" matrices to "dry" DBS will facilitate and support the precision dosing of caffeine for preterm infants.

Beta-Lactam Dose Optimisation in the Intensive Care Unit: Targets, Therapeutic Drug Monitoring and Toxicity.

Beta-lactams are an important family of antibiotics used to treat infections and are commonly used in critically ill patients. Optimal use of these drugs in the intensive care unit (ICU) is important because of the serious complications from sepsis. Target beta-lactam antibiotic exposures may be chosen using fundamental principles of beta-lactam activity derived from pre-clinical and clinical studies, although the debate regarding optimal beta-lactam exposure targets is ongoing. Attainment of target exposures in the ICU requires overcoming significant pharmacokinetic (PK) and pharmacodynamic (PD) challenges. For beta-lactam drugs, the use of therapeutic drug monitoring (TDM) to confirm if the desired exposure targets are achieved has shown promise, but further data are required to determine if improvement in infection-related outcomes can be achieved. Additionally, beta-lactam TDM may be useful where a relationship exists between supratherapeutic antibiotic exposure and drug adverse effects. An ideal beta-lactam TDM service should endeavor to efficiently sample and report results in identified at-risk patients in a timely manner. Consensus beta-lactam PK/PD targets associated with optimal patient outcomes are lacking and should be a focus for future research.

Evaluation Of Therapeutic Drug Monitoring Services In Duhok, Kurdistan Region, Iraq: Valproic Acid As Example

Introduction: &#x0D; Therapeutic drug monitoring (TDM) measures the level of medications within the biological fluids. Valproic acid (VPA) is a narrow therapeutic index anti-epileptic. Measurement of its level is essential for the evaluation of safety and efficacy. Aim was to evaluate the benefit of TDM services in patients taking Valproic acid with respect to outcome improvement and prevention of adverse events linked to dosage errors,&#x0D; Methodology&#x0D; The cohort was designed to take random samples of patients taking Valproic acid, measuring their VAP blood levels at the correct time. Patient demographic data were collected through face-to-face and phone interviews and from patient charts.&#x0D; Results&#x0D; Results indicated that most patients were male and below 18 years of age. No toxicity was observed in the patient. Very few patients experienced side effects and attacks per week. Patients had no knowledge of medical history, Renal Function Test (RFT), Liver Function Test (LFT), Protein Level, and other medications.&#x0D; Discussion&#x0D; The study found poor education of patients about therapeutic drug monitoring, and TDM is available in private facilities only. The patient had no education about Renal and liver function test protein levels and other medications being used by them. The study also found that side effects and frequency of attacks per week were not effects by valproic acid blood levels.

Effect of CYP2D6 and CYP2C19 genotypes on atomoxetine serum levels: A study based on therapeutic drug monitoring data.

Atomoxetine is mainly metabolized by CYP2D6 while CYP2C19 plays a secondary role. It is known that patients carrying genotypes encoding decreased/absent CYP2D6 metabolism obtain higher atomoxetine concentrations and are at increased risk of adverse effects. Here, we aimed to investigate the added effects of reduced-function CYP2C19 genotype on atomoxetine concentrations in real-world settings. Serum atomoxetine concentrations and CYP2D6/2C19 genotypes were included from a therapeutic drug monitoring service. Patients were first subgrouped according to CYP2D6 encoding normal, reduced or absent CYP2D6 metabolism, referred to as normal (NM), intermediate (IM) or poor metabolizers (PM). Then, the effect of reduced-function CYP2C19 genotypes was investigated. Genotyping of the CYP2D6 nonfunctional or reduced variant alleles comprised CYP2D6*3-*6, *9-*10 and *41. For CYP2C19, the CYP2C19*2 was analysed to define metabolizer phenotype. Dose-adjusted serum atomoxetine concentration was the exposure measure. Using a patient cohort (n= 315), it was found that CYP2D6 IM and PM patients had 1.9-fold (95% confidence interval: 1.4-2.7) and 9.6-fold (5.9-16) higher exposure of atomoxetine compared with CYP2D6 NMs. CYP2C19*2 carriers had 1.5-fold (1.1-2.2) higher atomoxetine exposure than noncarriers regardless of CYP2D6 genotype. CYP2D6 genotype has a great impact on atomoxetine exposure, where our real-world data suggest atomoxetine dose requirements to be around half and 1/10 in CYP2D6 IM and PM vs. NM patients, respectively. When adding CYP2C19 genotype as a factor of relevance for personalized atomoxetine dosing, CYP2C19*2 carriers should further reduce the dose by a third. These findings suggest that pre-emptive CYP2D6/CYP2C19 genotyping should be performed to individualize atomoxetine dosing and prevent adverse effects.

