Evaluation of the Homogenous Mobility Shift Assay for Infliximab and Adalimumab Anti-drug Antibody Detection in the Clinical Laboratory.

BACKGROUND: Detecting antidrug antibodies (ADAs) against infliximab or adalimumab is useful for therapeutic drug monitoring. Various ADA detection methods exist, and antibody titer is an output in some algorithms. Homogenous mobility shift assay (HMSA) measures relative ADA concentration and determines drug-ADA complex size in vitro. However, the relevance of complex size determination in drug monitoring remains unclear. Hence, the association between complex size, ADA concentration, and sample detectable neutralizing activity was evaluated. METHODS: Sera from infliximab-treated and adalimumab-treated patients who tested positive for ADA in the National Screening Service were analyzed using 3 ADA assays. HMSA determined the relative ADA concentrations and complex sizes, competitive ligand-binding assay evaluated the sample neutralizing capacity, and enzyme-linked immunosorbent assay detected immunoglobulin (Ig)G4 ADA. RESULTS: Most ADA-positive samples (>80%) formed drug-ADA dimer complexes, whereas 17% had dimer and multimer complexes, and 3% had multimeric complexes. Multimer presence had 100% positive predictive value for detectable neutralizing activity. ADA concentration and detectable neutralizing activity were moderately correlated (r = 0.65) in adalimumab-treated patients and strongly correlated (r = 0.81) in infliximab-treated patients. In adalimumab-treated patients, multimer presence was a stronger predictor of neutralizing activity than ADA concentration was, but not in infliximab-treated patients. However, in infliximab-treated patient samples, multimer presence revealed a distinct subset with high ADA concentrations, neutralizing activity, and IgG4 ADA. CONCLUSIONS: Multimers detected using HMSA had a strong positive predictive value for competitive ligand-binding assay detectable neutralizing activity. Multimeric IgG4-containing ADA-drug complexes revealed a distinct subset of infliximab-treated patient samples, whose clinical relevance merits further investigation.

Evaluation of the Prescribing Skills Assessment implementation, performance and medical student experience in Australia and New Zealand.

AIMS: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final-year medical students. METHODS: This study used a mixed-method approach involving student data (n = 6440) for 2017-2019 (PSA overall score and 8 domain subscores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open-ended survey comments were conducted. RESULTS: The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain subscores. There was low intercorrelation between subscores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training. CONCLUSION: The ANZ PSA was associated with high pass rates and acceptability, although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need.

Changes in inpatient medicine prescribing during COVID-19 lockdown.

BACKGROUND: New Zealand went into lockdown March 2020 successfully eliminating the circulation of the coronavirus disease 2019 (COVID-19) virus. During lockdown there were reduced rates of respiratory infections and hospital admission numbers were low. At the time, rumours of benefit and harm of medicines for COVID-19 were widespread in the lay and medical media. AIM: To describe changes in inpatient prescribing in an acute general medicine service during the New Zealand COVID-19 lockdown in 2020. METHODS: Rates of prescribing of medicines during the 33 days of lockdown were compared with a 33-day control period before lockdown. Prescriptions, patients and bed days were calculated from the hospital patient administration and electronic prescribing and administration systems. RESULTS: In the general medicine service, acute admissions were 20% lower during lockdown (from 1216 pre-lockdown to 974). There was a small decrease in the rate of prescriptions per patient (10.1 vs 10.4, P = 0.01) during lockdown, and the average length of stay was shorter (3.2 vs 3.6 days). Nebulised administration decreased by 75% (1.3% vs 5.3% of admissions) but unexpectedly there was no change in the prescribing rates of antibacterial medicines, e.g. amoxicillin (26% vs 26%). There were no changes in rates of prescribing of medicines being rumoured to potentially improve (e.g. hydroxychloroquine) or worsen (e.g. angiotensin-converting enzyme inhibitors) COVID-19 outcomes. CONCLUSIONS: Acute medical admissions decreased 20% during lockdown for COVID-19, with a proportional decrease in prescriptions. Reduced rates of respiratory tract infections did not lead to decreased prescribing of antibacterial medicines. Rumour-based prescribing did not eventuate.

Four-year review of New Zealand laboratory infliximab and adalimumab concentration results indicating potential for improved dosing.

