Results Of Drug Monitoring Research Articles

Initial therapeutic target attainment of perampanel in pediatric patients with epilepsy.

Perampanel is a promising option for the treatment of pediatric epilepsy, but its plasma concentration varies among patients. This retrospective study aimed to investigate the initial target attainment of perampanel plasma concentration in pediatric patients with epilepsy in China. Inpatients admitted from January 2020 to December 2021 in a tertiary hospital were retrospectively included according to pre-set criteria. Demographic characteristics of patients and dosing strategies and therapeutic drug monitoring results were collected. A total of 137 pediatric patients (84 females and 53 males, aged from 0.6 to 16.4years) were include for analysis. The perampanel concentrations varied greatly from 60 to 1,560mg/L among patients, but 89.8% had suitable perampanel concentrations (100-1,000ng/mL). The concomitant use of enzyme-inductive antiepileptic drugs (AEDs) was the only identified risk factor associated with target nonattainment (OR = 5.92, 95% confidence interval 1.68-20.9). Initial perampanel target attainment in pediatric patients is satisfactory. Routine therapeutic drug monitoring to achieved the suggested concentration range for these patients may be unnecessary, except for those receiving combined enzyme inductive AEDs.

Pharmacokinetic Models Scaled-up from Humanized-liver Mouse Data Can Account for Drug Monitoring Results of Atomoxetine and Its 4-Hydroxylated and N-Demethylated Metabolites i n Pediatric Patients Genotyped for Cytochrome P450 2D6.

Atomoxetine is a cytochrome P450 (P450) 2D6 probe substrate and an approved medicine for attention-deficit/hyperactivity disorder. In this humanized-liver mouse study, interactions between atomoxetine and the P450 2D6 probe drug paroxetine were observed. Human physiologically based pharmacokinetic (PBPK) models were established by scaling up humanized-liver mouse data obtained in the absence or presence of paroxetine. These models could explain the drug monitoring results of atomoxetine and its primary 4-hydroxylated and N-demethylated metabolites in Japanese children aged 8-14 years and could be used to help establish the correct dosage and for the evaluation of clinical outcomes. The results of simple PBPK models (using input parameters that reflected the subjects' small body size and normal or reduced P450 2D6-dependent clearance) were in general agreement with one-point measured plasma concentrations of atomoxetine and its 4-hydroxylated and N-demethylated metabolites in 13 pediatric participants. Unexpectedly high hepatic exposure, possibly in intermediate-metabolizer patients harboring CYP2D6*10 or 2D6*36 alleles, might in part explain the adverse effects of atomoxetine prescribed alone recorded in a Japanese adverse-event database. The steady-state, one-point drug monitoring data from the participants indicated extensive biotransformation of atomoxetine to 4-hydroxyatomoxetine under individually prescribed doses of atomoxetine. These results also suggest that a relatively narrow range of 4-hydroxyatomoxetine and N-desmethylatomoxetine concentration ratios in spot urine and/or plasma samples from pediatric patients could be a simple semiquantitative determinant factor for P450 2D6 intermediate metabolizers, compared with the wide range of concentrations of the two primary metabolites and substrate in extensive metabolizers. Significance Statement Validated simple pharmacokinetic models are able to predict steady-state plasma concentrations of the approved medicine atomoxetine and its primary metabolites in the majority of pediatric patients. The package insert advises careful dose escalation, especially for poor metabolizers; however, no simple way exists to determine P450 2D6 phenotypes. A relatively narrow range ratio of 4-hydroxyatomoxetine and N-desmethylatomoxetine in spot urine/plasma samples could be a simple semi-quantitative determinant factor for P450 2D6 intermediate metabolizers to optimize or confirm the correct dosage.

A 5-year retrospective study of amisulpride steady-state plasma concentration in patients with schizophrenia in real-life settings based on therapeutic drug monitoring data.

Here, we present a retrospective analysis of the last 5 years' data collected in real-life settings as direct evidence to evaluate the optimal therapeutic window of amisulpride (AMI) for psychiatric patients. Retrospective analysis of the therapeutic drug monitoring (TDM) results of AMI in outpatients and inpatients were obtained from the Xi'an Mental Health Center from 2017 to 2021. The interquartile (P25-P75) AMI concentrations ranged 212.20-574.25ng/mL. The results showed that the proportion of outpatients who received TDM once was significantly higher than that of inpatients who received TDM once (P<0.001), whereas the reverse was true for those who experienced TDM more than twice (P<0.001). Higher estimated plasma concentrations were identified in inpatients, female patients, and patients over 59 years of age. Nearly 57.21% of the samples had high concentrations (>320ng/mL). The optimal therapeutic reference range for AMI may require reconstruction to guide the use of AMI for the treatment of schizophrenia.

