Evaluation of the impact of a therapeutic drug monitoring program in a Swiss University Hospital

Background and objective: Therapeutic Drug Monitoring (TDM) has been introduced early 1970 in our hospital (CHUV). It represents nowadays an important routine activity of the Division of Clinical Pharmacology and Toxicology (PCL), and its impact and utility for clinicians required assessment. This study thus evaluated the impact of TDM recommendations in terms of dosage regimen adaptation. Design: A prospective observational study was conducted over 5 weeks. The primary objective was to evaluate the application of our TDM recommendations and to identify potential factors associated to variations in their implementation. The secondary objective was to identify pre-analytical problems linked to the collection and processing of blood samples. Setting: Four representative clinical units at CHUV. Main outcome measure: Clinical data, drug related data (intake, collection and processing) and all information regarding the implementation of clinical recommendations were collected and analyzed by descriptive statistics. Results: A total of 241 blood measurement requests were collected, among which 105 triggered a recommendation. 37% of the recommendations delivered were applied, 25 % partially applied and 34% not applied. In 4% it was not applicable. The factors determinant for implementation were the clinical unit and the mode of transmission of the recommendation (written vs oral). No clear difference between types of drugs could be detected. Pre-analytical problems were not uncommon, mostly related to completion of request forms and delays in blood sampling (equilibration or steady-state not reached). We have identified 6% of inappropriate and unusable drug level measurements that could cause a substantial cost for the hospital. Conclusion: This survey highlighted a better implementation of TDM recommendations in clinical units where this routine is well integrated and understood by the medical staff. Our results emphasize the importance of communication with the nurse or the physician in charge, either to transmit clinical recommendations or to establish consensual therapeutic targets in specific conditions. Development of strong partnerships between clinical pharmacists or pharmacologists and clinical units would be beneficial to improve the impact of this clinical activity.

Using active learning for monitoring networks design: The example of wind power plants sites evaluation

Locating new wind farms is of crucial importance for energy policies of the next decade. To select the new location, an accurate picture of the wind fields is necessary. However, characterizing wind fields is a difficult task, since the phenomenon is highly nonlinear and related to complex topographical features. In this paper, we propose both a nonparametric model to estimate wind speed at different time instants and a procedure to discover underrepresented topographic conditions, where new measuring stations could be added. Compared to space filling techniques, this last approach privileges optimization of the output space, thus locating new potential measuring sites through the uncertainty of the model itself.

Clinical benefits of an adherence monitoring program in the management of secondary hyperparathyroidism with cinacalcet: results of a prospective randomized controlled study.

BACKGROUND/AIMS: One of the causes of uncontrolled secondary hyperparathyroidism (sHPT) is patient's poor drug adherence. We evaluated the clinical benefits of an integrated care approach on the control of sHPT by cinacalcet. METHODS: Prospective, randomized, controlled, multicenter, open-label study. Fifty hemodialysis patients on a stable dose of cinacalcet were randomized to an integrated care approach (IC) or usual care approach (UC). In the IC group, cinacalcet adherence was monitored using an electronic system. Results were discussed with the patients in motivational interviews, and drug prescription adapted accordingly. In the UC group, drug adherence was monitored, but results were not available. RESULTS: At six months, 84% of patients in the IC group achieved recommended iPTH targets versus 55% in the UC group (P = 0.04). The mean cinacalcet taking adherence improved by 10.8% in the IC group and declined by 5.3% in the UC group (P = 0.02). Concomitantly, the mean dose of cinacalcet was reduced by 7.2 mg/day in the IC group and increased by 6.4 mg/day in the UC group (P = 0.03). CONCLUSIONS: The use of a drug adherence monitoring program in the management of sHPT in hemodialysis patients receiving cinacalcet improves drug adherence and iPTH control and allows a reduction in the dose of cinacalcet.

Application of detection probabilities to the design of amphibian monitoring programs in temporary ponds

Failure to detect a species in an area where it is present is a major source of error in biological surveys. We assessed whether it is possible to optimize single-visit biological monitoring surveys of highly dynamic freshwater ecosystems by framing them a priori within a particular period of time. Alternatively, we also searched for the optimal number of visits and when they should be conducted. We developed single-species occupancy models to estimate the monthly probability of detection of pond-breeding amphibians during a four-year monitoring program. Our results revealed that detection probability was species-specific and changed among sampling visits within a breeding season and also among breeding seasons. Thereby, the optimization of biological surveys with minimal survey effort (a single visit) is not feasible as it proves impossible to select a priori an adequate sampling period that remains robust across years. Alternatively, a two-survey combination at the beginning of the sampling season yielded optimal results and constituted an acceptable compromise between sampling efficacy and survey effort. Our study provides evidence of the variability and uncertainty that likely affects the efficacy of monitoring surveys, highlighting the need of repeated sampling in both ecological studies and conservation management.

