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Systems pharmacology integrates structural biological and pharmacological knowledge and experimental data, enabling dissection of organism and drug properties and providing excellent predictivity. The development of systems pharmacology models is a significant task requiring massive amounts of background information beyond individual trial data. The qualification of models needs repetitive demonstration of successful predictions. Open Systems Pharmacology is a community that develops, qualifies, and shares professional open source software tools and models in a collaborative open-science way.

Background A model-based meta-analysis (MBMA) is a type of meta-regression that uses nonlinear mixed-effects models estimated on trial-level data to relate patient and trial characteristics, dosing, biomarkers, and outcomes of treatment. Objectives To use a pharmacometric MBMA within a pharmacoeconomic model of chronic obstructive pulmonary disease (COPD). Methods A Markov microsimulation model was developed to estimate monthly changes in the key disease severity metrics of COPD (forced expiratory volume in 1 second [FEV 1 ] and exacerbations) to compare a hypothetical drug that increases FEV 1 to usual care. The MBMA was used to predict a baseline exacerbation rate in a group of actual trial patients, given their known baseline FEV 1 . The hypothetical drug increased FEV 1 , thereby decreasing individuals' predicted exacerbation rates. Individual patient simulations allowed stochastic changes in monthly FEV 1 decline. Results In a sample of 1097 trial patients with a mean FEV 1 of 50%, the MBMA predicted 0.93 exacerbations per year on average. The exacerbation rate ranged from 0.52 to 1.3 per year across moderate and severe patient subgroups. A hypothetical anti-inflammatory drug that increased FEV 1 by 50 ml decreased exacerbations by 26%. Given a simplified estimation of costs and quality-adjusted life-years (QALYs) associated with COPD, a drug with a 50-ml increase priced at €35/mo had an incremental cost-effectiveness ratio ranging from €13,000/QALY to approximately €207,000/QALY across patient severity subgroups. Conclusions The synergistic aspects of MBMA and pharmacoeconomic modeling are highlighted in this hypothetical example. Markov microsimulation modeling allows the finer predictions of MBMA to inform parameters. Such an approach has utility in both early-phase cost-effectiveness estimations and trial design.

This document was developed to enable greater consistency in the practice, application, and documentation of Model-Informed Drug Discovery and Development (MID3) across the pharmaceutical industry. A collection of "good practice" recommendations are assembled here in order to minimize the heterogeneity in both the quality and content of MID3 implementation and documentation. The three major objectives of this white paper are to: i) inform company decision makers how the strategic integration of MID3 can benefit RD ii) provide MID3 analysts with sufficient material to enhance the planning, rigor, and consistency of the application of MID3; and iii) provide regulatory authorities with substrate to develop MID3 related and/or MID3 enabled guidelines.

OBJECTIVES The aim of this study was to describe the contemporary practice of electroconvulsive therapy (ECT) in South Africa. METHODS A 36-item questionnaire was sent to all hospitals that practiced ECT in a 12-month period between 2011 and 2012. RESULTS Forty-two institutions had an ECT machine on site, but 13 institutions reported nonuse. Electroconvulsive therapy services were available in only 6 of the 9 provinces. Questionnaires were sent to the 29 active sites. Twenty-four units (82.8%) responded, and of these, 20 institutions (68.9%) responded to question on the number of patients treated with ECT. Pre-ECT procedures commonly involved informed consent, a physical examination, and basic blood investigations. Bilateral, unilateral, and bifrontal electrode placements were used, whereas dose titration methods and seizure monitoring were used by most respondents. The number of persons treated with ECT per 10,000 persons per year was 0.22, whereas the number of ECT procedures performed per 10,000 persons per year was 1.19. The most common indication for ECT was depression, with most patients being between the ages of 18 and 59 years. CONCLUSIONS The characteristics and rate of ECT utilization in South Africa have been determined and generally emulated international guidelines and trends. However, accessibility to services and aspects such as training and accreditation could be improved.