Impact of extracorporeal membrane oxygenation on voriconazole plasma concentrations: A retrospective study.

Aims: We aimed to assess the impact of extracorporeal membrane oxygenation (ECMO) on voriconazole exposure. Methods: Adult critically ill patients with or without ECMO support receiving intravenous voriconazole therapy were included in this retrospective study conducted in a tertiary referral intensive care unit. The first therapeutic drug monitoring (TDM) results of voriconazole in ECMO patients and non-ECMO patients were collected, and the prevalence of subtherapeutic concentrations was analyzed. Multivariate analyses were performed to evaluate the effect of ECMO on voriconazole exposure. Results: A total of 132 patients (including 66 patients with ECMO support) were enrolled and their respective first voriconazole trough concentrations (Cmin) were recorded. The median Cmin of the ECMO group and the non-ECMO group was 1.9 (1.4–4.4) and 4.4 (3.2–6.9) mg/L, respectively (p = 0.000), and the proportion of the two groups in subtherapeutic concentrations range (<2 mg/L) was 51.5% and 7.6%, respectively (p = 0.000). Multiple linear regression analysis of voriconazole Cmin identified that the use of ECMO and coadministration of glucocorticoids were associated with significantly reduced concentrations, while increasing SOFA score and increasing daily dose were associated with significantly increased concentrations. The model accounted for 32.2% of the variability of voriconazole Cmin. Furthermore, binary logistic regression demonstrated that the use of ECMO was an independent risk factor (OR = 7.78, p = 0.012) for insufficient voriconazole exposure. Conclusion: Our findings showed that, in addition to the known drug interactions, ECMO is a significant covariable affecting voriconazole exposure. In addition, SOFA score was identified as a factor associated with increased voriconazole concentration.

Features of toxic nephropathy development during antibiotic therapy

Scientist relevance. Antibacterials can have nephrotoxic effects because medicinal products of this class are primarily excreted by the kidneys.Aim. The study aimed to analyse literature data on the mechanisms, risk factors and specific features of toxic nephropathy development during antibiotic therapy.Discussion. The article considers mechanisms of development of acute interstitial nephritis, acute tubular necrosis, crystal deposits in the tubules, proximal or distal tubulopathy with electrolyte abnormalities during the use of antibiotics. Nephrotoxicity was shown to be most often associated with the use of aminoglycosides, beta-lactams, and vancomycin. The authors analysed the dependence of nephrotoxicity on antibacterial agent lipophilicity and drug–drug interactions. The main risk factors for developing nephropathy are older age; male sex; black race; hypovolaemia; arterial hypotension; angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs or their combinations; and individual genetic characteristics. Nephrotoxicity is associated with genetic characteristics of the systems responsible for metabolism and excretion of antibacterial products: cytochrome P450 isoenzymes, P-glycoprotein, multidrug resistance protein (MRP), multidrug and toxin extrusion (MATE), breast cancer resistance protein (BCRP), and organic anion transporters. Severe generalised infections change pharmacokinetic parameters of antibacterial products. This should be taken into account when prescribing the hydrophilic antibiotics that are excreted by tubular secretion and reabsorbed in the renal tubules.Conclusions. The study demonstrated the effectiveness of the method comprising a combination of dose adjustment based on therapeutic drug monitoring results and renal function monitoring for improving the safety of antibiotic therapy.

Serum or Plasma for Quantification of Direct Oral Anticoagulants?