A one-year monitoring of nicotine use in sport: frontier between potential performance enhancement and addiction issues.

Tobacco consumption is a global epidemic responsible for a vast burden of disease. With pharmacological properties sought-after by consumers and responsible for addiction issues, nicotine is the main reason of this phenomenon. Accordingly, smokeless tobacco products are of growing popularity in sport owing to potential performance enhancing properties and absence of adverse effects on the respiratory system. Nevertheless, nicotine does not appear on the 2011 World Anti-Doping Agency (WADA) Prohibited List or Monitoring Program by lack of a comprehensive large-scale prevalence survey. Thus, this work describes a one-year monitoring study on urine specimens from professional athletes of different disciplines covering 2010 and 2011. A method for the detection and quantification of nicotine, its major metabolites (cotinine, trans-3-hydroxycotinine, nicotine-N'-oxide and cotinine-N-oxide) and minor tobacco alkaloids (anabasine, anatabine and nornicotine) was developed, relying on ultra-high pressure liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-TQ-MS/MS). A simple and fast dilute-and-shoot sample treatment was performed, followed by hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) operated in positive electrospray ionization (ESI) mode with multiple reaction monitoring (MRM) data acquisition. After method validation, assessing the prevalence of nicotine consumption in sport involved analysis of 2185 urine samples, accounting for 43 different sports. Concentrations distribution of major nicotine metabolites, minor nicotine metabolites and tobacco alkaloids ranged from 10 (LLOQ) to 32,223, 6670 and 538 ng/mL, respectively. Compounds of interest were detected in trace levels in 23.0% of urine specimens, with concentration levels corresponding to an exposure within the last three days for 18.3% of samples. Likewise, hypothesizing conservative concentration limits for active nicotine consumption prior and/or during sport practice (50 ng/mL for nicotine, cotinine and trans-3-hydroxycotinine and 25 ng/mL for nicotine-N'-oxide, cotinine-N-oxide, anabasine, anatabine and nornicotine) revealed a prevalence of 15.3% amongst athletes. While this number may appear lower than the worldwide smoking prevalence of around 25%, focusing the study on selected sports highlighted more alarming findings. Indeed, active nicotine consumption in ice hockey, skiing, biathlon, bobsleigh, skating, football, basketball, volleyball, rugby, American football, wrestling and gymnastics was found to range between 19.0 and 55.6%. Therefore, considering the adverse effects of smoking on the respiratory tract and numerous health threats detrimental to sport practice at top level, likelihood of smokeless tobacco consumption for performance enhancement is greatly supported.

A one-year monitoring of nicotine use in sport: frontier between potential performance enhancement and addiction issues

Tobacco consumption is a global epidemic responsible for a vast burden of disease. With pharmacological properties sought-after by consumers and responsible for addiction issues, nicotine is the main reason of this phenomenon. Accordingly, smokeless tobacco products are of growing popularity in sport owing to potential performance enhancing properties and absence of adverse effects on the respiratory system. Nevertheless, nicotine does not appear on the 2011 World Anti-Doping Agency (WADA) Prohibited List or Monitoring Program by lack of a comprehensive large-scale prevalence survey. Thus, this work describes a one-year monitoring study on urine specimens from professional athletes of different disciplines covering 2010 and 2011. A method for the detection and quantification of nicotine, its major metabolites (cotinine, trans-3-hydroxycotinine, nicotine-N′-oxide and cotinine-N-oxide) and minor tobacco alkaloids (anabasine, anatabine and nornicotine) was developed, relying on ultra-high pressure liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-TQ-MS/MS). A simple and fast dilute-and-shoot sample treatment was performed, followed by hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) operated in positive electrospray ionization (ESI) mode with multiple reaction monitoring (MRM) data acquisition. After method validation, assessing the prevalence of nicotine consumption in sport involved analysis of 2185 urine samples, accounting for 43 different sports. Concentrations distribution of major nicotine metabolites, minor nicotine metabolites and tobacco alkaloids ranged from 10 (LLOQ) to 32,223, 6670 and 538 ng/mL, respectively. Compounds of interest were detected in trace levels in 23.0% of urine specimens, with concentration levels corresponding to an exposure within the last three days for 18.3% of samples. Likewise, hypothesizing conservative concentration limits for active nicotine consumption prior and/or during sport practice (50 ng/mL for nicotine, cotinine and trans-3-hydroxycotinine and 25 ng/mL for nicotine-N′-oxide, cotinine-N-oxide, anabasine, anatabine and nornicotine) revealed a prevalence of 15.3% amongst athletes. While this number may appear lower than the worldwide smoking prevalence of around 25%, focusing the study on selected sports highlighted more alarming findings. Indeed, active nicotine consumption in ice hockey, skiing, biathlon, bobsleigh, skating, football, basketball, volleyball, rugby, American football, wrestling and gymnastics was found to range between 19.0 and 55.6%. Therefore, considering the adverse effects of smoking on the respiratory tract and numerous health threats detrimental to sport practice at top level, likelihood of smokeless tobacco consumption for performance enhancement is greatly supported.