A review of laboratory results across New Zealand for therapeutic drug monitoring (TDM) of infliximab and adalimumab concentrations and antidrug antibodies (ADAs) over 4 years was completed. Of 6591 results, the median serum concentration for infliximab was 5.7 mg/L and for adalimumab was 5.5 mg/L. Subtherapeutic drug concentrations (<7 mg/L) were measured in 54% of samples. Drug concentrations <2 mg/L were measured in 23% of samples, with ADAs detected in 51% of these. The high number of samples with subtherapeutic drug concentrations and common ADA detection is consistent with failing therapy but could also suggest that standard dosing is frequently too low for patients. These results reinforce the value of antitumour necrosis factor drug TDM in making decisions to adjust dosing or switch agents in patients taking infliximab and adalimumab.

A nationwide survey on therapeutic drug monitoring of anti-tumour necrosis factor agents for inflammatory bowel disease.

BACKGROUND: Routine therapeutic drug monitoring (TDM) during treatment with anti-tumour necrosis factor (anti-TNF) agents in inflammatory bowel disease may increase treatment efficacy and cost-effectiveness, and reduce the risk of loss of response. AIMS: To assess the current use of anti-TNF agent TDM, including trough concentration and anti-drug antibodies, among gastroenterology practitioners in New Zealand. METHODS: A web-based survey was delivered to gastroenterologists and advanced trainees in New Zealand, identified by the New Zealand Society of Gastroenterology. RESULTS: The response rate was 36% (48/134). Adalimumab was the most common initial anti-TNF agent used (78%, infliximab 22%). Ninety-three percent of those who completed the survey used TDM, mainly in cases of non-response or loss or response. Most respondents (93% and 83% for adalimumab and infliximab, respectively) measured trough concentrations within 24 h prior to the next administration. In patients in clinical remission but with endoscopic inflammation on anti-TNF agents, 72% would measure drug concentrations. In the presence of anti-drug antibodies, 45% would add an immunomodulator in patients with active disease and 47% would add an immunomodulator in patients in remission. With low trough concentrations, 77% would make no changes if the patient was in remission, and 75% would increase the dose in case of active disease. CONCLUSION: TDM was routinely used among inflammatory bowel disease gastroenterology clinicians who responded to this survey. However, interpretation of results and decision-making is variable, suggesting more guidance is required.

Simultaneous Determination of Dabigatran, Rivaroxaban, and Apixaban in Human Plasma by Liquid Chromatography/Tandem Mass Spectrometry.

BACKGROUND: Pharmacokinetic studies and therapeutic drug monitoring of anticoagulants require a simple, rapid, and reliable analytical method for monitoring plasma concentrations. The aims of the current work were to develop and validate a liquid chromatography/tandem mass spectrometry method for the simultaneous determination of 3 direct oral anticoagulants (dabigatran, rivaroxaban, and apixaban) in human plasma that is suitable for pharmacokinetic studies and routine therapeutic drug monitoring in busy hospital laboratories. METHODS: This method included a hydrolysis step to account for the active acylglucuronide metabolites of dabigatran that demonstrate an equivalent anticoagulant effect as dabigatran. After hydrolysis, a simple one-step protein precipitation was used for sample preparation. Total dabigatran (the sum of free dabigatran and the contribution from dabigatran acylglucuronides), rivaroxaban, and apixaban, and their corresponding isotopically labeled internal standards were resolved on a C18(2) column. All compounds were detected using electrospray ionization liquid chromatography/tandem mass spectrometry in the positive mode. RESULTS: For all 3 anticoagulants, standard curves were linear over the concentration range of 1.0-1000 mcg/L (r > 0.99), bias was < ±10%, and intraday and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 1.0 mcg/L. For all 3 anticoagulants and corresponding isotopically labeled internal standards, the absolute recoveries were similar and consistent, with mean values of 93%-102%. No significant matrix effects were observed. CONCLUSIONS: This method is simple, rapid, robust, and reliable and can be used to analyze the plasma concentrations of the drugs in patients on dabigatran or rivaroxaban therapy.

Clinical decision support in a hospital electronic prescribing system informed by local data: experience at a tertiary New Zealand centre.

