Showing papers in "Therapeutic Drug Monitoring in 2021"

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

Abstract: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.

Is Europe Facing an Emerging Opioid Crisis Comparable to the U.S.

Abstract: In the U.S., an opioid overdose crisis has emerged, attributable to over-prescription of opioid analgesics, driven by aggressive marketing by pharmaceutical companies, followed by surging heroin overdose deaths, and more recently, by the high mortality rates predominately because of illicitly manufactured fentanyl and analogs of fentanyl. In Europe, the use of prescription opioids for pain management has also increased in the last 2 decades, although it is debatable as to whether this could lead to a similar opioid overdose crisis. To address this issue, recent trends in opioid prescription rates, prevalence rates of fatal and nonfatal incidents, and addiction care treatment were used as proxies of opioid-related harm. The current overview, comparing opioid use and its negative consequences in Germany, France, the U.K., and the Netherlands, using the same indicators as in the U.S., demonstrates that there is no evidence of a current or emerging opioid crisis in these European countries. Scotland, however, is an alarming exception, with high rates of opioid-related harms. Considering that the use of prescription opioids has been declining rather than increasing in Europe, an opioid crisis is not anticipated there yet. Authorities should, however, remain vigilant.

A Review of Synthetic Cathinone-Related Fatalities From 2017 to 2020.

Abstract: Background Synthetic cathinones (SCs) are designer analogs of the natural active principle of khat. Since their appearance on the black market in 2003, their popularity has increased annually, and they have become the most seized class of new psychoactive substances reported to the UNODC Early Warning Advisory system. The constant introduction of newly synthesized molecules makes this issue difficult to monitor. The authors reviewed the most recent SC-related fatalities worldwide to highlight new trends of consumption, reporting acute pharmacological and toxicological symptoms, scene investigations, analytical methods, and reported SC concentrations in diverse biological matrices. Methods A literature search was performed using scientific databases such as PubMed, Scopus, Science Direct, Web of Science, and Research Gate to identify relevant scientific publications from 2017 to 2020. In addition, a search was conducted through the EU EWS. Results From 2017 to 2020, 31 different SCs were identified in 75 reported fatal intoxications in the literature, alone or in combination with other substances. The most abused SCs were N-ethylpentylone, N-ethylhexedrone, and 4-chloromethcathinone. The EU EWS included less detail on 72 additional SC-related fatalities from 2017 to 2020. Conclusions New SCs continuously replace older natural and synthetic stimulant drugs, making determining the cause of death difficult. Analytical methods and high-performance mass spectrometry instruments are essential to detect the low concentrations of these potent new SCs. Little data are available on the pharmacology of these new drugs; the evaluation of toxicological antemortem and postmortem findings provides critical data on the drug's pharmacology and toxicology and for the interpretation of new SC cases.

Alternative Sampling Devices to Collect Dried Blood Microsamples: State-of-the-Art

Abstract: Dried blood spots (DBS) have been used in newborn screening programs for several years. More recently, there has been growing interest in using DBS as a home sampling tool for the quantitative determination of analytes. However, this presents challenges, mainly because of the well-known hematocrit effect and other DBS-specific parameters, including spotted volume and punch site, which could add to the method uncertainty. Therefore, new microsampling devices that quantitatively collect capillary dried blood are continuously being developed. In this review, we provided an overview of devices that are commercially available or under development that allow the quantitative (volumetric) collection of dried blood (-based) microsamples and are meant to be used for home or remote sampling. Considering the field of therapeutic drug monitoring (TDM), we examined different aspects that are important for a device to be implemented in clinical practice, including ease of patient use, technical performance, and ease of integration in the workflow of a clinical laboratory. Costs related to microsampling devices are briefly discussed, because this additionally plays an important role in the decision-making process. Although the added value of home sampling for TDM and the willingness of patients to perform home sampling have been demonstrated in some studies, real clinical implementation is progressing at a slower pace. More extensive evaluation of these newly developed devices, not only analytically but also clinically, is needed to demonstrate their real-life applicability, which is a prerequisite for their use in the field of TDM.

The Impact of Air Pollution on Neurodegenerative Diseases.

Abstract: Background With the development of industrialization in human society, ambient pollutants are becoming more harmful to human health. Epidemiological and toxicological studies indicate that a close relationship exists between particulate matter with a diameter ≤2.5 µm (PM2.5) and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). To further confirm the relationship, we focus on possible relevant mechanisms of oxidative stress and neuroinflammation underlying the association between PM2.5 and neurodegenerative diseases in the review. Methods A literature search was performed on the studies about PM2.5 and neurodegenerative diseases via PubMed. A total of 113 articles published were selected, and 31 studies were included. Results PM2.5 can enter the central nervous system through 2 main pathways, the blood-brain barrier and olfactory neurons. The inflammatory response and oxidative stress are 2 primary mechanisms via which PM2.5 leads to toxicity in the brain. PM2.5 abnormally activates microglia, inducing the neuroinflammatory process. Inflammatory markers such as IL-1β play an essential role in neurodegenerative diseases such as AD and PD. Moreover, the association between lipid mechanism disorders related to PM2.5 and neurodegenerative diseases has been gaining momentum. Conclusions In conclusion, PM2.5 could significantly increase the risk of neurological disorders, such as AD and PD. Furthermore, any policy aimed at reducing air-polluting emissions and increasing air quality would be protective in human beings.