To assess the link between tumor growth inhibition (TGI) and overall survival (OS) based on historical renal cell carcinoma (RCC) data. To illustrate how simulations can help to identify TGI thresholds based on target OS benefit [i.e., hazard ratio (HR) compared with standard of care] to support new drug development in RCC. Tumor size (TS) data were modeled from 2552 patients with first-line or refractory RCC who received temsirolimus, interferon, sunitinib, sorafenib or axitinib in 10 Phase II or Phase III studies. Three model-based TGI metrics estimates [early tumor shrinkage (ETS) at week 8, 10 or 12, time to tumor growth (TTG) and growth rate] as well as baseline prognostic factors were tested in multivariate lognormal models of OS. Model performance was evaluated by posterior predictive check of the OS distributions and hazard ratio across treatments. TTG was the best TGI metric to predict OS. However, week 8 ETS had a satisfactory performance and was employed in order to maximize clinical utilization. The week 8 ETS to OS model was then used to simulate clinically relevant ETS thresholds for future Phase II studies with investigational treatments. The published OS model and resultant simulations can be leveraged to support Phase II design and predict expected OS and HR (based on early observed TGI data obtained in Phase II or Phase III studies), thereby informing important mRCC development decisions, e.g., Go/No Go and dose regimen selection.

The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.

As part of the NOAA ECOHAB funded Gulf of Maine Toxicity (GOMTOX) 1 project, we determined Alexandrium fundyense abundance, paralytic shellfish poisoning (PSP) toxin composition, and concentration in quantitatively-sampled size-fractionated (20–64, 64–100, 100–200, 200–500, and >500 μm) particulate water samples, and the community composition of potential grazers of A. fundyense in these size fractions, at multiple depths (typically 1, 10, 20 m, and near-bottom) during 10 large-scale sampling cruises during the A. fundyense bloom season (May–August) in the coastal Gulf of Maine and on Georges Bank in 2007, 2008, and 2010. Our findings were as follows: (1) when all sampling stations and all depths were summed by year, the majority (94%±4%) of total PSP toxicity was contained in the 20–64 μm size fraction; (2) when further analyzed by depth, the 20–64 μm size fraction was the primary source of toxin for 97% of the stations and depths samples over three years; (3) overall PSP toxin profiles were fairly consistent during the three seasons of sampling with gonyautoxins (1, 2, 3, and 4) dominating (90.7%±5.5%), followed by the carbamate toxins saxitoxin (STX) and neosaxitoxin (NEO) (7.7%±4.5%), followed by n-sulfocarbamoyl toxins (C1 and 2, GTX5) (1.3%±0.6%), followed by all decarbamoyl toxins (dcSTX, dcNEO, dcGTX2&3) (

As part of the Gulf of Maine Toxicity (GOMTOX) project, we determined Alexandrium fundyense abundance, paralytic shellfish poisoning (PSP) toxin levels in various plankton size fractions, and the community composition of potential grazers of A. fundyense in plankton size fractions during blooms of this toxic dinoflagellate in the coastal Gulf of Maine and on Georges Bank in spring and summer of 2007, 2008, and 2010. PSP toxins and A. fundyense cells were found throughout the sampled water column (down to 50 m) in the 20-64 μm size fractions. While PSP toxins were widespread throughout all size classes of the zooplankton grazing community, the majority of the toxin was measured in the 20-64 μm size fraction. A. fundyense cellular toxin content estimated from field samples was significantly higher in the coastal Gulf of Maine than on Georges Bank. Most samples containing PSP toxins in the present study had diverse assemblages of grazers. However, some samples clearly suggested PSP toxin accumulation in several different grazer taxa including tintinnids, heterotrophic dinoflagellates of the genus Protoperidinium, barnacle nauplii, the harpacticoid copepod Microsetella norvegica, the calanoid copepods Calanus finmarchicus and Pseudocalanus spp., the marine cladoceran Evadne nordmanni, and hydroids of the genus Clytia. Thus, a diverse assemblage of zooplankton grazers accumulated PSP toxins through food-web interactions. This raises the question of whether PSP toxins pose a potential human health risk not only from nearshore bivalve shellfish, but also potentially from fish and other upper-level consumers in zooplankton-based pelagic food webs.