BACKGROUND: An electronic prescribing and administration (ePA) system has been progressively rolled out to Canterbury District Health Board (CDHB, Christchurch, New Zealand) public hospitals since 2014, and is currently used for around 1300 tertiary beds. ePA data can be used to monitor user behaviour, and to evaluate and inform the local customisation of clinical decision support (CDS) tools within the ePA system. AIMS: To describe retrospectively illustrative vignettes of CDHB ePA analyses that have been used for CDS. METHODS: Alerts were developed according to a set of common principles agreed upon by the CDHB CDS Working Group. Alerts were informed and evaluated by extracting and parsing data for various time periods during 2016 to 2018 from the CDHB ePA database. RESULTS: There was a median of 74 000 prescriptions a month. After examining 525 spironolactone prescriptions, the high dose alert threshold was set at 100 mg with an expected alert burden of 3%. The presence of a ceftriaxone shortage prescribing alert for 1 week was associated with a prescribing rate that was lower than 95% of the preceding 52 weeks. Following review of 367 fentanyl patch alerts, revision of the alert led to false positives falling from 43% to 3% (P < 0.0001). At the point of firing, 6% of antithrombotic drug interactions alerts led to immediate changes in prescriptions (94% overridden), and a further 22% were changed within 30 min after the alert. CONCLUSIONS: Local data extracts from ePA systems can inform iterative configuration of the software and monitor user behaviour.

Simultaneous Determination of Cefalexin, Cefazolin, Flucloxacillin, and Probenecid by Liquid Chromatography-Tandem Mass Spectrometry for Total and Unbound Concentrations in Human Plasma.

BACKGROUND: Pharmacokinetic studies and therapeutic drug monitoring of antibiotics require a simple, rapid, and reliable analytical method for monitoring the concentrations in plasma, including unbound concentrations for highly protein-bound drugs. The aim of the current work was to develop and validate a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of total and unbound concentrations of 3 widely used ß-lactam antibiotics (cefalexin, cefazolin, and flucloxacillin) and the often coadministered drug probenecid in human plasma, suitable for pharmacokinetic studies and for routine use in ordinary, busy hospital laboratories. METHODS: Unbound drug was separated from bound drug by ultrafiltration. A simple 1-step protein precipitation was used for sample preparation. Cefalexin, cefazolin, flucloxacillin, probenecid, and their corresponding isotopically labeled internal standards were then resolved on a C18 (2) column. All the compounds were detected using electrospray ionization in the positive mode. RESULTS: Standard curves were linear for all compounds over the concentration range of 0.2-100 mg/L (r > 0.99) for total drug in plasma and 0.01-10 mg/L (r > 0.99) for unbound drug in plasma ultrafiltrate. For both total and unbound drugs, bias was <±10%, and intra- and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 0.2 mg/L for total plasma concentrations and 0.01 mg/L for plasma ultrafiltrate concentrations of all drugs. CONCLUSIONS: The method has proven to be simple, rapid, robust, and reliable and is currently being used in clinical pharmacokinetic studies and in the routine clinical service to enhance the effective use of the ß-lactam antibiotics.

Anticoagulation Use and Clinical Outcomes After Major Bleeding on Dabigatran or Warfarin in Atrial Fibrillation.

BACKGROUND AND PURPOSE: Little is known about the clinical outcomes associated with posthemorrhage anticoagulation resumption for atrial fibrillation. This study had 2 objectives: first, to evaluate anticoagulation use after a first major bleed on warfarin or dabigatran and, second, to compare effectiveness and safety outcomes between patients discontinuing anticoagulation after a major bleed and patients restarting warfarin or dabigatran. METHODS: Using 2010 to 2012 Medicare Part D data, we identified atrial fibrillation patients who experienced a major bleeding event while using warfarin (n=1135) or dabigatran (n=404) and categorized them by their posthemorrhage use of anticoagulation. We followed them until an ischemic stroke, recurrent hemorrhage, or death through December 31, 2012. We constructed logistic regression models to evaluate factors affecting anticoagulation resumption and Cox proportional hazard models to compare the combined risk of ischemic stroke and all-cause mortality and the risk of recurrent bleeding between treatment groups. RESULTS: Resumption of anticoagulation with warfarin (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.59-0.97) or dabigatran (HR 0.66; 95% CI 0.44-0.99) was associated with lower combined risk of ischemic stroke and all-cause mortality than anticoagulation discontinuation. The incidence of recurrent major bleeding was higher for patients prescribed warfarin after the event than for those prescribed dabigatran (HR 2.31; 95% CI 1.19-4.76) or whose anticoagulation ceased (HR 1.56; 95% CI 1.10-2.22), but did not differ between patients restarting dabigatran and those discontinuing anticoagulation (HR 0.65; 95% CI 0.32-1.33). CONCLUSIONS: Dabigatran was associated with a superior benefit/risk ratio than warfarin and anticoagulation discontinuation in the treatment of atrial fibrillation patients who have survived a major bleed.