Therapeutic Drug Monitoring of Long-Acting Injectable Antipsychotic Drugs.

Abstract: Background The use of therapeutic drug monitoring (TDM) to guide treatment with long-acting injectable (LAI) antipsychotics, which are increasingly prescribed, remains a matter of debate. The aim of this review was to provide a practical framework for the integration of TDM when switching from an oral formulation to the LAI counterpart, and in maintenance treatment. Methods The authors critically reviewed 3 types of data: (1) positron emission tomography data evaluating dopamine (D2/D3) receptor occupancy related to antipsychotic concentrations in serum or plasma; D2/D3 receptors are embraced as target sites in the brain for antipsychotic efficacy and tolerability, (2) pharmacokinetic studies evaluating the switch from oral to LAI antipsychotics, and (3) pharmacokinetic data for LAI formulations. Based on these data, indications for TDM and therapeutic reference ranges were considered for LAI antipsychotics. Results Antipsychotic concentrations in blood exhibited interindividual variability not only under oral but also under LAI formulations because these concentrations are affected by demographic characteristics such as age and sex, genetic peculiarities, and clinical variables, including comedications and comorbidities. Reported data combined with positron emission tomography evidence indicated a trend toward lower concentrations under LAI administration than under oral medications. However, the available evidence is insufficient to recommend LAI-specific therapeutic reference ranges. Conclusions Although TDM evidence for newer LAI formulations is limited, this review suggests the use of TDM when switching an antipsychotic from oral to its LAI formulation. The application of TDM practice is more accurate for dose selection than the use of dose equivalents as it accounts more precisely for individual characteristics.

Levamisole - A Toxic Adulterant in Illicit Drug Preparations: A Review.

Abstract: Discovered in the 1960s, the common anthelminthic levamisole has seen widespread use in veterinary applications. Its use rapidly expanded thereafter to include human medical treatments for a variety of acute and chronic disorders. Due to reports of severe adverse effects, the US Food and Drug Administration withdrew levamisole's approval for human use in 2000; however, medical options outside the US and illicit options worldwide allow continued accessibility to levamisole. The compound is rapidly metabolized in the body, with at least two known active metabolites. Levamisole has a broad range of immunomodulatory effects, including both stimulatory and inhibitory effects on immune responses. It is generally well tolerated at therapeutic concentrations, although a variety of autoimmune-related adverse effects have been reported, including agranulocytosis, leukopenia, purpura, and visible necrotized skin tissue. Individuals with levamisole-compromised immune systems are more susceptible to infections, including COVID-19. Since the early 2000's, levamisole has been frequently used as an adulterating agent in illicit street drugs, especially cocaine, fentanyl, and heroin. Although its prevalence has varied over time and geographically, levamisole has been detected in up to 79% of the street supply of cocaine at levels up to 74% by weight. Its presence in illicit drug markets also raises concern over the potential for exposure of children and neonates, although this is supported by only limited anecdotal evidence. Levamisole is not currently included in routine drug testing panels, although a variety of confirmatory testing techniques exist across a range of antemortem and postmortem specimen options. Because of its varying presence in illicit drug markets, both the medical and forensic communities need to be aware of levamisole and its potential impact on toxicological investigations.

Optimization of Aztreonam in Combination With Ceftazidime/Avibactam in a Cystic Fibrosis Patient With Chronic Stenotrophomonas maltophilia Pneumonia Using Therapeutic Drug Monitoring: A Case Study.

Abstract: In this clinician-therapeutic drug monitoring (TDM) consultant interaction, the authors describe the use of TDM in an 11-year-old female patient with cystic fibrosis receiving ceftazidime/avibactam and aztreonam for the treatment of persistent pulmonary exacerbations caused by Stenotrophomonas pneumonia. Serum drug concentrations at a steady state confirmed inadequate antimicrobial exposure, and continuous infusions of both ceftazidime/avibactam and aztreonam were required to optimize the percentage of time when free drug remained above the minimum inhibitory concentration (MIC), known as fT > MIC. After dose adjustment, this continuous infusion strategy resulted in 100% target attainment for fT > MIC. This case illustrates the importance of TDM, and the logistical issues encountered with the use of alternative dosing strategies in pediatric patients with CF.

The North American Opioid Epidemic.

Abstract: BACKGROUND The culmination of the widespread overprescription of opioids, a resurgence of heroin use, and increased accessibility and use of illicit synthetic opioids is commonly referred to as the opioid epidemic in North America. METHODS This article is not intended to provide a comprehensive systematic literature review, but rather summarized recent publications and online governmental reports and datasets for English-written literature primarily published between January 1, 2015 and July 1, 2020. RESULTS In both the United States and Canada, opioids represent one of the most widely prescribed classes of medications. According to the US Centers for Disease Control and Prevention (CDC), an unprecedented increase in the use of opioid pain relievers has led to one of the worst drug overdose epidemics in US history and continues to be an ongoing major public health crisis based on recent Centers for Disease Control and Prevention mortality data, where almost two-thirds of all overdose deaths still involve opioids, including heroin and illicit opioids. In addition to the high mortality rates in both the United States and Canada, there has also been an increase in emergency department visits for nonmedical use of opioid pain relievers, along with additional individuals seeking treatment for opioid addiction, and a rise in neonatal abstinence syndrome. CONCLUSIONS This article highlights the history, underlying issues, ongoing national regulatory efforts, and future strategies and therapies to help mitigate the opioid crisis in North America.