A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status.

Guidance on clozapine dosing in treatment-resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and N-desmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status and body weight. A population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993-2017. There were 17 787 measurements from 5960 patients (4315 male) aged 18-86 years. The estimated clozapine plasma clearance was reduced from 20.2 to 12.0L h-1 between 20 and 80 years. Model-based dose predictions to attain a predose plasma clozapine concentration of 0.35 mg L-1 was 275 (90% prediction interval 125, 625) mg day-1 in nonsmoking, White males weighing 70 kg and aged 40 years. The corresponding predicted dose was increased by 30% in smokers, decreased by 18% in females, and was 10% higher and 14% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. Overall, the predicted dose decreased by 56% between 20 and 80 years. The large sample size and wide age range of the patients studied allowed precise estimation of dose requirements to attain predose clozapine concentration of 0.35 mg L-1 . The analysis was, however, limited by the absence of data on clinical outcome and future studies are required to determine optimal predose concentrations specifically in those aged over 65 years.

A national survey of individualized pharmaceutical care practice in Chinese hospitals in 2019.

Background: Individualized pharmaceutical care, which consists of therapeutic drug monitoring (TDM), pharmacogenetic (PGx) testing and pharmacist-managed clinic (PMC), is one of the most important trends in clinical pharmacy development in the future. While relevant studies in China were primarily single-center or regional. This study aims to explore the current status of individualized pharmaceutical care in China, find out the existing problems and provide references for its further development. Methods: An electronic questionnaire was used and national hospitals' pharmaceutical administration data from January to December 2019 were collected. The data were sorted into Excel for further statistical analysis. All analyses were descriptive. Results: The proportions of hospitals that performed TDM and PGx testing were 12.83% and 9.48%, respectively. The major responsible departments were the clinical laboratory and pharmacy department. External quality control was carried out in around 70% of hospitals for both TDM and PGx testing. More than half of hospitals provided TDM services for valproate sodium, digoxin, carbamazepine, vancomycin and cyclosporine. And an average of 6.84 drugs were performed TDM in 540 hospitals. Clopidogrel and warfarin were the top two drugs that performed PGx testing. As for the PMC, 10.03% of hospitals opened PMC, of which 60.00% had independent PMC. Approximately 80% of PMC services were free of charge. Conclusion: The development of individualized pharmaceutical care in China is still in the early stage. Different sectors have to coalesce to promote its implementation, including the appropriate education, coverage, reimbursement policies, high-quality evidence, data systems, health system processes and health policies, etc.

A Survey of Therapeutic Drug Monitoring Status in China.

To understand the status of therapeutic drug monitoring (TDM) in China Mainland, and thus lay down the foundation for further improvement in TDM. In the present study, a nationwide questionnaire survey was conducted, which was distributed and collected using a mobile-based application. Clinicians, pharmacists, and clinical laboratory physicians belonging to different levels of public hospitals were involved as subjects/objects. The contents of the survey included TDM implementation in their hospital and information regarding their opinions and suggestions on TDM work. Mann-Whitney test was used to compare the difference between top tertiary hospitals and non-top tertiary hospitals. A total of 475 questionnaires were collected, 383 from top tertiary hospitals (3A hospitals) and 92 from non-top tertiary hospitals (other than 3A hospitals). A total of 240 clinicians, TDM pharmacists, and clinical laboratory physicians were involved, with an effective rate of 50.5%. Top tertiary hospitals were associated with certain advantages, such as the number of TDM testing facilities, annual sample size, number of monitoring varieties, and interpretation rate of monitoring reports, compared with non-top tertiary hospitals. In particular, β-lactamase inhibitor, olanzapine, carbamazepine, and glucocorticoids seemed to be the main projects that clinicians wanted to assess. The drugs for which TDM was commonly performed included vancomycin, valproic acid, carbamazepine, phenytoin sodium, and methotrexate. The most commonly used detection methods include high-performance liquid chromatography, immunization, 2D-LC, and LC-MS. The monitoring concentration range was found to be inconsistent for most of the drugs. Currently, no unified regulation exists for TDM charges in China, which is no more than ¥200 in general. Clinicians rely on pharmacists for professional guidance. Importantly, improvement in the interpretation of monitoring reports, proficiency testing, and cooperation with clinical departments may aid in improving the level of TDM service. This survey objectively reflected the current status of TDM work in hospitals in China, and provided a strong reference base for devising strategies for improvement and effective execution of TDM work.

Age, Sex, and Comedication Effects on the Steady-State Plasma Concentrations of Amisulpride in Chinese Patients with Schizophrenia.