Background:Direct oral anticoagulants are increasingly replacing vitamin K antagonists for prevention of stroke in patients with atrial fibrillation, partly owing to the lack of a need for routine monitoring. Therapeutic drug monitoring may still be warranted under certain circumstances. It is generally assumed that serum and plasma can be interchangeably used for this purpose. The aim of this study was to investigate possible differences between the serum, citrate-plasma, and ethylenediaminetetraacetic acid (EDTA)-plasma concentrations of apixaban and rivaroxaban in a larger patient group and their relation to factor X measurements.Methods:Plasma and serum samples were drawn during the same venipuncture from patients treated with apixaban or rivaroxaban. Drug levels were measured using ultrahigh-performance liquid chromatography combined with tandem mass spectrometry. Three sample matrices were obtained from 8 healthy volunteers for measurement of factor X antigen and activity.Results:Mean concentrations of apixaban and rivaroxaban were 16.8% and 36.6% higher in serum than in citrate-plasma, respectively (both P < 0.001). The corresponding differences in serum versus EDTA-plasma were 4.5% for apixaban and 13.1% for rivaroxaban (both P < 0.001). Factor X antigen measurements in citrate-plasma, EDTA-plasma, serum with clot activator, and serum without additives yielded comparable results, and factor X activity was significantly higher in serum than in plasma.Conclusions:Apixaban and rivaroxaban concentrations were significantly higher in serum than in plasma. The difference was more pronounced with rivaroxaban and was larger between serum and citrate-plasma than between serum and EDTA-plasma. Higher factor X activity in serum may explain the observed concentration differences. The choice of matrix is, thus, important when interpreting therapeutic drug monitoring results and in research involving analyses of direct oral anticoagulants. The authors recommend citrate-plasma as the preferred matrix.

Charting and Handling Therapeutic Drug Monitoring Results: How they Differ From Most Laboratory Results.

Therapeutic drug monitoring (TDM) results are a biological measure of the ability of the patient to clear a drug as long as the patient is adhering to the prescribed dosage. If the patient is not adherent, then TDM can provide evidence of such nonadherence. To properly interpret TDM results, several variables must be considered. First and foremost is the dose the patient is supposed to be taking. The second variable is whether the patient should have achieved a steady-state condition, which means that the amount of drug the patient is taking in a day is equal to the amount the patient is eliminating in the same day so that the level will not change unless changes occur in either the dosing rate or the ability of the patient to clear the drug. For drugs with a half-life of 24 hours, steady state typically occurs when the patient has been taking the same dose for 5 to 7 days (ie, 5 x the half-life). The third variable is the time between when the last dose was taken and the sample was obtained. Ideally, for most drugs, that desired interval is 10 to 12 hours after the last dose was taken assuming the patient is taking the dose daily as different rules apply for depot medications. There are 2 reasons for this stipulation. First, this interval will best reflect the average concentration that the patient achieves over the daily dosing interval on that drug. Second, for most orally administered drugs, the value that is obtained 10 to 12 hours after the last dose will not be influenced by differences in the absorption of the drug. In contrast, if the sample is obtained during the absorption phase, the plasma concentration can be both much higher and less predictable than is the case when absorption is complete. Therefore, these 3 variables must be included when recording TDM results in the chart. As explained in this column, the TDM result without this information is not optimally interpretable. Parenthetically, TDM results do not need to be repeated (unless specific concerns arise as explained in this column), because these results are a measure of the ability of the patient to clear the drug. For depot medications (eg, antipsychotics), the results should be obtained at the end of the dosing cycle just before the administration of the drug and after the patient has ideally received 4 to 5 injections at equal intervals (eg, monthly) to be near steady-state. Parenthetically, TDM at the appropriate fixed interval (usually monthly) with depot medications is much less sensitive to timing issues than TDM of orally administered drugs. This column explains the rationale for obtaining TDM results, principally focusing on orally administered drugs and how to optimally chart and disseminate these results.

Prospektives Audit des Gentamicin Drug Monitorings in einem Kinderkrebszentrum

Many pediatric cancer centers still use Gentamicin as first line combination treatment in patients with fever and neutropenia. Since 2011, our center has implemented a dosing regimen with 250 mg/m2 BSA (max. 10 mg/kg, max. 400 mg) as a single daily infusion according to the German guideline. In this prospective audit (February 2011 to December 2019), 105 Gentamicin treatment cycles were analyzed in 66 pediatric cancer patients, focusing on adherence to the dosing regimen and the drug monitoring results. Adherence to the dosing regimen was high (89%). In 64% of all cycles, the Cmax (drawn 1 h after the 2nd dose) reached the target of 10-20 µg/ml. Cmax significantly correlated with dosing in mg/m2 BSA (p=0,007), but not with dosing in mg/kg (p=0,366). Age below 6 years did not influence these results. The Gentamicin Ctrough (drawn 8-10 h after the second dose) was < 2 µg/ml in 93% of all cycles without any dose correlation. None of the patients experienced Gentamicin-associated nephrotoxicity. This prospective audit of single daily infusion Gentamicin in pediatric cancer patients without impaired renal function elicits the feasibility and safety of the dosing regimen in mg/m2 BSA according to the German guideline. Since indications for first-line gentamicin are limited, a multicenter prospective study would be advantageous to confirm these observations.