Tacrolimus Measured in Capillary Volumetric Microsamples in Pediatric Patients-A Cross-Validation Study.

Abstract: BACKGROUND Therapeutic drug monitoring of tacrolimus (Tac) is mandatory in solid organ transplant (SOT) recipients. Finger-prick microsampling is more flexible and tolerable during the therapeutic drug monitoring of tacrolimus and has been shown to be applicable in adult SOT recipients. In this study, a previously validated method applying volumetric absorptive microsampling (VAMS) to measure Tac in adults was cross-validated in a pediatric population. METHODS Patients with SOT scheduled for standard posttransplant follow-up visits were recruited. Blood samples were obtained by trained phlebotomists using standard venipuncture and capillary microsampling, before the morning dose of Tac as well as 2 and 5 hours after dosing. Tac concentrations were quantified using liquid chromatography-tandem mass spectrometry. Concordance between Tac concentrations obtained with venipuncture and VAMS was evaluated using Passing-Bablok regression, calculation of absolute and relative differences, and percentage of samples within ±20% and ±30% difference. RESULTS A total of 39 SOT patients aged 4-18 years (22 male) were included. The median (range) predose venous blood concentration was 4.8 (2.6-13.6) mcg/L, with a difference between VAMS and venous blood samples of -0.2 ± 0.7 mcg/L. The relative mean difference was -1.3% [95% confidence interval (CI), -5.9% to 3.4%]. Ninety-two percent and 97% of the sample pairs demonstrated differences within ±20% and ±30%, respectively. Postdose (2 hours and/or 5 hours, n = 17) median concentration in venous blood was 7.9 (4.8-19.2) mcg/L. The difference between VAMS and venous blood samples was 0.1 ± 1.0 mcg/L, with a relative mean difference of -2.5% (95% confidence interval, -8.8% to 3.8%). Eighty-eight percent of the postdose sample pairs were within ±20% difference, and all were within ±30% difference. CONCLUSIONS Tac concentrations can be accurately measured using VAMS technology in pediatric SOT recipients. This makes home-based Tac monitoring feasible in the pediatric population.

Establishing Serum Reference Ranges for Antihypertensive Drugs.

Abstract: Background Therapeutic drug monitoring (TDM) involves the measurement of serum drug concentrations to optimize pharmacotherapy. Traditionally, blood pressure measurements alone, and not TDM, have been used to evaluate the antihypertensive drug response. However, approximately 50% of hypertensive patients treated with lifestyle changes and antihypertensive drugs fail to achieve blood pressure control. Serum drug concentration measurements could be useful to select the optimal drugs in adjusted doses and to identify nonadherence. Implementation of TDM in clinical routine for antihypertensive drugs depends on established serum reference ranges. Methods Commonly used antihypertensive drugs were identified based on prescription data. The authors performed a review of authoritative literature on reported serum drug concentrations and calculated expected concentrations from previously reported pharmacokinetic parameters with commonly prescribed daily doses. Finally, serum drug concentrations in samples from patients undergoing antihypertensive treatment were measured. Results Serum reference ranges for 24 frequently used antihypertensive drugs were established based on results from 3 approaches. Conclusions Serum drug concentration measurements, interpreted in light of the established reference ranges, together with blood pressure measurements and other clinical data, may help identify nonadherent patients and tailor individual antihypertensive treatment when deviant drug responses appear in line with the concept of personalized medicine.

Addressing New Possibilities and New Challenges: Automated Nondestructive Hematocrit Normalization for Dried Blood Spots.

Abstract: The patient's hematocrit (HCT) level can adversely affect the analysis results when dried blood spots (DBS) are used for sampling. Volumetric DBS sampling has been proposed to nullify the impact of HCT area bias (spreading area) on DBS by normalizing to a known sample volume. However, this strategy ignores DBS-related parameters such as analyte properties (red blood cell-to-plasma ratio) and HCT recovery bias. With the recent release of fully automated HCT measurement systems for DBS analysis, a broad range of end users are now able to measure and correct a sample's HCT level in a nondestructive manner. These systems permit correction for all known HCT-related impacts on DBS, such as analyte properties, HCT recovery bias, HCT area bias, and venous blood-to-DBS ratio, supporting and accelerating future quantitative DBS applications. However, with these novel tools, new questions arise concerning the normalization of analytical results, the choice of technique (single-wavelength reflectance vs near-infrared spectroscopy), and the DBS card-handling process post sampling. Herein, the necessary considerations for end users are addressed and examples are provided.

Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients.

Abstract: BACKGROUND Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase. METHODS This single-center, prospective, observational study included stable renal Tx recipients, >18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC0-24)], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. RESULTS In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC0-24 = 3821 (2232-5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3-47)%]. A negative correlation (r = -0.83) between PL AUC0-24 and morning CL levels was observed. The best single PK variable to predict PL AUC0-24 was PL C6 (r2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC0-24 with a low percentage prediction error (PPE = 5.2 ± 1.5%) and a good correlation of determination (r2 = 0.91). PL AUC0-24 varied 3-fold among study participants, whereas CL AUC0-24 varied by 18-fold. CONCLUSIONS The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC0-24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.

