Benchmarking therapeutic drug monitoring software: A review of available computer tools

Therapeutic drug monitoring (TDM) aims to optimize treatments by individualizing dosage regimens based on the measurement of blood concentrations. Dosage individualization to maintain concentrations within a target range requires pharmacokinetic and clinical capabilities. Bayesian calculations currently represent the gold standard TDM approach but require computation assistance. In recent decades computer programs have been developed to assist clinicians in this assignment. The aim of this survey was to assess and compare computer tools designed to support TDM clinical activities. The literature and the Internet were searched to identify software. All programs were tested on personal computers. Each program was scored against a standardized grid covering pharmacokinetic relevance, user friendliness, computing aspects, interfacing and storage. A weighting factor was applied to each criterion of the grid to account for its relative importance. To assess the robustness of the software, six representative clinical vignettes were processed through each of them. Altogether, 12 software tools were identified, tested and ranked, representing a comprehensive review of the available software. Numbers of drugs handled by the software vary widely (from two to 180), and eight programs offer users the possibility of adding new drug models based on population pharmacokinetic analyses. Bayesian computation to predict dosage adaptation from blood concentration (a posteriori adjustment) is performed by ten tools, while nine are also able to propose a priori dosage regimens, based only on individual patient covariates such as age, sex and bodyweight. Among those applying Bayesian calculation, MM-USC*PACK© uses the non-parametric approach. The top two programs emerging from this benchmark were MwPharm© and TCIWorks. Most other programs evaluated had good potential while being less sophisticated or less user friendly. Programs vary in complexity and might not fit all healthcare settings. Each software tool must therefore be regarded with respect to the individual needs of hospitals or clinicians. Programs should be easy and fast for routine activities, including for non-experienced users. Computer-assisted TDM is gaining growing interest and should further improve, especially in terms of information system interfacing, user friendliness, data storage capability and report generation.

Systematic identification of genomic markers of drug sensitivity in cancer cells.

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

Productivity growth and competition in Spanish manufacturing firms: What has happened in recent years?

This paper addresses the issue of the relationship between productivity and market competition. In comparison to the economies of other European countries, the Spanish economy has been growing, while productivity growth has stagnated. Here we provide empirical evidence about the relationship between productivity and market competition from Spanish manufacturing firms at firm level between 1994 and 2004. Correcting for selection bias, our study pays special attention to the patterns of productivity growth between openness and non-openness firms. When market competition increases the effect on firms operating in domestic markets is positive but when the level of competition is high incentives to invest in innovation and productivity gains disappear. The empirical relationship between competition and productivity is an inverted U-shape, where productivity growth is highest at intermediate levels of competition. The productivity growth of firms operating in international markets is higher than that of non-openness firms, but when market competition rises they moderate their productivity growth. Our empirical results suggest that the correct competition policy in the Spanish economy should remove the barriers to competition in internal markets in order to increase the incentives for manufacturing firms to invest in innovation and productivity growth.

Pharmacokinetic aspects of Tert-Butylaminoethyl disulfide, an experimental drug against schistosomiasis in mice

A preliminary study of the pharmacokinetic parameters of t-Butylaminoethyl disulfide was performed after administration of two different single doses (35 and 300 mg/kg) of either the cold or labelled drug. Plasma or blood samples were treated with dithiothreitol, perchloric acid, and, after filtration, submitted to further purification with anionic resein. In the final step, the drug was retained on a cationic resin column, eluted with NaCl 1M and detected according to the method of Ellman (1958). Alternatively, radioactive drug was detected by liquid scintillation counting. The results corresponding to the smaller dose of total drug suggested a pharmacokinetic behavior related to a one open compartment model with the following parameters: area under the intravenous curve (AUC i.v.):671 ± 14; AUC oral: 150 ± 40 µg.min. ml [raised to the power of -1]; elimination rate constant: 0.071 min [raised to the power of -1]; biological half life: 9.8 min; distribution volume: 0.74 ml/g. For the higher dose, the results seemed to obey a more complex undertermined model. Combining the results, the occurence of a dose-dependent pharmacokinetic behavior is suggested, the drug being rapidly absorbed and rapidly eliminated; the elimination process being related mainly to metabolization. The drug seems to be more toxic when administered I.V. because by this route it escapes first pass metabolism, while being quickly distributed to tissues. The maximum tolerated blood level seems to be around 16 µg/ml.

Population Normalization with Ammonium in Wastewater-Based Epidemiology: Application to Illicit Drug Monitoring

Fluctuations in ammonium (NH4+), measured as NH4-N loads using an ion-selective electrode installed at the inlet of a sewage treatment plant, showed a distinctive pattern which was associated to weekly (i.e., commuters) and seasonal (i.e., holidays) fluctuations of the population. Moreover, population size estimates based on NH4-N loads were lower compared to census data. Diurnal profiles of benzoylecgonine (BE) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) were shown to be strongly correlated to NH4-N. Characteristic patterns, which reflect the prolonged nocturnal activity of people during the weekend, could be observed for BE, cocaine, and a major metabolite of MDMA (i.e., 4-hydroxy-3-methoxymethamphetamine). Additional 24 h composite samples were collected between February and September 2013. Per-capita loads (i.e., grams per day per 1000 inhabitants) were computed using census data and NH4-N measurements. Normalization with NH4-N did not modify the overall pattern, suggesting that the magnitude of fluctuations in the size of the population is negligible compared to those of illicit drug loads. Results show that fluctuations in the size of the population over longer periods of time or during major events can be monitored using NH4-N loads: either using raw NH4-N loads or population size estimates based on NH4-N loads, if information about site-specific NH4-N population equivalents is available.