Relationships between imatinib plasma levels and efficacy

Purpose: While imatinib has revolutionized the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumors (GIST), its pharmacokinetic-pharmacodynamic relationships have been poorly studied. This study aimed to explore the issue in oncologic patients, and to evaluate the specific influence of the target genotype in a GIST subpopulation. Patients and methods: Data from 59 patients (321 plasma samples) were collected during a previous pharmacokinetic study. Based on a population model purposely developed, individual post-hoc Bayesian estimates of pharmacokinetic parameters were derived, and used to estimate drug exposure (AUC; area under curve). Free fraction parameters were deduced from a model incorporating plasma alpha1-acid glycoprotein levels. Associations between AUC (or clearance) and therapeutic response (coded on a 3-point scale), or tolerability (4-point scale), were explored by ordered logistic regression. Influence of KIT genotype on response was also assessed in GIST patients. Results: Total and free drug exposure correlated with the number of side effects (p < 0.005). A relationship with response was not evident in the whole patient set (with good-responders tending to receive lower doses and bad-responders higher doses). In GIST patients however, higher free drug exposure predicted better responses. A strong association was notably observed in patients harboring an exon 9 mutation or a wild type KIT, known to decrease tumor sensitivity towards imatinib (p < 0.005). Conclusions: Our results are arguments to further evaluate the potential benefit of a therapeutic monitoring program for imatinib. Our data also suggest that stratification by genotype will be important in future trials.

Population pharmacokinetic study of gentamicin: A retrospective analysis in a large cohort of neonate patients

Objectives: Gentamicin is one of the most commonly prescribed antibiotics for suspected or proven infection in newborns. Because of age-associated (pre- and post- natal) changes in body composition and organ function, large interindividual variability in gentamicin drug levels exists, thus requiring a close monitoring of this drug due to its narrow therapeutic index. We aimed to investigate clinical and demographic factors influencing gentamicin pharmacokinetics (PK) in a large cohort of unselected newborns and to explore optimal regimen based on simulation. Methods: All gentamicin concentration data from newborns treated at the University Hospital Center of Lausanne between December 2006 and October 2011 were retrieved. Gentamicin concentrations were measured within the frame of a routine therapeutic drug monitoring program, in which 2 concentrations (at 1h and 12h) are systematically collected after the first administered dose, and a few additional concentrations are sampled along the treatment course. A population PK analysis was performed by comparing various structural models, and the effect of clinical and demographic factors on gentamicin disposition was explored using NONMEM®. Results: A total of 3039 concentrations collected in 994 preterm (median gestational age 32.3 weeks, range 24.2-36.5 weeks) and 455 term newborns were used in the analysis. Most of the data (86%) were sampled after the first dose (C1 h and C12 h). A two-compartment model best characterized gentamicin PK. Average clearance (CL) was 0.044 L/h/kg (CV 25%), central volume of distribution (Vc) 0.442 L/kg (CV 18%), intercompartmental clearance (Q) 0.040 L/h/kg and peripheral volume of distribution (Vp) 0.122 L/kg. Body weight, gestational age and postnatal age positively influenced CL. The use of both gestational age and postnatal age better predicted CL than postmenstrual age alone. CL was affected by dopamine and furosemide administration and non-significantly by indometacin. Body weight, gestational age and dopamine coadminstration significantly influenced Vc. Model based simulation confirms that preterm infants need higher dose, superior to 4 mg/kg, and extended interval dosage regimen to achieve adequate concentration. Conclusions: This study, performed on a very large cohort of neonates, identified important factors influencing gentamicin PK. The model will serve to elaborate a Bayesian tool for dosage individualization based on a single measurement.