External Evaluation of Population Pharmacokinetics and Pharmacodynamics in Linezolid-Induced Thrombocytopenia: The Transferability of Published Models to Different Hospitalized Patients.

Abstract: Background The objective of this study was to perform an external evaluation of published linezolid population pharmacokinetic and pharmacodynamic models, to evaluate the predictive performance using an independent data set. Another aim was to offer an elegant environment for display and simulation of both the concentration and platelet count after linezolid administration. Methods We performed a systematic literature search in PubMed for all studies evaluating the population pharmacokinetic and pharmacodynamic parameters of linezolid in patients and selected the models to be used for the external validation. The bias of predictions was visually evaluated by plotting prediction errors (PEs) and relative PEs. The precision of prediction was evaluated by calculating the mean absolute error (MAE), root mean squared error (RMSE), and mean relative error (MRE). Results Three articles (models A, B, and C) provided linezolid-induced platelet dynamic models using population pharmacokinetic and pharmacodynamic modeling approaches. The PE and relative PE of both linezolid concentrations and platelet counts for models A and C showed similar predictive distributions. With respect to the prediction accuracy of total linezolid concentration, the MAE, RMSE, and MRE of population prediction values for model C was the smallest. The comparison of the MAE, RMSE, and MRE of patient-individual prediction values for the 3 pharmacodynamic models revealed no large differences. Conclusions We confirmed the transferability of published population pharmacokinetic and pharmacodynamic models and showed that they were suitable for extrapolation to other hospitals and/or patients. This study also introduced application software based on model C for the therapeutic drug monitoring of linezolid.

Development and Validation of a Simple and Rapid Ultrahigh-Performance Liquid Chromatography Tandem Spectrometry Method for the Quantification of Hydroxychloroquine in Plasma and Blood Samples in the Emergency Context of SARS-CoV-2 Pandemic.

Abstract: Therapeutic drug monitoring (TDM) of hydroxychloroquine has been recommended to optimize the treatment of COVID-19 patients. The authors describe an ultra-high-performance liquid chromatography tandem spectrometry ( UHPLC-MS/MS) method developed in a context of emergency, to analyze hydroxychloroquine (HCQ) in both human plasma and blood samples.After adding the labeled internal standard and simple protein precipitation, plasma samples were analyzed using a C18 column. Blood samples required evaporation before analysis. The total chromatographic run time was 4 min (including 1.5 min of column equilibration). The assay was linear over the calibration range (r > 0.99) and up to 1.50 µg/mL for the plasma samples (5.00 µg/ml for the blood matrix). The limit of quantification was 0.0150 µg/mL for plasma samples (0.05 µg/ml blood matrix) with accuracy and precision ranging from 91.1 % to 112 % and from 0.750 % to 11.1 %, respectively. Intra- and inter-day precision and accuracy values were within 15.0 %. No significant matrix effect was observed in the plasma or blood samples. This method was successfully applied to patients treated for COVID-19 infection. A simple and rapid UHPLC-MS/MS method adapted to HCQ TDM in the context of SARS-CoV-2 infection was successfully developed and validated.

Bayesian forecasting for intravenous tobramycin dosing in adults with cystic fibrosis using one versus two serum concentrations in a dosing interval.

Abstract: BACKGROUND Intravenous tobramycin treatment requires therapeutic drug monitoring (TDM) to ensure safety and efficacy when used for prolonged treatment, as in infective exacerbations of cystic fibrosis. The 24-hour area under the concentration-time curve (AUC24) is widely used to guide dosing; however, there remains variability in practice around methods for its estimation. The objective of this study was to determine the potential for a sparse-sampling strategy using a single postinfusion tobramycin concentration and Bayesian forecasting to assess the AUC24 in routine practice. METHODS Adults with cystic fibrosis receiving once-daily tobramycin had paired concentrations measured 2 hours (c1) and 6 hours (c2) after the end of infusion as routine monitoring. AUC24 exposures were estimated using Tucuxi, a Bayesian forecasting application that incorporates a validated population pharmacokinetic model. Simulations were performed to estimate AUC24 using the full data set using c1 and c2, compared with estimates using depleted data sets (c1 or c2 only), with and without concentration data from earlier in the course. The agreement between each simulation condition and the reference was assessed graphically and numerically using the median difference (∆) AUC24 and (relative) root mean square error (rRMSE) as measures of bias and accuracy, respectively. RESULTS A total of 55 patients contributed 512 concentrations from 95 tobramycin courses and 256 TDM episodes. Single concentration methods performed well, with median ∆AUC24 <2 mg·h·L-1 and rRMSE of <15% for sequential c1 and c2 conditions. CONCLUSIONS Bayesian forecasting implemented in Tucuxi, using single postinfusion concentrations taken 2-6 hours after tobramycin administration, yield similar exposure estimates to more intensive (two-sample) methods and are suitable for routine TDM practice.