Which patients may benefit from dose adjustment of non-vitamin K antagonist oral anticoagulants?

The commercially available non-vitamin K antagonist oral anticoagulants (NOAC) are an emerging therapeutic class, which includes dabigatran, rivaroxaban, apixaban, and edoxaban. Dose adjustment of the NOAC currently takes into account the presence of particular patient characteristics that may alter NOAC concentrations. These characteristics include the presence of renal impairment and concomitant drugs affecting proteins involved with the transport and metabolism of the NOAC. NOAC concentrations reflect anticoagulant activity; some studies have shown some correlation with the risks of adverse events, while others have not, and the association is debated by workers in the field. However, dose adjustment based on characteristics before dosing assumes that the patient has drug oral availability and clearance at the mean of patients with these characteristics. Direct quantification of NOAC concentrations, for example, through the use of calibrated coagulation assays, is likely to add further to individualization of dosing to the particular patient.

The performance of contemporary cystatin C-based GFR equations in predicting gentamicin clearance.

AIMS: We aimed to compare the performances of contemporary cystatin C (Cys)-based GFR equations, and the creatinine only Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for predicting gentamicin clearance. METHODS: The bias and imprecision of the CKD-EPI, CKD-EPI_Cys and creatinine-cystatin C CKD-EPI (CKD-EPI_CrCys) equations for predicting gentamicin clearances, were assessed in 260 patients treated with gentamicin during 2012-2013. The creatinine-cystatin C Berlin Initiative Study equation (BIS_CrCys) was examined in the ≥70 year subgroup. The reference gentamicin clearance was calculated using post-dose plasma concentrations. RESULTS: The CKD-EPI_CrCys equation had the highest percentage of estimates within 30% of the reference gentamicin clearance (70%, P = 0.003) and lowest root mean square error (95% CI) of 29 (25, 23) ml min(-1) of the three equations for the entire cohort. There was no significant improvement in the performances of the equations with the exclusion of 41 patients with abnormal thyroid function tests or steroid co-prescription at the time of the index gentamicin dose. Of the remaining 219 patients, adjustment for individual BSA improved the performances of all GFR equations (P ≤ 0.003) in those with body mass indices (BMI) <18.5 or ≥30 kg m(-2) , but not those with BMI 18.5-29.9 kg m(-2) . There was no advantage of the BIS_CrCys over the CKD-EPI_CrCys equation in the ≥70 year subgroup. CONCLUSIONS: The CKD-EPI_CrCys equation provided the best estimate of gentamicin clearance. If used for guiding gentamicin dosing, the results from GFR equations should be adjusted for individual BSA at the extremes of body size.

Gentamicin and renal function: lessons from 15 years' experience of a pharmacokinetic service for extended interval dosing of gentamicin.