Imatinib plasma concentrations variability in oncologic patients

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occurs in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P-glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualization. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after the latest dose, were measured in 59 patients receiving Glivec at diverse regimens, using a validated HPLC-UV method developed for this study. The results were analyzed by non-linear mixed effect modeling (NONMEM). A one-compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. At present, only the MDR1 polymorphism has been assessed and seems to affect the pharmacokinetic parameters of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40 %) and distribution volume (71 %). Together with intra-patient variability (34 %), this translates into an 8-fold width of the 90 %-prediction interval of plasma concentrations expected under a fixed dosing regimen. This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring program for imatinib. It may help to individualize the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Imatinib plasma concentrations variability in oncologic patients

The anticancer drug imatinib has transformed the treatment and prognosis of chronic myeloid leukemia and gastrointestinal stromal tumor. However, the treatment must be taken indefinitely and is not devoid of inconveniences and toxicity. Moreover, resistance or escape from disease control are occurring. Considering the large interindividual differences in the function of the enzymatic and transport systems involved in imatinib disposition, exposure to this drug can be expected to vary widely among patients. This book describes an observational clinical trial aiming at exploring the influence of these covariates on imatinib pharmacokinetics and assessing the interindividual variability of the pharmacokinetic parameters of the drug. A large interindividual variability was observed, together with some preliminary concentration-effect relationships. These elements are arguments to further investigate the potential benefit of a therapeutic drug monitoring program to optimize the use of imatinib in patients. Such results should be especially useful to clinical oncologists or scientists involved in clinical oncology research.

Shift of spawning season and effects of climate warming on developmental stages of a grayling (Salmonidae)

River-dwelling fish, such as European graylings (Thymallus thymallus), are susceptible to changes in climate because they can often not avoid suboptimal temperatures, especially during early developmental stages. We analyzed data collected in a 62-year-long (1948-2009) population monitoring program. Male and female graylings were sampled about three times/week during the yearly spawning season in order to follow the development of the population. The occurrence of females bearing ripe eggs was used to approximate the timing of each spawning season. In the last years of the study, spawning season was more than 3 weeks earlier than in the first years. This shift was linked to increasing water temperatures as recorded over the last 39 years with a temperature logger at the spawning site. In early spring water temperatures rose more slowly than in later spring. Thus, embryos and larvae were exposed to increasingly colder water at a stage that is critical for sex determination and pathogen resistance in other salmonids. In summer, however, fry were exposed to increasingly warmer temperatures. The changes in water temperatures that we found embryos, larvae, and fry were exposed to could be contributing to the decline in abundance that has occurred over the last 30-40 years.

Pharmacokinetic variability of extended interval tobramycin in burn patients.

BACKGROUND: Aminoglycosides are mandatory in the treatment of severe infections in burns. However, their pharmacokinetics are difficult to predict in critically ill patients. Our objective was to describe the pharmacokinetic parameters of high doses of tobramycin administered at extended intervals in severely burned patients. METHODS: We prospectively enrolled 23 burned patients receiving tobramycin in combination therapy for Pseudomonas species infections in a burn ICU over 2 years in a therapeutic drug monitoring program. Trough and post peak tobramycin levels were measured to adjust drug dosage. Pharmacokinetic parameters were derived from two points first order kinetics. RESULTS: Tobramycin peak concentration was 7.4 (3.1-19.6)microg/ml and Cmax/MIC ratio 14.8 (2.8-39.2). Half-life was 6.9 (range 1.8-24.6)h with a distribution volume of 0.4 (0.2-1.0)l/kg. Clearance was 35 (14-121)ml/min and was weakly but significantly correlated with creatinine clearance. CONCLUSION: Tobramycin had a normal clearance, but an increased volume of distribution and a prolonged half-life in burned patients. However, the pharmacokinetic parameters of tobramycin are highly variable in burned patients. These data support extended interval administration and strongly suggest that aminoglycosides should only be used within a structured pharmacokinetic monitoring program.