Tacrolimus Bayesian Dose Adjustment in Pediatric Renal Transplant Recipients.

Abstract: BACKGROUND Immunosuppressant Bayesian Dose Adjustment (ISBA) is an online expert system that estimates the area under the curve (AUC) of immunosuppressive drugs through pharmacokinetic modelling and Bayesian estimation to propose dose adjustments to reach predefined exposure targets. The ISBA database was retrospectively analyzed to describe tacrolimus pharmacokinetics and exposure, evaluate the efficiency of ISBA dose recommendations, and propose tacrolimus AUC0-12h target ranges for pediatric renal allograft recipients treated with immediate release tacrolimus. METHODS The database included 1935 tacrolimus dose adjustment requests from 419 patients <19 years old who were treated with immediate-release tacrolimus and followed in 21 French hospitals. The tacrolimus exposure evolution with patient age and posttransplantation time, the correlation between trough tacrolimus concentration (C0) and AUC0-12h at different periods posttransplantation, and the efficiency of dose recommendations to avoid underexposure and overexposure and to decrease between-patient AUC variability were investigated. RESULTS Tacrolimus AUC showed large between-patient variability (CV% = 40%) but moderate within-patient variability (median = 24.3% over a 3-month period). Dose-standardized exposure but not the AUC/C0 ratio significantly decreased with time posttransplantation and patient age. We derived AUC0-12h ranges from the consensual C0 ranges using linear regression equations. When the ISBA recommended dose was applied, the AUC distribution was narrower and a significantly higher proportion was within the targets (P < 0.0001). CONCLUSIONS ISBA efficiently reduced tacrolimus underexposure and overexposure. The AUC0-12h target ranges for pediatric patients derived from the database were similar to those previously reported for adults. Estimating the AUC/C0 ratio could help determine personalized C0 targets.

A Population Pharmacokinetic Modeling and Simulation Study of Posaconazole Oral Suspension in Immunocompromised Pediatric Patients: A Short Communication

Abstract: BACKGROUND Posaconazole oral suspension emerged as a promising candidate for prophylaxis of invasive fungal infections in immunocompromised children Its pharmacodynamic advantages include a broad-spectrum activity and a favorable safety profile; however, they are overshadowed by its large pharmacokinetic (PK) variability, which might cause subtherapeutic exposure The aim of this study was to develop a population (pop) PK model based on rich sampling data to better understand the PK of posaconazole oral suspension in pediatric patients METHODS Data were obtained from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension After constructing the popPK model, the probability of target attainment (PTA; 100% T ≥ 07 mg/L) for prophylaxis under fixed, body weight-based, and body surface area-based dosing was evaluated using Monte Carlo simulation RESULTS Fourteen patients contributed 112 posaconazole plasma concentrations The PK of posaconazole was adequately described by a 1-compartment model with lag time 271 hours [13%]; nonlinear bioavailability ED50 991 mg/m2 (fixed); first-order absorption rate constant 0325 hour-1 [27%]; apparent volume of distribution 1150 L [34%]; and apparent clearance 154 L/h [24%] (∼70-kg individual) The bioavailability decreased in the presence of diarrhea and co-treatment with a proton pump inhibitor (PPI) The unexplained interindividual variability in posaconazole PK remained large The PTA was <85%, irrespective of the simulated dosing strategy Patients without diarrhea and not administered a PPI had the highest PTA (85% under the fixed 300-mg dosing 4 times per day) CONCLUSIONS Therapeutic drug monitoring is recommended during prophylactic posaconazole therapy in immunocompromised pediatric patients Large-scale comparative studies are needed to characterize the PK variability between different posaconazole formulations in this cohort

Quantitative Method for the Analysis of Ivacaftor, Hydroxymethyl Ivacaftor, Ivacaftor Carboxylate, Lumacaftor, and Tezacaftor in Plasma and Sputum Using Liquid Chromatography With Tandem Mass Spectrometry and Its Clinical Applicability.

Abstract: BACKGROUND The novel cystic fibrosis transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, and tezacaftor, are the first drugs directly targeting the underlying pathophysiological mechanism in cystic fibrosis (CF); however, independent studies describing their pharmacokinetics are lacking. The aim of this study was to develop a quantification method for ivacaftor and its 2 main metabolites, lumacaftor and tezacaftor, in plasma and sputum using liquid chromatography with tandem mass spectrometry. METHODS The developed method used a small sample volume (20 µL) and simple pretreatment method; protein precipitation solution and internal standard were added in one step to each sample. Liquid chromatography with tandem mass spectrometry was performed for a total run time of 6 minutes. The method was validated by assessing selectivity, carryover, linearity, accuracy and precision, dilution, matrix effects, and stability. RESULTS The selectivity was good as no interference from matrices was observed. In the concentration range from 0.01 to 10.0 mg/L, calibration curves were linear with a correlation coefficient >0.9997 for all compounds. The within-run and between-run accuracy were between 99.7% and 116% at the lower limit of quantitation (LLOQ) and between 95.8% and 112.9% for all concentrations above LLOQ for all analytes in plasma and sputum. Within-run and between-run precisions were <12.7% for LLOQ and <6.7% for the higher limit of quantitation. Samples were stable, with no significant degradation at examined temperatures and time points. Clinical applicability was revealed by analyzing samples from 2 patients with CF. CONCLUSIONS The presented method enables simultaneous quantification of ivacaftor, lumacaftor, and tezacaftor in plasma and sputum and is an improvement over previous methods because it uses smaller sample volumes, a simple pretreatment protocol, and includes tezacaftor. In future studies, it can be applied for examining pharmacokinetics characteristics of new CF transmembrane conductance regulator modulators.