To assess the link between early tumor shrinkage (ETS) and progression-free survival (PFS) based on historical first-line metastatic renal cell carcinoma (mRCC) data. Tumor size data from 921 patients with first-line mRCC who received interferon-alpha, sunitinib, sorafenib or axitinib in two Phase III studies were modeled. The relationship between model-based estimates of ETS at week 8 as well as the baseline prognostic factors and PFS was tested in multivariate log-logistic models. Model performance was evaluated using simulations of PFS distributions and hazard ratio (HR) across treatments for the two studies. In addition, an external validation was conducted using data from an independent Phase II RCC study. The relationship between expected HR of an investigational treatment vs. sunitinib and the differences in ETS was simulated. A model with a nonlinear ETS-PFS link was qualified to predict PFS distribution by ETS quartiles as well as to predict HRs of sunitinib vs. interferon-alpha and axitinib vs. sorafenib. The model also performed well in simulations of an independent study of axitinib (external validation). The simulations suggested that if a new investigational treatment could further reduce the week 8 ETS by 30 % compared with sunitinib, an expected HR [95 % predictive interval] of the new treatment vs. sunitinib would be 0.59 [0.46, 0.79]. A model has been developed that uses early changes in tumor size to predict the HR for PFS differences between treatment arms for first-line mRCC. Such a model may have utility in predicting the outcome of ongoing studies (e.g., as part of interim futility analyses), supporting early decision making and future study design for investigational agents in development for this indication.

The delineation of near-surface (0-300m) hydrostratigraphy and tectonic features is essential for successful characterisation of groundwater systems and subsequent hydrogeological modeling. While most remote sensing of such systems is commonly achieved using high-resolution airborne electromagnetic data, validated by drilling data, and complemented by the use of terrain and multispectral data, it is shown that there is also a useful role for high-resolution magnetic survey data. Various filtering of gridded magnetic data, when image-enhanced and interrogated with other datasets, reveal features such as faults, dykes and other structures which may influence the distribution and movement of groundwater. One of the most useful enhancements of magnetic data is tilt, in which the range of data from ±90° acts as an automatic gain control to highlight both strong and weak source responses. While it is difficult to obtain accurate depth information from magnetic data, useful relative depth estimates can be obtained by using, for example, the Tilt-depth method, in which half the width between the ±45° contours of the tilt grid is a measure of the depth to source. These depth estimates can be calibrated, where possible, by comparison with other data. Dip directions of source contacts can be estimated by using the attitudes of multiscale edges, derived from the maxima of total horizontal derivative data. Examples of the utility of high-resolution magnetic data, in its complementary role, are presented for two groundwater assessment project areas — the Menindee Lakes region in western NSW and the Keep River catchment in the Northern Territory.

Objective To examine the impact of telephone follow-up interventions on glycaemic control in patients with Type 2 diabetes. The global epidemic of diabetes continues to rise with the epicentre in the Middle East and South Asia. Further evidence is provided with a 1.8 fold increase in diabetes in Iran over 8 years (See Estegahamahti et al, page 1233). Landmark trials in Finland and North America have shown that a healthy lifestyle or the use of pharmacotherapy in those people at high risk of diabetes can reduce the progression to overt diabetes. However, a critical question that needs to be addressed is whether this effect is equal across all ethnic groups. Boyko et al (page 1226) have done a post hoc analysis of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial. Whilst the use of rosiglitazone was associated with a 60% decrease in the progression to diabetes, in this month’sDiabeticMedicine, the investigators find heterogeneity of effect by ethnicity, with a smaller effect in South Asians and a greater effect in Latinos. This mirrors findings in the Indian Prevention Trials led by Prof A Ramachandraninwhichasignificantbutlesser effectwasseeninSouthAsianswiththe use of lifestyle or pioglitazone compared to published studies in North American or European populations. These studies highlight the need to tailor diabetes prevention strategies to different ethnic groups and the requirement for further research of this important subject that includes engagement with the local communities who can provideadeeperunderstandingofdietandlifestylefactorsrelevanttotheethnicgroup. Cover image: Karela on sale in London UK (Credit: Photograph from Sarah Finer) Manycommunitiesworldwideusetraditionaltreatmentstopreventandtreatdiabetes. InSouthAsiancommunitiesKarelaisoneofseveralvegetablescommonlyusedforthis purposewhichhasbeenproventohaveanactiveingredientthatlowersbloodglucose.