BACKGROUND: Extended interval dosing (EID) of gentamicin most commonly involves dosing every 24 hours, but patients with impaired renal function may require a longer dose interval. This study examines a large database of patients treated with gentamicin from 1996 to 2010 to see how many patients with renal impairment would have benefited from dose intervals >24 hours and to define the incidence of nephrotoxicity. METHODS: All patients aged ≥ 16 years who had received gentamicin by EID over the 14-year period and had concentration data available were examined. End points included the numbers (%) achieving the target peak concentration [predicted maximum gentamicin concentration (C(max))] >10 mg/L, the target trough concentration at 24 hours [predicted minimum gentamicin concentration (C(min24)] <0.5 mg/L, and the target area under the curve over 24 hours of 70-100 mg/L · h. How these related to various creatinine clearance (CL(cr)) groupings was also examined, as was the number who developed nephrotoxicity (increase in creatinine of ≥ 0.04 mmol/L). RESULTS: After exclusions, information was available on 4523 patients. Of these, 96% achieved the target C(max), 83% the target C(min24), and 54% the target area under the curve over 24 hours. Of the 73% of patients with CL(cr) ≥ 60 mL/min, 98% and 97% achieved the target Cmax and C(min24), respectively. Of the 19% of patients with CL(cr) of 40-59 mL/min, 94% and 61% achieved the target C(max) and C(min24), respectively. Of the 8% of patients with CL(cr) of 20-39 mL/min, 83% and 15% achieved the target Cmax and C(min24), respectively. Nephrotoxicity, "probably" because of gentamicin, was observed in approximately 4% of the patients studied, which was irreversible in 25% of these (ie, 1% overall). CONCLUSIONS: Extending the dose interval of gentamicin to >24 hours is useful in patients with renal impairment to achieve the aims of EID. These results support initial dose intervals for gentamicin of 24, 36, and 48 hours for patients with CL(cr) ≥ 60, 40-59, and 20-39 mL/min, respectively. Irreversible nephrotoxicity was observed in approximately 1% of the patients studied.

A proposal for dose-adjustment of dabigatran etexilate in atrial fibrillation guided by thrombin time.

Dabigatran is an oral anticoagulant that is increasingly used for atrial fibrillation (AF). Presently, many authorities state that routine laboratory coagulation monitoring is not required. However, data have recently been published demonstrating that higher trough plasma dabigatran concentrations are associated with lower thromboembolic and higher haemorrhagic event rates. Using these data, we simulate a range of AF patients with varying risks for these events and derive a target range of trough plasma dabigatran concentrations (30-130 µg l(-1) ). Finally, we propose that a conventional screening coagulation assay, the thrombin time (TT), can be used to discern whether or not patients are within this range of dabigatran concentrations.

Coagulation assays and plasma fibrinogen concentrations in real-world patients with atrial fibrillation treated with dabigatran.

AIMS: In patients with atrial fibrillation prescribed dabigatran, the aim was to examine the correlation between plasma dabigatran concentrations and the three screening coagulation assays [international normalized ratio (INR), activated partial thromboplastin time (aPTT) and thrombin time (TT)] as well as the dilute thrombin time (dTT) and to examine the contribution of plasma fibrinogen concentrations to the variability in TT results. METHODS: Plasma from patients with atrial fibrillation on dabigatran were analysed for clotting times and concentrations of fibrinogen and dabigatran. Correlation plots (and associated r(2) values) were generated using these data. The variability in TT results explained by fibrinogen concentrations was quantified using linear regression. RESULTS: Fifty-two patients (38-94 years old) contributed 120 samples, with plasma dabigatran concentrations ranging from 9 to 408 µg l(-1) . The r(2) values of INR, aPTT, TT and dTT against plasma dabigatran concentrations were 0.49, 0.54, 0.70 and 0.95, respectively. Plasma fibrinogen concentrations explained some of the residual variability in TT values after taking plasma dabigatran concentrations into account (r(2) = 0.12, P = 0.02). CONCLUSIONS: Of the screening coagulation assays, the TT correlated best with plasma dabigatran concentrations. Variability in fibrinogen concentrations accounts for some of the variability in the TT.

Thirteen years' experience of pharmacokinetic monitoring and dosing of busulfan: can the strategy be improved?

BACKGROUND: A busulfan concentration monitoring and dosing service has been provided by Christchurch Hospital since 1998. This study aimed to see (1) the percentage of patients with an area under the concentration time curve (AUC) outside the target range and had dose adjustment, (2) how busulfan clearance (CL) relates to body weight, and (3) if fewer samples could be used to predict doses. METHODS: Blood samples were taken from patients after oral administration, usually at 0.5, 1, 1.5, and 6 hours, and after the start of a 2-hour intravenous (IV) infusion of busulfan, at 1, 2, 2.5, 3, 6, and 8 hours. Dose adjustment was made based on the AUC compared with the target range. The relationship of CL and body weight for the IV group was used to develop a revised IV dosing schedule. The bias and imprecision of AUCs estimated using fewer sampling points were examined to see if sampling could be economized. RESULTS: Data were available for 150 patients but for 6 patients, data were incomplete and excluded. Of the remaining 144 patients (256 sample sets, 209 oral, 47 IV, 62% with repeats), 38% (IV) and 35% (oral) of patients had AUCs within the target range after the first dose. Dose adjustment was made in 47% and 34% of patients dosed IV and orally, respectively, after which there was a trend to more patients achieving the target AUC. A nonlinear relationship was found between CL and body weight. The initial IV dosing schedule was revised to take this into account. Sampling for busulfan concentration measurement at 3 points (2.5, 4, 8 hours) or 2 points (2.5, 8 hours) after the start of the infusion enabled accurate and precise estimates of AUC0₋24. CONCLUSIONS: Around two thirds of patients treated with busulfan were outside the target AUC range after the first dose. Dose adjustment was made in 37% of patients. The relationship between CL and body weight was used to revise the initial IV dosing schedule. Sampling for AUC estimation could be reduced to 2 time points after IV dosing.