Energy deficit and length of hospital stay can be reduced by a two-step quality improvement of nutrition therapy: the intensive care unit dietitian can make the difference.

OBJECTIVE: Critically ill patients are at high risk of malnutrition. Insufficient nutritional support still remains a widespread problem despite guidelines. The aim of this study was to measure the clinical impact of a two-step interdisciplinary quality nutrition program. DESIGN: Prospective interventional study over three periods (A, baseline; B and C, intervention periods). SETTING: Mixed intensive care unit within a university hospital. PATIENTS: Five hundred seventy-two patients (age 59 ± 17 yrs) requiring >72 hrs of intensive care unit treatment. INTERVENTION: Two-step quality program: 1) bottom-up implementation of feeding guideline; and 2) additional presence of an intensive care unit dietitian. The nutrition protocol was based on the European guidelines. MEASUREMENTS AND MAIN RESULTS: Anthropometric data, intensive care unit severity scores, energy delivery, and cumulated energy balance (daily, day 7, and discharge), feeding route (enteral, parenteral, combined, none-oral), length of intensive care unit and hospital stay, and mortality were collected. Altogether 5800 intensive care unit days were analyzed. Patients in period A were healthier with lower Simplified Acute Physiologic Scale and proportion of "rapidly fatal" McCabe scores. Energy delivery and balance increased gradually: impact was particularly marked on cumulated energy deficit on day 7 which improved from -5870 kcal to -3950 kcal (p < .001). Feeding technique changed significantly with progressive increase of days with nutrition therapy (A: 59% days, B: 69%, C: 71%, p < .001), use of enteral nutrition increased from A to B (stable in C), and days on combined and parenteral nutrition increased progressively. Oral energy intakes were low (mean: 385 kcal*day, 6 kcal*kg*day ). Hospital mortality increased with severity of condition in periods B and C. CONCLUSION: A bottom-up protocol improved nutritional support. The presence of the intensive care unit dietitian provided significant additional progression, which were related to early introduction and route of feeding, and which achieved overall better early energy balance.

Design and evaluation of a solid sampler for the monitoring of airborne 1,6-hexamethylene diisocyanate (HDI) and its prepolymers in 2-component spray painting

An active, solvent-free solid sampler was developed for the collection of 1,6-hexamethylene diisocyanate (HDI) aerosol and prepolymers. The sampler was made of a filter impregnated with 1-(2-methoxyphenyl)piperazine contained in a filter holder. Interferences with HDI were observed when a set of cellulose acetate filters and a polystyrene filter holder were used; a glass fiber filter and polypropylene filter cassette gave better results. The applicability of the sampling and analytical procedure was validated with a test chamber, constructed for the dynamic generation of HDI aerosol and prepolymers in commercial two-component spray paints (Desmodur(R) N75) used in car refinishing. The particle size distribution, temporal stability, and spatial uniformity of the simulated aerosol were established in order to test the sample. The monitoring of aerosol concentrations was conducted with the solid sampler paired to the reference impinger technique (impinger flasks contained 10 mL of 0.5 mg/mL 1-(2-methoxyphenyl)piperazine in toluene) under a controlled atmosphere in the test chamber. Analyses of derivatized HDI and prepolymers were carried out by using high-performance liquid chromatography and ultraviolet detection. The correlation between the solvent-free and the impinger techniques appeared fairly good (Y = 0.979X - 0.161; R = 0.978), when the tests were conducted in the range of 0.1 to 10 times the threshold limit value (TLV) for HDI monomer and up to 60-mu-g/m3 (3 U.K. TLVs) for total -N = C = O groups.

Immune monitoring design within the developmental pipeline for an immunotherapeutic or preventive vaccine

Immunotherapy is defined as the treatment of disease by inducing, enhancing, or suppressing an immune response, whereas preventive vaccination is intended to prevent the development of diseases in healthy subjects. Most successful prophylactic vaccines rely on the induction of high titers of neutralizing antibodies. It is generally thought that therapeutic vaccination requires induction of robust T-cell mediated immunity. The diverse array of potential or already in use immunotherapeutic and preventive agents all share the commonality of stimulating the immune system. Hence, measuring those vaccination-induced immune responses gives the earliest indication of vaccine take and its immune modulating effects.