Copepods of the genus Acartia dominate zooplankton assemblages in northwestern Atlantic estuaries, many of which originated after the last glacial maximum 10,000–18,000 years ago. Acartia hudsonica occurs, at least seasonally, in estuaries from Chesapeake Bay to Labrador/Newfoundland. We sequenced the mitochondrial gene Cytochrome B (CytB) of 75 individuals of A. hudsonica from 26 estuaries from New Jersey to Maine, covering four biogeographic regions, and 11 individuals of Acartia tonsa from four of these estuaries in the southern part of the sampling range. A. hudsonica exhibited exceptionally high intraspecific DNA sequence variation. Uncorrected p-distances between sequences ranged from 0.3 to 31%. Five highly divergent sequence groups differed in frequencies across populations and biogeographic regions. One sequence group dominated northern localities, and two sequence groups were found at intermediate to high frequencies in two southern biogeographic regions. Ages of the sequence groups were estimated to be 11, 13, 30, and 37 million years, by applying a molecular clock calibrated by divergence in Alpheus snapping shrimps across the Isthmus of Panama. These ages were compared with independent biogeographic paleoceanographic data, and may have coincided with periods of global climate change over the past 40 MY.

The clinical assessment of metabolic drug–drug interactions (mDDI) may involve population-based pharmacokinetic (POPPK) assessment as part of Phase 3 clinical trials. The elements of such POPPK study design have not been linked to prior information from in vitro experiments. Using in vitro–in vivo extrapolation techniques, implemented within Simcyp® algorithms, the influence of POPPK study design (sample size, concentration-time data points, proportion of the population receiving a concomitant medication (COMED)) was studied in relation to the inhibitory potency of the each COMED. Steady-state concentrations of a candidate compound (compound X; mainly metabolized by cytochrome P450 enzymes, CYP3A4 and CYP2D6) in the presence and absence of COMEDs (including ketoconazole, fluconazole, quinidine and paroxetine as inhibitors) were analysed using non-linear mixed effect modelling (NONMEM®). The NONMEM operator was blind to the nature of the COMEDs and the inhibitory effects on model parameters were classified as either statistically (p>0.01 for a change in objective function) or kinetically (COMED effect>2 fold) significant. Using a population study size of 2000, no false-positive cases were identified and, except in one case, no false-negative interaction was observed when >2.5% of patients had received an interacting COMED. The findings increase the confidence in the ability of the mixed effects modelling approach to identify ‘true’ interactions. However, they also emphasize the importance of study design and the potential value of using pre-clinical information from in vitro studies. Recent US Food and Drug Administration guidance on mDDI has put more emphasis on the use of in vitro systems for detecting and anticipating such effects. Combining these data with the framework of non-linear mixed effect modelling seems a natural progression in the field of assessing mDDI. Copyright © 2009 John Wiley & Sons, Ltd.

Voriconazole is a potent triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present population pharmacokinetic analysis evaluated voriconazole plasma concentration-time data from three studies of pediatric patients of 2 to P < 0.001) influence of the CYP2C19 genotype and of the alanine aminotransferase level on clearance. The model was used in a number of deterministic simulations (based on various fixed, mg/kg of body weight, and individually adjusted doses) aimed at finding suitable i.v. and p.o. voriconazole dosing regimens for pediatric patients. As a result, 7 mg/kg twice a day (BID) i.v. or 200 mg BID p.o., irrespective of body weight, was recommended for this patient population. At these doses, the pediatric area-under-the-curve (AUC) distribution exhibited the least overall difference from the adult AUC distribution (at dose levels used in clinical practice). Loading doses or individual dosage adjustments according to baseline covariates are not considered necessary in administering voriconazole to children.

In spite of the extensive use of long-acting β2-agonist (LABA) bronchodilators in asthma, the actual mechanism of their in vivo duration of action is not well understood, primarily due to limitations of standard pharmacokinetic–pharmacodynamic (PKPD) analysis methodologies. We have developed a novel method of analysing lung efficacy vs. time profiles for LABAs that can be used to provide comparative information on the lung PK. We hypothesised that for compounds that do not differ in their PK at the site of PD action, but differ in their in vivo potencies, the relationship between the area under the effect curve (AUEC) and the observed maximum effect (OME) at different doses is described by the same sigmoid curve. We have illustrated this property for standard PKPD models by obtaining analytical solution and through simulations. Anaesthetised dog in vivo effect vs. time profiles were gathered for six inhaled LABA candidates that differ in their in vitro potencies. Neither lung nor systemic PK was available for any compound. Analysis of the AUEC vs. OME data, derived from the efficacy profiles, using nonlinear mixed effects modelling indicated that for four compounds, the observed differences in in vivo duration of action was due to differences in their in vivo potencies and not because of lung PK differences. Therefore, it was concluded that for these compounds, characterisation of lung PK was unlikely to differentiate their PKPD characteristics. Thus, the proposed approach helped focus resources during translational research leading to lead candidate selection.