Amisulpride, a second-generation atypical antipsychotic drug, was first marketed in Europe in the 1990s. This study aimed to provide a reference for the clinical application of amisulpride. The effects of age, sex, or specific comedications on amisulpride concentrations in Chinese patients with schizophrenia in the real world were investigated. A retrospective study was conducted of data on amisulpride based on the therapeutic drug monitoring service database at the Zigong Affiliated Hospital of Southwest Medical University. Based on the inclusion criteria, 195 plasma samples from 173 patients (67.05% female and 32.95% male patients) were included for in-depth analysis. The median daily dose of amisulpride was 400 mg/d, median plasma concentration was 457.50 ng/mL, and median concentration/dose (C/D) ratio was 1.04 ng/mL/mg/d. The daily dose of amisulpride positively correlated with measured steady-state plasma concentrations. A significant difference was observed in the subgroup analysis of the combination with valproic acid, zopiclone, or aripiprazole on plasma concentrations. Combining amisulpride with these drugs increased the C/D ratios by 0.56-, 2.31-, and 0.77-fold, respectively. After adjusting for age, the median C/D ratio was found to be significantly different between female and male patients. However, no significant differences in daily dose, plasma concentration, and C/D ratio were noted with respect to sex and age of the patients. Sex differences were inferred for the first time in this study, with differential effects on daily dose, steady-state plasma concentration, and C/D ratio associated with the population. In the included study samples, blood concentrations were distributed in the range of 223.25-823.55 ng/mL, which perhaps needs to be evaluated in line with the reference range of ammonia-sulfur ratios in the Chinese population.

Building clinical pharmacology laboratory capacity in low- and middle-income countries: Experience from Uganda.

Research and clinical use of clinical pharmacology laboratories are limited in low- and middle-income countries. We describe our experience in building and sustaining laboratory capacity for clinical pharmacology at the Infectious Diseases Institute, Kampala, Uganda. Existing laboratory infrastructure was repurposed, and new equipment was acquired. Laboratory personnel were hired and trained to optimise, validate, and develop in-house methods for testing antiretroviral, anti-tuberculosis and other drugs, including 10 high-performance liquid chromatography methods and four mass spectrometry methods. We reviewed all research collaborations and projects for which samples were assayed in the laboratory from January 2006 to November 2020. We assessed laboratory staff mentorship from collaborative relationships and the contribution of research projects towards human resource development, assay development, and equipment and maintenance costs. We further assessed the quality of testing and use of the laboratory for research and clinical care. Fourteen years post inception, the clinical pharmacology laboratory had contributed significantly to the overall research output at the institute by supporting 26 pharmacokinetic studies. The laboratory has actively participated in an international external quality assurance programme for the last four years. For clinical care, a therapeutic drug monitoring service is accessible to patients living with HIV at the Adult Infectious Diseases clinic in Kampala, Uganda. Driven primarily by research projects, clinical pharmacology laboratory capacity was successfully established in Uganda, resulting in sustained research output and clinical support. Strategies implemented in building capacity for this laboratory may guide similar processes in other low- and middle-income countries.

Clozapine: Dose, Sex, Ethnicity, Smoking Habit, Age, Body Weight, and Plasma Clozapine and N-Desmethylclozapine (Norclozapine) Concentrations in Clinical Practice.

Guidance on clozapine dosing in treatment refractory schizophrenia is based largely on data from young adult male White patients. This study aimed to audit the plasma clozapine and N-desmethylclozapine (norclozapine) concentrations attained in male and female patients of different ethnicity and smoking habit. The effect of dose, sex, ethnicity, age, body weight, and smoking habit on plasma clozapine and norclozapine concentrations were studied using data from a therapeutic drug monitoring service, 1993 to 2017. There were 371,610 samples (48,098 patients, 32,855 male). Ethnicity was recorded for 763 Afro-Caribbean, 536 Asian, and 7940 White patients. Males were prescribed significantly higher median doses than females but attained significantly lower median plasma clozapine and norclozapine concentrations. Asian and Afro-Caribbean males were prescribed significantly lower and higher median doses, respectively, than White males but attained significantly higher and lower median plasma clozapine and norclozapine concentrations, respectively. Data from 78,431 samples (23,516 patients) were analyzed using a linear mixed model. The predicted dose to attain a predose plasma clozapine concentration of 0.35 mg/L in a nonsmoking White male aged 40 years, with weight of 70 kg, and plasma clozapine-norclozapine ratio of 1.32 was 344 mg/d (95% confidence interval, 227-526 mg/d). The predicted dose was 33% higher and 20% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. In all cases, the predicted dose was increased by 36% in smokers and decreased by 22% in females. Research is needed to further investigate the complex relationships between dose, sex, ethnicity, plasma clozapine and norclozapine concentrations, and clinical outcome such as weight gain.