Dose-Related Concentrations of Neuroactive/Psychoactive Drugs Expected in Blood of Children and Adolescents.

Therapeutic drug monitoring is highly recommended for children and adolescents treated with neurotropic/psychotropic drugs. For interpretation of therapeutic drug monitoring results, drug concentrations (C/D) expected in a "normal" population are helpful to identify pharmacokinetic abnormalities or nonadherence. Using dose-related concentration (DRC) factors obtained from pharmacokinetic data, C/D ranges expected under steady state can be easily calculated by multiplication of DRC by the daily dose. DRC factors, however, are defined only for adults so far. Therefore, it was the aim of this study to estimate DRC factors for children and adolescents and compare them with those of adults. To obtain pharmacokinetic data (apparent total clearance of drugs from plasma after oral administration, elimination half-life, area under the curve, and minimum serum drug concentration) from children and adolescents treated with psychotropic drugs, a systematic review of published literature was performed, and the pharmaceutical companies that market these drugs were contacted. Available information was used for the calculation of DRC factors. Fourteen of 26 drugs had similar DRC factors to those reported for adults; 8 and 4 had higher and lower factors, respectively. The antidepressants citalopram, clomipramine, fluvoxamine, and imipramine and the antipsychotics haloperidol and olanzapine showed higher DRC factors than those calculated for adults. The DRC factors of amphetamine and methylphenidate were higher in children (6-12 years) but not in adolescents (13-17 years). On the contrary, the antipsychotic quetiapine and the mood-stabilizing antiepileptics lamotrigine, oxcarbazepine, and topiramate showed lower DRC factors than those calculated for adults. It was concluded that concentrations of neuroactive/psychoactive drugs to be expected in blood for a given dose may differ between adults and children or adolescents, most probably owing to age-dependent differences in the elimination of these drugs.

P092 COMPARISON OF INFLIXIMAB AND ADALIMUMAB CONCENTRATIONS BETWEEN THE ENZYME-LINKED IMMUNOSORBENT ASSAY AND THE HOMOGENEOUS MOBILITY SHIFT ASSAY (HMSA) IN INFLAMMATORY BOWEL DISEASE: AN UPDATE FOLLOWING IMPLEMENTATION OF CORRECTIVE MEASURES FOR THE HMSA

Abstract Background and aims We previously showed a discrepancy between a commercially available enzyme-linked immunosorbent assay (ELISA) and the homogenous mobility shift assay (HMSA) for both infliximab and adalimumab concentrations in patients with inflammatory bowel disease (IBD).1 Based also on the results of this study, Prometheus Laboratories initiated a comprehensive review of their HMSA assays and found that there was an upward drift for both infliximab and adalimumab over a 2-year period, including when our study was being performed. Prometheus corrected the errant values and reported the revised drug concentrations to physicians. We aimed to compare these two assays following the implementation of these corrective measures. Methods Samples from patients with IBD either on infliximab or adalimumab maintenance therapy were prospectively evaluated using both ELISA (InformTx™, Inform Diagnostics) (for research purposes) and the HMSA (ANSER™, Prometheus Laboratories) (performed clinically). Comparison of drug concentrations between assays was performed as previously described.1 Results In total 74 samples were analysed (infliximab, n=45; adalimumab, n=29). Drug concentrations (median [interquartile range, IQR]) were still significantly higher when measured by the HMSA compared to ELISA for foth infliximab (9 [7.1–12.4] vs. 5.7 [4.8–9] μg/ml; p&amp;lt;0.001, respectively) and adalimumab (12.9 [10.3–16.9] vs. 10.6 [8.6–14] μg/ml; p=0.036, respectively). The correlation of infliximab and adalimumab concentrations between assays is depicted in Figure 1. Agreement between assays was moderate [ICC: 0.658; 95% confidence interval (CI): -0.080 to 0.892; p&amp;lt;0.001] for infliximab and strong (ICC = 0.826, 95%CI: -0.066 to 0.949, p&amp;lt;0.001) for adalimumab. A Bland–Altman plot of infliximab and adalimumab concentrations to compare the two assays is shown in Figure 2. Qualitative agreement in drug concentration status (therapeutic or sub-therapeutic) was only minimal between assays using &amp;gt;5 μg/ml (K = 0.299, p=0.005), &amp;gt;7 μg/ml (K = 0.303, p=0.005) or &amp;gt;10 μg/ml (K = 0.323, p=0.003) as therapeutic drug concentrations for infliximab, while for adalimumab was weak using &amp;gt;10 μg/ml as therapeutic drug concentrations (K = 0.437, p=0.004), although overall agreement using either &amp;gt;5 or &amp;gt;7 μg/ml as therapeutic drug concentrations was 97%. Conclusions These data suggest that although the correlation between the ELISA and the HMSA was very good for both infliximab and adalimumab it is difficult to compare absolute drug concentrations. Until commercial assays are properly cross-validated and standardized, assay-dependent drug concentration thresholds may need to be applied to better interpret therapeutic drug monitoring results and it is advisable that patients are monitored with the same assay. 1Inflamm Bowel Dis. 2019 Sep 27. https://doi.org/10.1093/ibd/izz202. [Epub ahead of print]