The low productivity and escalating costs of drug development have been well documented over the past several years. Less than 10% of new compounds that enter clinical trials ultimately make it to the market, and many more fail in the preclinical stages of development. These challenges in the "critical path" of drug development are discussed in a 2004 publication by the US Food and Drug Administration. The document emphasizes new tools and various opportunities to improve drug development. One of the opportunities recommended is the application of "model-based drug development (MBDD)." This paper discusses what constitutes the key elements of MBDD and how these elements should fit together to inform drug development strategy and decision-making.

As part of the NOAA ECOHAB funded Gulf of Maine Toxicity (GOMTOX)1 project, we determined Alexandrium fundyense abundance, paralytic shellfish poisoning (PSP) toxin composition, and concentration in quantitatively-sampled size-fractionated (20–64, 64–100, 100–200, 200–500, and > 500 μm) particulate water samples, and the community composition of potential grazers of A. fundyense in these size fractions, at multiple depths (typically 1, 10, 20 m, and near-bottom) during 10 large-scale sampling cruises during the A. fundyense bloom season (May–August) in the coastal Gulf of Maine and on Georges Bank in 2007, 2008, and 2010. Our findings were as follows: (1) when all sampling stations and all depths were summed by year, the majority (94% ± 4%) of total PSP toxicity was contained in the 20–64 μm size fraction; (2) when further analyzed by depth, the 20–64 μm size fraction was the primary source of toxin for 97% of the stations and depths samples over three years; (3) overall PSP toxin profiles were fairly consistent during the three seasons of sampling with gonyautoxins (1, 2, 3, and 4) dominating (90.7% ± 5.5%), followed by the carbamate toxins saxitoxin (STX) and neosaxitoxin (NEO) (7.7% ± 4.5%), followed by n-sulfocarbamoyl toxins (C1 and 2, GTX5) (1.3% ± 0.6%), followed by all decarbamoyl toxins (dcSTX, dcNEO, dcGTX2&3) (< 1%), although differences were noted between PSP toxin compositions for nearshore coastal Gulf of Maine sampling stations compared to offshore Georges Bank sampling stations for 2 out of 3 years; (4) surface cell counts of A. fundyense were a fairly reliable predictor of the presence of toxins throughout the water column; and (5) nearshore surface cell counts of A. fundyense in the coastal Gulf of Maine were not a reliable predictor of A. fundyense populations offshore on Georges Bank for 2 out of the 3 years sampled.

Background QT prolongation is an important biomarker of the arrhythmia torsades de pointes and appears to be related mainly to blockade of delayed inward cardiac rectifier potassium currents. The aim of this study was to quantify the relationship between in vitro human ether-a-go-go-related gene (hERG) potassium channel blockade and the magnitude of QT prolongation in humans for the class III antiarrhythmic dofetilide. Methods The in vitro affinity and activity of dofetilide were determined in recombinant cell cultures expressing the hERG channel, and the QT-prolonging effect of dofetilide was assessed in 5 clinical studies (80 healthy volunteers and 17 patients with ischemic heart disease). A population pharmacokinetic-pharmacodynamic analysis of the in vitro and in vivo data was performed in NONMEM by use of the operational model of pharmacologic agonism to estimate the efficiency of transduction from ion channel binding to Fridericia-corrected QT response. Results A 3-compartment pharmacokinetic model with first-order absorption characterized the time course of dofetilide concentrations. On the basis of an in vitro potency of 5.13 ng/mL for potassium current inhibition and predicted unbound dofetilide concentrations, the estimated transducer ratio (τ) of 6.2 suggests that the QT response plateaus before currents are fully blocked. In our study population, 10% hERG blockade corresponds to a QT prolongation of 20 ms (95% confidence interval, 12–32 ms). With long-term dofetilide administration, tolerance develops with a half-life of 4.7 days. Conclusions The current mechanism-based pharmacokinetic-pharmacodynamic model quantified the relationship between in vitro hERG channel blockade and clinical QT prolongation for dofetilide. This model may prove valuable for assessing the risk of QT prolongation in humans for other drugs that selectively block the hERG channel on the basis of in vitro assays and pharmacokinetic properties. Clinical Pharmacology & Therapeutics (2005) 77, 572–582; doi: 10.1016/j.clpt.2005.02.004