Measurement of Free Plasma Concentrations of Beta-Lactam Antibiotics: An Applicability Study in Intensive Care Unit Patients.

Abstract: BACKGROUND The antibacterial effect of antibiotics is linked to the free drug concentration. This study investigated the applicability of an ultrafiltration method to determine free plasma concentrations of beta-lactam antibiotics in ICU patients. METHODS Eligible patients included adult ICU patients treated with ceftazidime (CAZ), meropenem (MEM), piperacillin (PIP)/tazobactam (TAZ), or flucloxacillin (FXN) by continuous infusion. Up to 2 arterial blood samples were drawn at steady state. Patients could be included more than once if they received another antibiotic. Free drug concentrations were determined by high-performance liquid chromatography with ultraviolet detection after ultrafiltration, using a method that maintained physiological conditions (pH 7.4/37°C). Total drug concentrations were determined to calculate the unbound fraction. In a post-hoc analysis, free concentrations were compared with the target value of 4× the epidemiological cut-off value (ECOFF) for Pseudomonas aeruginosa as a worst-case scenario for empirical therapy with CAZ, MEM or PIP/tazobactam and against methicillin-sensitive Staphylococcus aureus for targeted therapy with FXN. RESULTS Fifty different antibiotic treatment periods in 38 patients were evaluated. The concentrations of the antibiotics showed a wide range because of the fixed dosing regimen in a mixed population with variable kidney function. The mean unbound fractions (fu) of CAZ, MEM, and PIP were 102.5%, 98.4%, and 95.7%, with interpatient variability of 8 × ECOFF for methicillin-sensitive Staphylococcus aureus. CONCLUSIONS For therapeutic drug monitoring purposes, measuring total or free concentrations of CAZ, MEM, or PIP is seemingly adequate. For highly protein-bound beta-lactams such as FXN, free concentrations should be favored in ICU patients with prevalent hypoalbuminemia.

Perspectives in Evaluating Selective Androgen Receptor Modulators in Human Hair: A Short Communication.

Abstract: BACKGROUND As hair testing increases the window of drug detection and permits the differentiation of long-term use from a single exposure when performing segmental analyses (which also allows establishing the pattern of use), this matrix should be considered as a suitable complement to standard investigations in clinical, forensic, and sport toxicology. The authors were recently involved in 3 cases where hair analysis was used to demonstrate the use of selective androgen receptor modulators (SARMs), including ligandrol (LGD-4033), andarine (S-4), and ostarine (S-22). SARMs are increasingly being abused as "safe" alternatives to steroids. METHODS After decontamination using dichloromethane, hair specimens were segmented, cut into very small segments (<1 mm), incubated overnight in a buffer, and extracted using a mixture of organic solvents. Drugs were tested using liquid chromatography-tandem mass spectrometry and confirmed using liquid chromatography/HRMS. RESULTS The determined concentrations were as follows: ligandrol, 14-42 pg/mg; andarine, 0.1-0.7 pg/mg; and ostarine, 3-21 pg/mg. CONCLUSIONS To enhance performance, SARMs must be used on a long-term basis, which can have serious clinical consequences, including liver damage, myocardial infarction, and blood clots. Hair testing for SARMs has additional benefits versus urine analysis as it can detect the parent compound and numerous metabolites.

A Broad Range High-Throughput Assay for Lenvatinib Using Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry With Clinical Application in Patients With Hepatocellular Carcinoma.

Abstract: Background Lenvatinib is increasingly being selected as the first-line treatment for unresectable hepatocellular carcinoma (HCC) based on the results of the REFLECT trial. However, early discontinuation of lenvatinib because of adverse effects is a frequent occurrence. Hence, lenvatinib is a difficult drug for use in the clinical setting. One of the causes is that the dose of lenvatinib is mainly determined by body weight alone, despite high interindividual variability. To overcome this problem, a dosing regimen of lenvatinib based on a population pharmacokinetic (PPK) model for HCC patients is proposed. The aim of this study was to develop a high-throughput quantification method for lenvatinib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) that can be applied to a PPK analysis of HCC patients in the future. Methods After a simple solid-phase extraction step using a 96-well plate, lenvatinib was analyzed by UHPLC-MS/MS in a positive electrospray ionization mode. Results The novel method fulfilled the requirements of the US Food and Drug Administration guidance on bioanalytical method validation. The calibration curve was linear over the 0.2-1000 ng/mL concentration range. The average recovery rate was 98.63 ± 4.55% (mean ± SD). The precision was below 6.05%, and the accuracy was within 12.96% for all quality control levels. The matrix effect varied between 103.33% and 134.61%. This assay was successfully applied to the measurement of plasma concentrations in 6 HCC patients receiving lenvatinib. Conclusions A novel high-throughput UHPLC-MS/MS assay for quantification of lenvatinib in human plasma was successfully developed. This method can be applied to PPK analysis for patients receiving lenvatinib in the clinical setting.