Adult and infant pharmacokinetic profiling of dihydrocodeine using physiologically based pharmacokinetic modeling.

We previously analysed the serum concentrations of dihydrocodeine in a 1-month-old infant with respiratory depression after being prescribed dihydrocodeine phosphate 2.0 mg/day divided t.i.d. for 2 days. The purpose was to develop a full physiologically based pharmacokinetic (PBPK) model that could account for these and other drug monitoring results. Based on experiments in Caco-2 cell monolayers, the effective permeability of dihydrocodeine in human jejunum was established as 1.28 × 10-4 cm/s. The in vitro Vmax /Km values for dihydrocodeine demethylation mediated by recombinant cytochrome P450 2D6 and 3A4 were 0.19 and 0.066 μl/min/pmol, respectively, and for dihydrocodeine 6-O-glucuronidation mediated by recombinant UGT2B4 and 2B7, the Vmax /Km values were 0.14 and 0.22 μl/min/mg protein, respectively. Renal clearance was calculated as 5.37 L/h on the total clearance value multiplied by the fraction recovered in urine. The reported plasma concentration-time profiles of dihydrocodeine after intravenous administration in healthy volunteers were used to adjust the tissue partitioning ratios. The developed model simulated the pharmacokinetic profiles of dihydrocodeine after single and multiple oral administrations reasonably well in the same population. Subsequently, the validated model was used to simulate pharmacokinetic profiles for five pediatric cases, including the 1-month-old Japanese boy and a 14-year-old Japanese girl who took an overdose of dihydrocodeine phosphate (37 mg). The simulated pharmacokinetic profiles for five virtual pediatric subjects matching the age, gender, and P450 2D6 phenotype of each case approximately reflected the observed values. These results suggested that our dihydrocodeine PBPK model reproduced the results of clinical cases reasonably well for subjects.

Simple pharmacokinetic models accounting for drug monitoring results of atomoxetine and its 4-hydroxylated metabolites in Japanese pediatric patients genotyped for cytochrome P450 2D6

Atomoxetine is an approved medicine for attention-deficit/hyperactivity disorder and a cytochrome P450 2D6 (CYP2D6) probe substrate. Simple physiologically based pharmacokinetic (PBPK) models and compartment models were set up to account for drug monitoring results of 33 Japanese patients (6–15 years of age) to help establish the correct dosage for the evaluation of clinical outcomes. The steady-state one-point drug monitoring data for the most participants indicated the extensive biotransformation of atomoxetine to 4-hydroxyatomoxetine under individually prescribed doses of atomoxetine. However, 5 participants (with impaired CYP2D6 activity scores based on the CYP2D6 genotypes) showed high plasma concentrations of atomoxetine (0.53–1.5 μM) compared with those of total 4-hydroxyatomoxetine (0.49–1.4 μM). Results from full PBPK models using the in-built Japanese pediatric system of software Simcyp, one-compartment models, and new simple PBPK models (using parameters that reflected the subjects' small body size and normal/reduced CYP2D6-dependent clearance) could overlay one-point measured drug/metabolite plasma concentrations from almost common 28 participants within threefold ranges. Validated one-compartment or simple PBPK models can be used to predict steady-state plasma concentrations of atomoxetine and/or its primary metabolites in Japanese pediatric patients (>6 years) who took a variety of individualized doses in a clinical setting.