Adolescent Drug Abuse Diagnosis (ADAD) vs. Health of Nation Outcome Scale for Children and Adolescents (HoNOSCA) in clinical outcome measurement.

BACKGROUND: The Adolescent Drug Abuse Diagnosis (ADAD) and Health of Nation Outcome Scales for Children and Adolescents (HoNOSCA) are both measures of outcome for adolescent mental health services. AIMS: To compare the ADAD with HoNOSCA; to examine their clinical usefulness. METHODS: Comparison of the ADAD and HoNOSCA outcome measures of 20 adolescents attending a psychiatric day care unit. RESULTS: ADAD change was positively correlated with HoNOSCA change. HoNOSCA assesses the clinic's day-care programme more positively than the ADAD. The ADAD detects a group for which the mean score remains unchanged whereas HoNOSCA does not. CONCLUSIONS: A good convergent validity emerges between the two assessment tools. The ADAD allows an evidence-based assessment and generally enables a better subject discrimination than HoNOSCA. HoNOSCA gives a less refined evaluation but is more economic in time and possibly more sensitive to change. Both assessment tools give useful information and enabled the Day-care Unit for Adolescents to rethink the process of care and of outcome, which benefited both the institution and the patients.

HIV-1 drug resistance transmission networks in southwest Switzerland.

To determine viral subtypes and resistance mutations to antiretroviral treatment (ART) in untreated HIV-1 acutely infected subjects from Southwest Switzerland. Clinical samples were obtained from the HIV primary infection cohort from Lausanne. Briefly, pol gene was amplified by nested PCR and sequenced to generate a 1?kb sequence spanning protease and reverse transcriptase key protein regions. Nucleotide sequences were used to assess viral genotype and ART resistance mutations. Blood specimens and medical information were obtained from 30 patients. Main viral subtypes corresponded to clade B, CRF02_AG, and F1. Resistant mutations to PIs consisted of L10V and accessory mutations 16E and 60E present in all F1 clades. The NNRTI major resistant mutation 103N was detected in all F1 viruses and in other 2 clades. Additionally, we identified F1 sequences from other 6 HIV infected and untreated individuals from Southwest Switzerland, harboring nucleotide motifs and resistance mutations to ART as observed in the F1 strains from the cohort. These data reveal a high transmission rate (16.6%) for NNRTI resistant mutation 103N in a cohort of HIV acute infection. Three of the 5 resistant strains were F1 clades closely related to other F1 isolates from HIV-1 infection untreated patients also coming from Southwest Switzerland. Overall, we provide strong evidence towards an HIV-1 resistant transmission network in Southwest Switzerland. These findings have relevant implications for the local molecular mapping of HIV-1 and future ART surveillance studies in the region.

The Estimation of Technical Efficiency Effects Models with an Example Applied to the Thai Manufacturing Sector

This paper does two things. First, it presents alternative approaches to the standard methods of estimating productive efficiency using a production function. It favours a parametric approach (viz. the stochastic production frontier approach) over a nonparametric approach (e.g. data envelopment analysis); and, further, one that provides a statistical explanation of efficiency, as well as an estimate of its magnitude. Second, it illustrates the favoured approach (i.e. the ‘single stage procedure’) with estimates of two models of explained inefficiency, using data from the Thai manufacturing sector, after the crisis of 1997. Technical efficiency is modelled as being dependent on capital investment in three major areas (viz. land, machinery and office appliances) where land is intended to proxy the effects of unproductive, speculative capital investment; and both machinery and office appliances are intended to proxy the effects of productive, non-speculative capital investment. The estimates from these models cast new light on the five-year long, post-1997 crisis period in Thailand, suggesting a structural shift from relatively labour intensive to relatively capital intensive production in manufactures from 1998 to 2002.

The Changing Inter-Industry Wage Structure of the Organised Manufacturing Sector in India, 1973-74 to 2003-04

This study examines the inter-industry wage structure of the organised manufacturing sector in India for the period 1973-74 to 2003-04 by estimating the growth of average real wages for production workers by industry. In order to estimate the growth rates, the study adopts a methodological framework that differs from other studies in that the time series properties of the concerned variables are closely considered in order to obtain meaningful estimates of growth that are unbiased and (asymptotically) efficient. Using wage data on 51 manufacturing industries at three digit level of the National Industrial Classification 1998 (India), our estimation procedure obtains estimates of growth of real wages per worker that are deterministic in nature by accounting for any potential structural break(s). Our findings show that the inter-industry wage structure in India has changed a lot in the period 1973-74 to 2003-04 and that it provides some evidence that the inter-industry wage differences have become more pronounced in the post-reforms period. Thus this paper provides new evidence from India on the need to consider the hypothesis that industry affiliation is potentially an important determinant of wages when studying any relationship between reforms and wages.

Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: a multicohort European case-control study using centralized ultrasensitive 454 pyrosequencing.

OBJECTIVES: It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART. METHODS: This Europe-wide case-control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%-25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression. RESULTS: Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%), were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR = 2.75, 95% CI = 1.35-5.60, P = 0.005); similar associations were observed for at least one MV versus no NRTI MVs (OR = 2.27, 95% CI = 0.76-6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12-5.18, P = 0.024). A dose-effect relationship between virological failure and mutational load was found. CONCLUSIONS: Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART.

Pharmacokinetic drug interaction potential of risperidone with cytochrome p450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test.

Two published case reports showed that addition of risperidone (1 and 2 mg/d) to a clozapine treatment resulted in a strong increase of clozapine plasma levels. As clozapine is metabolized by cytochrome P450 isozymes, a study was initiated to assess the in vivo interaction potential of risperidone on various cytochrome P450 isozymes. Eight patients were phenotyped with dextromethorphan (CYP2D6), mephenytoin (CYP2C19), and caffeine (CYP1A2) before and after the introduction of risperidone. Before risperidone, all eight patients were phenotyped as being extensive metabolizers of CYP2D6 and CYP2C19. Risperidone at dosages between 2 and 6 mg/d does not appear to significantly inhibit CYP1A2 and CYP2C19 in vivo (median plasma paraxanthine/caffeine ratios before and after risperidone: 0.65, 0.69; p = 0.89; median urinary (S)/(R) mephenytoin ratios before and after risperidone:0.11, 0.12; p = 0.75). Although dextromethorphan metabolic ratio is significantly increased by risperidone (median urinary dextromethorphan/dextrorphan ratios before and after risperidone: 0.010, 0.018; p = 0.042), risperidone can be considered a weak in vivo CYP2D6 inhibitor, as this increase is modest and none of the eight patients was changed from an extensive to a poor metabolizer. The reported increase of clozapine concentrations by risperidone can therefore not be explained by an inhibition of CYP1A2, CYP2D6, CYP2C19 or by any combination of the three.

Reduced quality of life associated adverse events in intermediate hepatocellular carcinoma patients treated with PRECISION TACE with drug eluting beads: Results from the PRECISION V randomized trial : B-241

Purpose: To evaluate the extent of quality of life (QoL) associated adverse events (AEs) following PRECISION TACE with DC Bead compared with conventional transarterial chemoembolisation (cTACE). Methods and Materials: 201 intermediate HCC patients were treated with DC Bead (PRECISION TACE) or conventional TACE (cTACE) with doxorubicin in the PRECISION V clinical study. 93 patients were treated with DC Bead and 108 Patients with cTACE every 2 months and followed up for 6 months. AEs were classified according to the South West Oncology Group criteria. QoL associated AEs were defined as alopecia, constipation, nausea, vomiting, pyrexia, chills, asthenia, fatigue, and headache. Results: The biggest difference in QoL associated AEs was for alopecia: 2 patients (2.2%) for DC-Bead versus 21 patients (19.4%) for cTACE. For other clinical symptoms, constipation (n=10; 10.8% vs. n=13; 12%), vomiting (n=10; 10.8% vs. n=14; 13.0%), pyrexia (n=16; 17.2% vs. n=26; 24.1%), chills (n=1; 1.1% vs. n=5; 4.6%), and headache (n=2; 2.2% vs. n=8; 7.4%) showed lower incidence in the DC Bead group versus cTACE. Nausea, n= 15; 13.9% (n=15; 16.1%) and fatigue, n=6; 5.6% (n=13; 14.0%) were lower for cTACE. Total dose of doxorubicin was on average 35% higher in the DC Bead group. Conclusion: Although patients in the DC Bead group received a higher doxorubicin dose, less QoL associated AEs were reported for this group. Alopecia, the most obvious outward sign of toxicity, was only reported in a tenth of DC Bead patients. Thus, PRECISION TACE with DC Bead improves quality of life associated adverse events.

Valproic acid related idiosyncratic drug induced hepatotoxicity in a glioblastoma patient treated with temozolomide.

Glioblastoma patients undergoing treatment with surgery followed by radiation and temozolomide chemotherapy often develop a state of immunosuppression and are at risk for opportunistic infections and reactivation of hepatitis and herpes viruses. We report the case of a 48-year-old glioblastoma patient who developed acute cholestatic hepatitis with hepatic failure during adjuvant treatment with temozolomide and the integrin inhibitor cilengitide. A viral hepatitis was excluded and valproic acid treatment was stopped. Upon normalisation of the liver tests, temozolomide treatment was resumed without perturbation of the liver tests. Valproic acid related idiosyncratic drug induced hepatotoxicity should be considered as a differential diagnosis in glioblastoma patients undergoing adjuvant therapy.