Optimising interruptive clinical decision support alerts for antithrombotic duplicate prescribing in hospital.

INTRODUCTION: Duplicate prescribing clinical decision support alerts can prevent important prescribing errors but are frequently the cause of much alert fatigue. Stat dose prescriptions are a known reason for overriding these alerts. This study aimed to evaluate the effect of excluding stat dose prescriptions from duplicate prescribing alerts for antithrombotic medicines on alert burden, prescriber adherence, and prescribing. MATERIALS AND METHODS: A before (January 1st, 2017 to August 31st, 2022) and after (October 5th, 2022 to September 30th, 2023) study was undertaken of antithrombotic duplicate prescribing alerts and prescribing following a change in alert settings. Alert and prescribing data for antithrombotic medicines were joined, processed, and analysed to compare alert rates, adherence, and prescribing. Alert burden was assessed as alerts per 100 prescriptions. Adherence was measured at the point of the alert as whether the prescriber accepted the alert and following the alert as whether a relevant prescription was ceased within an hour. Co-prescribing of antithrombotic stat dose prescriptions was assessed pre- and post-alert reconfiguration. RESULTS: Reconfiguration of the alerts reduced the alert rate by 29 % (p < 0.001). The proportion of alerts associated with cessation of antithrombotic duplication significantly increased (32.8 % to 44.5 %, p < 0.001). Adherence at the point of the alert increased 1.2 % (4.8 % to 6.0 %, p = 0.012) and 11.5 % (29.4 % to 40.9 %, p < 0.001) within one hour of the alert. When ceased after the alert over 80 % of duplicate prescriptions were ceased within 2 min of overriding. Antithrombotic stat dose co-prescribing was unchanged for 4 out of 5 antithrombotic duplication alert rules. CONCLUSION: By reconfiguring our antithrombotic duplicate prescribing alerts, we reduced alert burden and increased alert adherence. Many prescribers ceased duplicate prescribing within 2 min of alert override highlighting the importance of incorporating post-alert measures in accurately determining prescriber alert adherence.

The pharmacogenetics of CYP2D6 and CYP2C19 in a case series of antidepressant responses.

Pharmacogenetics has potential for optimizing use of psychotropics. CYP2D6 and CYP2C19 are two clinically relevant pharmacogenes in the prescribing of antidepressants. Using cases recruited from the Understanding Drug Reactions Using Genomic Sequencing (UDRUGS) study, we aimed to evaluate the clinical utility of genotyping CYP2D6 and CYP2C19 in antidepressant response. Genomic and clinical data for patients who were prescribed antidepressants for mental health disorders, and experienced adverse reactions (ADRs) or ineffectiveness, were extracted for analysis. Genotype-inferred phenotyping of CYP2D6 and CYP2C19 was carried out as per Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. A total of 52 patients, predominantly New Zealand Europeans (85%) with a median age (range) of 36 years (15-73), were eligible for analysis. Thirty-one (60%) reported ADRs, 11 (21%) ineffectiveness, and 10 (19%) reported both. There were 19 CYP2C19 NMs, 15 IMs, 16 RMs, one PM and one UM. For CYP2D6, there were 22 NMs, 22 IMs, four PMs, three UMs, and one indeterminate. CPIC assigned a level to each gene-drug pair based on curated genotype-to-phenotype evidence. We analyzed a subgroup of 45 cases, inclusive of response type (ADRs/ineffectiveness). Seventy-nine (N = 37 for CYP2D6, N = 42 for CYP2C19) gene-drug/antidepressant-response pairs with CPIC evidence levels of A, A/B, or B were identified. Pairs were assigned as 'actionable' if the CYP phenotypes potentially contributed to the observed response. We observed actionability in 41% (15/37) of CYP2D6-antidepressant-response pairs and 36% (15/42) of CYP2C19-antidepressant-response pairs. In this cohort, CYP2D6 and CYP2C19 genotypes were actionable for a total of 38% pairs, consisting of 48% in relation to ADRs and 21% in relation to drug ineffectiveness.