Development and Validation of an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Concurrent Measurement of Gabapentin, Lamotrigine, Levetiracetam, Monohydroxy Derivative of Oxcarbazepine, and Zonisamide Concentrations in Serum in a Clinical Setting.

Therapeutic drug monitoring of antiepileptic drugs (AEDs) is often necessary to prevent associated destructive toxicities. Tandem mass spectrometry (MS/MS) with stable-isotope-labeled internal standards is considered the gold standard for the measurement of AEDs. This study presents the development and validation of a clinical ultra-performance liquid chromatography-MS/MS method for the concurrent measurement of gabapentin, lamotrigine, levetiracetam, monohydroxy derivative of oxcarbazepine, and zonisamide in human serum. To determine the optimal assay analyte range, one year of AED therapeutic drug monitoring results (n = 1825) were evaluated. Simple protein precipitation with acetonitrile containing isotopically labeled internal standards was used. Reverse-phase ultra-performance liquid chromatography chromatographic separation was used, having a total run time of 3 minutes. Quantification of analytes was accomplished using electrospray ionization in positive ion mode and collision-induced dissociation MS. Assay parameters were evaluated per Food and Drug Administration bioanalytical guidelines. After evaluating internal patient data, the analytical measuring range (AMR) of the assay was established as 0.1-100 mcg/mL. All AEDs were linear across the AMR, with R values ranging from 0.9988 to 0.9999. Imprecision (% coefficient of variation) and inaccuracy (% difference) were calculated to be <20% for the lower limit of quantitation and <15% for the low, mid, and high levels of quality controls across the AMR. All AEDs demonstrated acceptable assay parameters for carryover, stability under relevant storage conditions, matrix effects, recovery, and extraction and processing efficiency. In addition, the assay displayed acceptable concordance to results obtained from a national reference laboratory, with Deming regression R of 0.99 and slope values ranging from 0.89 to 1.17. A simple, cost-effective, and robust ultra-performance liquid chromatography-tandem mass spectrometry method for monitoring multiple AEDs was developed and validated to address the clinical needs of patients at our institution.

Outcomes of a National Cohort of Children with Acute Severe Ulcerative Colitis.

All Irish children with ulcerative colitis (UC) attend the National Centre for Paediatric Gastroenterology at Our Lady's Children's Hospital, Crumlin. The aim of this study was to determine the outcomes of children with acute severe ulcerative colitis (ASC) and the impact of infliximab on these outcomes following its introduction for this indication in 2011. A retrospective chart review of all patients admitted with ASC between January 1, 2009 and December 31, 2015 was undertaken. Patients were identified from the departmental database cross-referenced with the hospital inpatient enquiry system. Inpatients with a paediatric ulcerative colitis activity index (PUCAI) of ≥65 were included. Data collected included baseline demographic and laboratory data, concomitant treatments, PUCAI scores on days 3 and 5, second-line treatments, surgery, and discharge outcomes. Infliximab dose, frequency, and available therapeutic drug monitoring results were recorded, along with clinical response outcomes (remission, primary, and secondary loss of response). The cohort was sub-analysed to determine if there was any era effect pre- and post-introduction of infliximab (2009-2010 and 2011-2015, respectively). Fifty-five patients (M:F = 1.4:1) were treated for acute severe colitis over the study period (8 in the pre-infliximab and 47 in the post-infliximab era) and 46/55 (86%) had steroid-refractory disease. Of these, 7/8 (88%) required colectomy in the pre-infliximab era, compared with 15/47 (36%) in the post-infliximab era. The remission rate with second-line infliximab was 61% at maximal follow-up. There were no identifiable factors that predicted likely success or failure of infliximab, including gender, CRP, day-3 and day-5 PUCAI scores. Of the 33 patients treated with infliximab, dose increase was required in 23/33 (70%); 21/33 (64%) received an accelerated dose schedule, and 9/33 (27%) eventually needed colectomy. Primary and secondary loss of response to infliximab was seen in one and nine patients, respectively. This is the first population-based study of the outcomes of severe UC in Irish children, and suggests a higher burden of steroid-refractory disease compared with previous international studies. While infliximab treatment has led to reduction in colectomy rates, a significant proportion of patients lose therapeutic effect.