If appropriately accounted for in a pharmacokinetic (PK)–pharmacodynamic (PD) model, time-varying covariates can provide additional information to that obtained from time-constant covariates. The aim was to present and apply two models applicable to time-varying covariates that capture such additional information. The first model estimates different covariate–parameter relationships for within- and between-individual variation in covariate values, by splitting the standard covariate model into a baseline covariate (BCOV) effect and a difference from baseline covariate (DCOV) effect. The second model allows the magnitude of the covariate effect to vary between individuals, by inclusion of interindividual variability in the covariate effect. The models were applied to four previously analysed data sets. The models were applied to 10 covariate–parameter relationships and for three of these the first extended model resulted in a significant improvement of the fit. Even when this model did not improve the fit significantly, it provided useful information because the standard covariate model, which assumes within- and between-patient covariate relationships of the same magnitude, was only supported by the data in four cases. The inclusion of BCOV was not supported in two cases and DCOV was unnecessary in three cases. In one case, significantly different, nonzero, relationships were found for DCOV and BCOV. The second extended model was found to be significant for four of the 10 covariate–parameter relationships. On the basis of the examples presented, traditionally made simplifications of covariate–parameter relationships are often inadequate. Extensions to the covariate–parameter relationships that include time-varying covariates have been developed, and their appropriateness and benefits have been described.

Aims To describe the population pharmacokinetic–pharmacodynamic relationship between darifenacin (UK-88,525) and its hydroxylated metabolite (UK-148,993), and the reduction in salivary flow (SF, a M3-mediated response). This enabled an estimation of the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. Methods A total of 262 individuals were pooled from 11 Phase 1 studies and one Phase 2 study. A comparison was made between a series of pharmacodynamic models (direct-effect, indirect-effect, link and binding model) using NONMEM. Results The binding model yielded the best description of the decrease in SF by fully accounting for the time course of the pharmacodynamic effect. An internal validation exercise demonstrated the robustness of this model. Covariate analysis identified a circadian rhythm in SF. This model, with confidence intervals (CI) determined by likelihood profiling, indicated that the relative potency of the metabolite to darifenacin to reduce SF was 11.1% (95% CI 3.8, 19.6). This implied that the metabolite was ninefold less potent than darifenacin in vivo. Accounting for the unbound fraction of darifenacin (2%) and its metabolite (13%), the in vivo protein binding-corrected relative potency was estimated to be 2.1%, indicating that the metabolite was 50-fold less potent than the parent drug. The model supported the assumption that no other metabolites contributing to the impairment of the SF were formed during first-pass, and that the development of sensitization or tolerance was not evident over time. The validation process indicated that the i.v.–oral crossover study was necessary for the estimation of the relative potency. Conclusions Population modelling of darifenacin and its hydroxylated metabolite yielded individual pharmacokinetic predictions that could be used to assess the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. The metabolite had a negligible effect on SF.

Aims A model describing the population pharmacokinetics of darifenacin and its hydroxylated metabolite was developed from a combined analysis of 18 studies. The relationships between explanatory covariates and pharmacokinetic parameters were explored.

Aims To analyse the pharmacokinetics of sildenafil citrate in patients with erectile dysfunction in order to characterize covariate relationships and assist in the development of rational dosage strategies. Methods A population pharmacokinetic sampling strategy was incorporated into five phase III clinical study protocols. Overall, 2077 patients, 1335 of whom received sildenafil, were asked to take an additional dose of study drug before their scheduled clinic visits on four or five occasions throughout the study duration. A single plasma sample was obtained at random times postdose (range 1–7 h), and a total of 4582 samples were assayed (average 3.4 samples per individual). Results For the population average patient (age 58 years; aspartate transaminase [AST], 24 IU l−1; weight, 87 kg; not receiving CYP3A4 potential inhibitors), typical values for sildenafil (mean±SE) were 58.5±1.4 l h−1 for apparent clearance (CL/F), 310±6.92 l for volume of distribution (V/F), and 2.6±0.176 h−1 for first-order absorption constant (ka). The value for ka is associated with meal consumption within 2 h predose, at all other times ka was equivalent to an instantaneous bolus administration. The interindividual variabilities were 29% for CL/F, 20% for V/F, and 210% for ka. Over a dose range of 25–100 mg sildenafil, the pharmacokinetics exhibited dose proportionality. There was evidence of nonproportionality (40% increase on average) in relative bioavailability with respect to the 200-mg dose (P