Frequency of pharmacological target attainment with flucloxacillin and cefazolin in invasive methicillin-susceptible Staphylococcus aureus infection: a prospective cohort study in hospitalized patients.

BACKGROUND: The proportion of patients with invasive methicillin-susceptible Staphylococcus aureus (MSSA) infection who achieve target concentrations of flucloxacillin or cefazolin with standard dosing regimens is uncertain. This study measured drug concentrations in a prospective cohort of patients with invasive S. aureus infections to determine the frequency of target concentration attainment, and risk factors for failure to achieve target concentrations. PATIENTS AND METHODS: Unbound flucloxacillin and cefazolin plasma concentrations were measured at the midpoint between intravenous doses. Adequate and optimal targets were defined as an unbound plasma concentration of ≥1 and ≥2 times the minimum inhibitory concentration (MIC) (flucloxacillin 0.5 mg/L, cefazolin 2 mg/L), respectively (50%fT≥1MIC, 50%fT≥2MIC). RESULTS: There were 50 patients in each of the flucloxacillin and cefazolin groups. Eighty-five (85%) patients met the target of 50%fT≥2MIC and 95 (95%) patients met the target of 50%fT≥1MIC. The median unbound flucloxacillin concentration was 2.6 mg/L [interquartile range (IQR) 1.0-8.1]. The median unbound cefazolin concentration was 15.4 mg/L (IQR 8.8-28.2). A higher proportion of patients in the flucloxacillin group failed to achieve the optimal target compared with the cefazolin group [13 (26%) vs 2 (4%); P=0.002]. Younger age and higher creatinine clearance were associated with lower plasma concentrations. CONCLUSIONS: Standard dosing of flucloxacillin and cefazolin in the treatment of invasive MSSA infections may not achieve target plasma concentrations for a subgroup of patients. Measuring drug concentrations identifies this subgroup and facilitates dose individualization.

A meta-analysis of protein binding of flucloxacillin in healthy volunteers and hospitalized patients.

OBJECTIVES: The aim of this study was to develop a mechanistic protein-binding model to predict the unbound flucloxacillin concentrations in different patient populations. METHODS: A mechanistic protein-binding model was fitted to the data using non-linear mixed-effects modelling. Data were obtained from four datasets, containing 710 paired total and unbound flucloxacillin concentrations from healthy volunteers, non-critically ill and critically ill patients. A fifth dataset with data from hospitalized patients was used for evaluation of our model. The predictive performance of the mechanistic model was evaluated and compared with the calculation of the unbound concentration with a fixed unbound fraction of 5%. Finally, we performed a fit-for-use evaluation, verifying whether the model-predicted unbound flucloxacillin concentrations would lead to clinically incorrect dose adjustments. RESULTS: The mechanistic protein-binding model predicted the unbound flucloxacillin concentrations more accurately than assuming an unbound fraction of 5%. The mean prediction error varied between -26.2% to 27.8% for the mechanistic model and between -30.8% to 83% for calculation with a fixed factor of 5%. The normalized root mean squared error varied between 36.8% and 69% respectively between 57.1% and 134%. Predicting the unbound concentration with the use of the mechanistic model resulted in 6.1% incorrect dose adjustments versus 19.4% if calculated with a fixed unbound fraction of 5%. CONCLUSIONS: Estimating the unbound concentration with a mechanistic protein-binding model outperforms the calculation with the use of a fixed protein binding factor of 5%, but neither demonstrates acceptable performance. When performing dose individualization of flucloxacillin, this should be done based on measured unbound concentrations rather than on estimated unbound concentrations from the measured total concentrations. In the absence of an assay for unbound concentrations, the mechanistic binding model should be preferred over assuming a fixed unbound fraction of 5%.