Quality Control of Busulfan Plasma Quantitation, Modeling, and Dosing: An Interlaboratory Proficiency Testing Program.

Abstract: Background Personalizing busulfan doses to target a narrow plasma exposure has improved the efficacy and lowered the toxicity of busulfan-based conditioning regimens used in hematopoietic cell transplant. Regional regulations guide interlaboratory proficiency testing for busulfan concentration quantification and monitoring. To date, there have been no comparisons of the busulfan pharmacokinetic modeling and dose recommendation protocols used in these laboratories. Here, in collaboration with the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring and Clinical Toxicology, a novel interlaboratory proficiency program for the quantitation in plasma, pharmacokinetic modeling, and dosing of busulfan was designed. The methods and results of the first 2 rounds of this proficiency testing are described herein. Methods A novel method was developed to stabilize busulfan in N,N-dimethylacetamide, which allowed shipping of the proficiency samples without dry ice. In each round, participating laboratories reported their results for 2 proficiency samples (one low and one high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. All participants were blinded to the answers; descriptive statistics were used to evaluate their overall performance. The guidelines suggested that answers within ±15% for busulfan concentrations and ±10% for busulfan plasma exposure and dose recommendation were to be considered accurate. Results Of the 4 proficiency samples evaluated, between 67% and 85% of the busulfan quantitation results were accurate (ie, within 85%-115% of the reference value). The majority (88% round #1; 71% round #2) of the dose recommendation answers were correct. Conclusions A proficiency testing program by which laboratories are alerted to inaccuracies in their quantitation, pharmacokinetic modeling, and dose recommendations for busulfan in hematopoietic cell transplant recipients was developed. These rounds of proficiency testing suggests that additional educational efforts and proficiency rounds are needed to ensure appropriate busulfan dosing.

Can We Predict Individual Concentrations of Tacrolimus After Liver Transplantation? Application and Tweaking of a Published Population Pharmacokinetic Model in Clinical Practice.

Abstract: Background Various population pharmacokinetic models have been developed to describe the pharmacokinetics of tacrolimus in adult liver transplantation However, their extrapolated predictive performance remains unclear in clinical practice The purpose of the present study was to predict concentrations using a selected literature model and to improve these predictions by tweaking the model with a subset of the target population Methods A literature review was conducted to select an adequate population pharmacokinetic model (L) Pharmacokinetic data from Therapeutic Drug Monitoring of tacrolimus in liver-transplanted adults were retrospectively collected A subset of these data (70%) was exploited to tweak the L-model using the $PRIOR subroutine of the NONMEM software, with two strategies to weight the prior information: full informative (F) and optimized (O) An external evaluation was performed on the remaining data, bias and imprecision were evaluated for predictions a priori and for Bayesian forecasting Results 79 patients (851 concentrations) were enrolled in the study The predictive performance of L-model was insufficient for a priori predictions, while it was acceptable with Bayesian forecasting, from the third prediction (ie with ≥ 2 previously observed concentrations), corresponding to one week after transplantation Overall, the tweaked models showed a better predictive ability than the L-model The bias of a priori predictions was -41% with literature model versus -285% and -873% with tweaked F and O models, respectively The imprecision was 454% with literature model versus 380% and 392% with tweaked F and O models, respectively For Bayesian predictions, whatever the forecasting state, the tweaked models tend to obtain better results Conclusions A pharmacokinetic model can be used, and to improve the predictive performance, tweaking the literature model with the $PRIOR approach allows to obtain better predictions

Impact of the Opioid Epidemic on Drug Testing.

Abstract: BACKGROUND This review provides a description of how the opioid epidemic has impacted drug testing. METHODS Four major service areas of drug testing were considered, including emergency response, routine clinical care, routine forensics, and death investigations. RESULTS Several factors that the opioid epidemic has impacted in drug testing are discussed, including specimens, breadth of compounds recommended for testing, time to result required for specific applications, analytical approaches, interpretive support requirements, and examples of published practice guidelines. CONCLUSIONS Both clinical and forensic laboratories have adapted practices and developed new testing approaches to respond to the opioid epidemic. Such changes are likely to continue evolving in parallel with changes in both prescription and nonprescription opioid availability and use patterns, as well as emerging populations that are affected by the "waves" of the opioid epidemic.

Do Vancomycin Pharmacokinetics Differ Between Obese and Non-obese Patients? Comparison of a General-Purpose and Four Obesity-Specific Pharmacokinetic Models.

Abstract: Objectives: Over the past decade, numerous obesity-specific pharmacokinetic (PK) models and dosage regimens have been developed. However, it is unclear whether vancomycin PKs differ between obese and other patients after accounting for weight, age, and kidney function. In this study, the authors investigated whether using obesity-specific population PK models for vancomycin offers any advantage in accuracy and precision over using a recently developed general-purpose model. Methods: Vancomycin plasma concentrations in a cohort of 49 obese patients (body mass index [BMI] > 30 kg/m), not previously used in the development of any of the evaluated models, were used to validate the performance of four obesity-specific models and a general model. Bias and imprecision were calculated for the a priori and a posteriori predictive performance. Results: The bias of the a priori prediction was lowest for one of the obesity-specific models (-1.40%) and that of the general model was a close second (-7.0%). The imprecision was lowest for the general model (4.34 mg/L). The predictive performance for the a posteriori predictions was best for the general model, both for bias (1.96%) and imprecision (2.75 mg/L). Conclusions: The results of the external validation of vancomycin PK in obese patients showed that currently available obesity-specific models do not necessarily outperform a broadly supported general-purpose model. Based on these results, the authors conclude that there is no advantage in using vancomycin PK models specifically tailored to obese patients over the general-purpose model reported by Colin et al.