The anaerobic biodegradability and transformationof the mono-and dichlorinated salicylates(2-hydroxybenzoates) was examined under denitrifying,Fe (III) reducing, sulfate reducing andmethanogenic conditions. 3,6-Dichlorosalicylateand 6-chlorosalicylate are anaerobic microbialmetabolites of dicamba, a widely used herbicide.Anaerobic microcosms were established withdicamba treated soil from Wyoming, and golfcourse drainage stream sediments from NewJersey, which were each spiked with salicylate,3,6-dichlorosalicylate or one of the fourmonochlorosalicylate isomers. Salicylatewas degraded under denitrifying, sulfidogenic andmethanogenic conditions. In methanogenicenrichments 5-chlorosalicylate and 3-chlorosalicylatewere reductively dehalogenated to salicylatewhich was then utilized. Dehalogenation ofmonochlorinated salicylates to salicylate wasalso observed in denitrifying chlorosalicylatedegrading cultures. The study revealed thatthe position of the chlorine substituent as well as thepredominant electron accepting process affectthe rate and extent of chlorosalicylate degradationin anoxic environments.

We examined the anaerobic biodegradability and transformation of dicamba under denitrifying, iron Fe(III) reducing, sulfate reducing, and methanogenic conditions. Anaerobic microcosms were establis...

We examined the anaerobic degradation of catechol (1,2-dihydroxybenzene), resorcinol (1,3-dihydroxybenzene), and hydroquinone (1,4-dihydroxybenzene), which are widely used industrial reagents and central intermediates in the biodegradation of numerous aromatic compounds. Anaerobic denitrifying enrichments were established with sediments from an estuarine tidal strait in New Jersey, USA. The three dihydroxybenzene isomers were provided as a sole carbon source in separate enrichment series. Resorcinol- and catechol-degrading consortia used their respective substrates over repeated feedings. Initial loss of hydroquinone was observed, but activity could not be maintained. The degradation of resorcinol and catechol was coupled to denitrification and was dependent on nitrate or nitrite as an electron acceptor. Nitrate consumption and N2 production corresponded to the stoichiometric values predicted for the oxidation of dihydroxybenzenes to CO2.

The pharmaceutical industry continues to face significant challenges. Very few compounds that enter development reach the marketplace, and the investment required for each success can surpass $1.8 billion. Despite attempts to improve efficiency and increase productivity, total investment continues to rise whereas the output of new medicines declines. With costs increasing exponentially through each development phase, it is failure in phase II and phase III that is most wasteful. In today's development paradigm, late-stage failure is principally a result of insufficient efficacy. This is manifested as either a failure to differentiate sufficiently from placebo (shown for both novel and precedented mechanisms) or a failure to demonstrate sufficient differentiation from existing compounds. Set in this context, this article will discuss the role model-based drug development (MBDD) approaches can and do play in accelerating and optimizing compound development strategies through a series of illustrative examples.

Image enhancement consists of raising subtle trends above the detectability threshold usually either by increasing the relative amplitude or by emphasising the continuity of the feature. Images of the vertical magnetic gradient are in themselves an enhancement of the shallow source anomalies present in total magnetic intensity data. Even in the gradient image, low amplitude anomalies may be obscured by intense anomalies which may be several orders higher in amplitude. One way to overcome this is to sacrifice amplitude fidelity, retain anomaly shape, and enhance the gradient data using automatic gain control (AGC). By definition automatic gain control implies that for a given frequency, output amplitude is independent of input amplitude. The controlling parameters when applying automatic gain control are the window size over which the gain is computed and the gain function which controls the relative amplification of signal and noise. Since gradient data are only rarely collected during an aeromagnetic survey, the creation of an AGC-enhanced gradient image can be achieved in different ways. The computation of the vertical gradient and subsequently of the AGC can be carried out either on profile data or on gridded data. The results are similar but the noise level and the amount of high-frequency information in the output may be significantly different depending on the order of the processing. Experiments using high-resolution aeromagnetic data indicated that for the purposes of trend identification, the image derived from gridded AGC-enhanced profile data was preferable to that obtained from AGC-enhanced grid data. A suitable gain function was the inverse root mean square value computed within a sliding window. The image could be significantly improved by setting the base-level of the gradient profile data to zero before applying the AGC.