Low Risk of Producing an Opioid Use Disorder in Primary Care by Prescribing Opioids to Prescreened Patients with Chronic Noncancer Pain.

To examine the risk of developing aberrant behaviors that might lead to a substance use disorder (addiction) when prescribing opioids for the relief of chronic noncancer pain in primary care settings. Longitudinal, prospective, descriptive design with repeated measures. Private community-based internal medicine and family medicine clinics. Patients with chronic musculoskeletal pain. Standardized measures of patient status (pain, functional impairment, psychiatric disorders, family history) and treatments provided, urine drug monitoring, and medical chart audits (presence of aberrant drug-related behaviors) were obtained in a cohort of 180 patients at the time of initiating opioids for chronic noncancer pain and at three, six, and 12 months thereafter. Over the 12-month follow-up period, subjects demonstrated stable, mild to moderate levels of depression (PHQ-9 scores ranging from 9.43 to 10.92), mild anxiety (BAI scores ranging from 11.80 to 14.67), minimal aberrant drug-related behaviors as assessed by chart reviews, and a low percentage of illicit drug use as revealed by results of urine drug monitoring. Less than 5% of our study population revealed any evidence of substance use disorder. This prospective study suggests that patients without a recent or prior history of substance use disorder who were prescribed primarily short-acting opioids in low doses for chronic noncancer pain have a low risk for developing a substance use disorder. This finding supports the importance of prescreening patients being considered for opioid therapy and that prescription of opioids for noncancer pain may carry a lower risk of abuse in selected populations such as in private, community-based practices.

Therapeutic drug monitoring and use of an adjusted body weight strategy for high-dose voriconazole therapy.

A high-dose 12 mg/kg/day (6 mg/kg twice daily) voriconazole regimen was recommended by the CDC to treat patients injected with contaminated methylprednisolone acetate that caused a multi-state fungal outbreak in 2012-13. Therapeutic drug monitoring results of this unique regimen are unknown, as is the most appropriate dosing weight for obese patients. We evaluated voriconazole trough measurements for this dosing scheme, as well as the use of adjusted body weight dosing for obese patients. Voriconazole trough levels were analysed in obese (BMI ≥35 kg/m 2 ) and non-obese (BMI <35 kg/m 2 ) patients who were given initial therapy with 12 mg/kg/day. Of 138 patients, the first steady-state voriconazole troughs were supratherapeutic (>5 mg/L) in 65 (47%) patients, therapeutic (2-5 mg/L) in 57 (41%) patients and subtherapeutic (<2 mg/L) in 16 (12%) patients. Twenty-three patients had pre-steady-state dose decreases due to supratherapeutic levels, with subsequent first steady-state troughs in the therapeutic ( n = 17) and subtherapeutic ( n = 6) categories. Voriconazole doses >11 and >8 mg/kg/day produced mainly first steady-state supratherapeutic troughs in 44 obese and 94 non-obese patients, respectively. An initial 12 mg/kg/day was progressively lowered to a median maintenance dose of 8.5 mg/kg/day in the obese and 8.6 mg/kg/day in the non-obese. A high-dose voriconazole regimen produced initial supratherapeutic troughs that required dose adjustment downward by nearly 30%. Adjusted body weight dosing in obese patients resulted in a similar maintenance dose to total body weight dosing in the non-obese, and appears to be a sensible dosing strategy for these patients.

Measurement and Comparison of Carbamazepine Plasma Levels for Assessment of Compliance, Safety and Toxicity