Population Pharmacokinetic Models of Antituberculosis Drugs in Patients: A Systematic Critical Review.

Abstract: BACKGROUND Tuberculosis (TB) remains one of the most important infectious diseases. Population pharmacokinetic (pop-PK) models are widely used to individualize dosing regimens of several antibiotics, but their application in anti-TB drug studies is scant. The aim of this study was to provide an insight regarding the status of pop-PK for these drugs and to compare results obtained through both parametric and nonparametric approaches to design precise dosage regimens. METHODS First, a systematic approach was implemented, searching in PubMed and Google Scholar. Articles that did not include human patients, that lacked an explicit structural model, that analyzed drugs inactive against M. tuberculosis, or were without full-text access, were excluded. Second, the PK parameters were summarized and categorized as parametric versus nonparametric results. Third, a Monte Carlo simulation was performed in Pmetrics using the results of both groups, and an error term was built to describe the imprecision of each PK modeling approach. RESULTS Thirty-three articles reporting at least 1 pop-PK model of 19 anti-TB drug were found; 46 different models including PK parameter estimates and their relevant covariates were also reported. Only 9 models were based on nonparametric approaches. Rifampin was the drug most studied, but only using parametric approaches. The simulations showed that nonparametric approaches improve the error term compared with parametric approaches. CONCLUSIONS More and better models, ideally using nonparametric approaches linked with clear pharmacodynamic goals, are required to optimize anti-TB drug dosing, as recommended in the WHO End TB strategy.

Impact of Body Mass Index on Serum Concentrations of Antidepressants and Antipsychotics.

Abstract: BACKGROUND Rates of overweight and obesity are higher in patients suffering from psychiatric disorders than in the general population. Body composition and enzyme functions are affected by overweight, and consequently, the pharmacokinetics of drugs may vary in overweight patients. Thus, overweight and obesity are important factors in psychiatric disorders and their treatment. This analysis aimed to investigate the impact of body mass index (BMI) on serum concentrations of the antidepressant drugs amitriptyline, doxepin, escitalopram, mirtazapine, and venlafaxine, and the antipsychotic drugs clozapine, quetiapine, and risperidone, taking into account the following confounding parameters: age, sex, and smoking habit. METHODS Inpatients and outpatients (N = 1657) who took at least one of the target drugs were included in this retrospective analysis. Serum concentrations of the target drugs and their metabolites were determined at the Department of Psychiatry, Psychosomatics, and Psychotherapy of the University Hospital of Wurzburg during routine therapeutic drug monitoring (January 2009-December 2010), which was performed in the morning (trough level) at steady state. RESULTS Dose-corrected serum concentrations (CD) of the active moiety of doxepin and venlafaxine and of O-desmethylvenlafaxine were negatively associated with BMI (partial Pearson correlation, R = -0.267, P = 0.002; R = -0.206, P ≤ 0.001; R = -0.258, P ≤ 0.001), and the CDs were different in normal weight, overweight, and obese patients (analysis of covariance, P = 0.004, P < 0.001, P ≤ 0.001). No association was found between BMI and serum concentrations of amitriptyline, escitalopram, mirtazapine, clozapine, quetiapine, and risperidone. CONCLUSIONS In obese patients, higher doses of doxepin and venlafaxine are necessary to achieve similar serum concentrations as in normal weight patients and to avoid treatment-resistant depression.

Microsampling Devices for Routine Therapeutic Drug Monitoring-Are We There Yet?

Abstract: Background The use of microsampling for therapeutic drug monitoring (TDM) is increasingly feasible as sensitive methods have become more accessible. There exists an increasing interest in the use of microsampling, and new microsampling devices and techniques can potentially improve patient convenience and care, among other features. This review provides an update on currently validated methods for measuring drugs pertinent to TDM, including data from clinical samples. Methods A literature record search was undertaken, including PubMed and Google Scholar. Reports that included the use of microsampling to measure concentrations of drugs associated with TDM were reviewed and included if data from patient samples were reported. The studies are described in brief, including sample preparation and analyte stability, with the most pertinent findings reported. Results Sensitive analyses and innovative designs and materials have resulted in an increasing number of reported evaluations and validations for measuring drugs using microsamples. Novel designs largely overcome common problems associated with traditional dried blood spot sampling. Although examples of patient self-sampling are rare at present, studies that evaluated feedback found it to be largely positive, revealing the feasibility of microsampling for TDM. Conclusions Microsampling is suited to the TDM of numerous drugs in diverse situations, and it will play an increasingly important role. The issues with traditional dried blood spot samples have been largely overcome by employing novel methods to obtain volumetric samples.