Carbamazepine is one of the most frequently prescribed antiepileptic drugs and influence of genetic differences, sex, age and race on the plasma levels of carbamazepine and its metabolites is well known. The objective of this study was to assess and compare the compliance, safety and toxicity in different age and gender groups of Chinese epileptic patients on the basis of therapeutic drug monitoring results of carbamazepine, since Han-Chinese are at higher risk of developing serious and fatal adverse effects when exposed to carbamazepine. The therapeutic drug monitoring results of carbamazepine in epileptic patients, obtained with validated methods were complied, evaluated and compared for compliance, safety and toxicity in different age and gender groups of Chinese epileptic patients. The therapeutic drug monitoring results of males and females were separately compiled and thereafter each gender group was further divided into children, adults and elderly as different age group. All age groups in both gender groups were evaluated for therapeutic, sub-therapeutic and toxic ranges. It was found that 45% of samples of total samples had sub-therapeutic levels and 55% of all samples had carbamazepine levels in therapeutic range, and none of gender and age group found in toxic range. Compared to males, female samples were more in number of sub-therapeutic levels. Populations of children males and children females were having more samples in sub-therapeutic levels as compared to adult and elderly males and females, respectively. However, it needs further evaluation. The findings of present study revealed that majority of patients were in sub- therapeutic levels. It is suggested that regularly therapeutic drug monitoring of carbamazepine should be performed and dose of carbamazepine in epileptic patients should be adjusted only after therapeutic drug monitoring results in order to assess the compliance, optimize the efficacy, safety and minimize the toxicity.

Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure-Response Relationships in Renal Transplant Patients.

Sirolimus, an immunosuppressive agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (the ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially because of inconsistencies in sirolimus exposure-response relationships. The authors used retrospective therapeutic drug monitoring data from the electronic health records of patients treated in a tertiary health care system from 2008 to 2014 to (1) develop a population pharmacokinetic (PK) model, (2) use the model to simulate sirolimus concentrations, and (3) characterize the exposure-response relationship. Using Wilcoxon rank-sum and Fisher exact tests, the authors determined relationships between sirolimus exposure and adverse events (AEs) (anemia, leukopenia, thrombocytopenia, hyperlipidemia, and decline in renal function) and the composite efficacy end point of graft loss or rejection. The developed 2-compartment population PK model showed appropriate goodness of fit. In a late-phase (>12 months), postrenal transplant population of 27 inpatients, the authors identified statistically significant relationships between 83 simulated peak and trough sirolimus concentrations and outcomes: graft loss or rejection (P = 0.018) and decline in renal function (P = 0.006), respectively. Use of therapeutic drug monitoring results and PK modeling permitted correlation of sirolimus concentrations with graft loss or rejection and decline in renal function. However, the method was limited in its assessment of other AEs. To better evaluate sirolimus exposure-response relationships, the method should be applied to a larger sample of newly transplanted patients with a higher propensity toward AEs or efficacy failure.

Pediatric Patients With Solid or Hematological Tumor Disease: Vancomycin Population Pharmacokinetics and Dosage Optimization

In pediatric cancer patients, determination of optimal vancomycin dosage is essential because of high risk of inadequate concentrations and bacterial resistance. The aim of this study was to determine vancomycin pharmacokinetic parameters in this population and propose dosage optimization to achieve optimal concentration. We retrospectively reviewed the use of vancomycin in pediatric cancer patients with febrile neutropenia (hematological or solid tumor disease). Vancomycin was administered by continuous infusion, and dosages were adapted according to therapeutic drug monitoring results. Blood cultures were performed before the first dose of antibiotic. Vancomycin pharmacokinetic population parameters were determined using NONMEM software, and dosage simulations were performed according to the target concentration (20-25 mg/L). One hundred twenty-one patients were included in this study, representing 301 vancomycin concentrations. Blood cultures were positive in 37.5% of patients, and observed pathogens were mainly Staphylococcus spp. (43.8% methicillin resistant). Volume of distribution (95% confidence interval) was 34.7 L (17.3-48.0), and total apparent clearance (CL) (95% confidence interval) was correlated to body weight, tumor disease, and cyclosporine coadministration: CL = θCL × (WT/70) L/h with θCL = 3.49 (3.02-3.96), 4.66 (3.98-5.31), and 4.97 (4.42-5.41) in patients managed for hematological malignancies with or without cyclosporine coadministration and for solid malignancies, respectively. Based on simulation results, vancomycin dosage (milligram per kilogram) should be adapted to each child on the basis of its body weight and cyclosporine coadministration. Our results highlight the requirement to adapt vancomycin dosage in cancer pediatric population. Simulations have allowed to describe new dosage schedules, and a chart was created for clinicians to adapt vancomycin dosage.

Practical approach for medical validation of therapeutic drug monitoring results

Practical approach for medical validation of therapeutic drug monitoring results