The pharmacokinetics of voriconazole in children receiving 4 mg/kg intravenously (i.v.) demonstrate substantially lower plasma exposures (as defined by area under the concentration-time curve [AUC]) than those in adults receiving the same therapeutic dosage. These differences in pharmacokinetics between children and adults limit accurate prediction of pediatric voriconazole exposure based on adult dosages. We therefore studied the pharmacokinetics and tolerability of higher dosages of an i.v.-to-oral regimen of voriconazole in immunocompromised children aged 2 to

A simple and sensitive liquid chromatographic method with ultraviolet detection is described for the determination of the nonsteroidal anti-inflammatory drug piroxicam and its major metabolites in human plasma, urine and bile. Separation of these components occurs on a reversed phase C10CN column with a mobile phase consisting of acetonitrile-water-sodium dihydrogenphosphate solution. The detection limit of the assay was 50 ng/ml with intra- and inter-assay coefficients of variation for piroxicam of the order of 2 and 5%, respectively. The assay linearity was good (typically r = 0.9999). This method can be readily utilised for clinical pharmacokinetic and mass-balance studies.

To describe the population pharmacokinetic-pharmacodynamic relationship between darifenacin (UK-88,525) and its hydroxylated metabolite (UK-148,993), and the reduction in salivary flow (SF, a M3-mediated response). This enabled an estimation of the in vivo potency of the metabolite to decrease SF relative to that of the parent drug.A total of 262 individuals were pooled from 11 Phase 1 studies and one Phase 2 study. A comparison was made between a series of pharmacodynamic models (direct-effect, indirect-effect, link and binding model) using NONMEM.The binding model yielded the best description of the decrease in SF by fully accounting for the time course of the pharmacodynamic effect. An internal validation exercise demonstrated the robustness of this model. Covariate analysis identified a circadian rhythm in SF. This model, with confidence intervals (CI) determined by likelihood profiling, indicated that the relative potency of the metabolite to darifenacin to reduce SF was 11.1% (95% CI 3.8, 19.6). This implied that the metabolite was ninefold less potent than darifenacin in vivo. Accounting for the unbound fraction of darifenacin (2%) and its metabolite (13%), the in vivo protein binding-corrected relative potency was estimated to be 2.1%, indicating that the metabolite was 50-fold less potent than the parent drug. The model supported the assumption that no other metabolites contributing to the impairment of the SF were formed during first-pass, and that the development of sensitization or tolerance was not evident over time. The validation process indicated that the i.v.-oral crossover study was necessary for the estimation of the relative potency.Population modelling of darifenacin and its hydroxylated metabolite yielded individual pharmacokinetic predictions that could be used to assess the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. The metabolite had a negligible effect on SF.

To analyse the pharmacokinetics of sildenafil citrate in patients with erectile dysfunction in order to characterize covariate relationships and assist in the development of rational dosage strategies.A population pharmacokinetic sampling strategy was incorporated into five phase III clinical study protocols. Overall, 2077 patients, 1335 of whom received sildenafil, were asked to take an additional dose of study drug before their scheduled clinic visits on four or five occasions throughout the study duration. A single plasma sample was obtained at random times postdose (range 1--7 h), and a total of 4582 samples were assayed (average 3.4 samples per individual).For the population average patient (age 58 years; aspartate transaminase [AST], 24 IU l(-1); weight, 87 kg; not receiving CYP3A4 potential inhibitors), typical values for sildenafil (mean +/- SE) were 58.5 +/- 1.4 l h(-1) for apparent clearance (CL/F), 310 +/- 6.92 l for volume of distribution (V/F), and 2.6 +/- 0.176 h(-1) for first-order absorption constant (ka). The value for ka is associated with meal consumption within 2 h predose, at all other times ka was equivalent to an instantaneous bolus administration. The interindividual variabilities were 29% for CL/F, 20% for V/F, and 210% for ka. Over a dose range of 25--100 mg sildenafil, the pharmacokinetics exhibited dose proportionality. There was evidence of nonproportionality (40% increase on average) in relative bioavailability with respect to the 200-mg dose (P0.001) relative to the other doses. Age, AST concentration, and co-administration with CYP3A4 potential inhibitors significantly influenced CL/F of sildenafil (P0.001, for each relationship). For age and AST, the extent of the linear relationships (extrapolated from population average values) included a 4% decrease in CL/F for every decade increase and a 6% decrease in CL/F for every 10-unit increase, respectively. Following co-administration of CYP3A4 potential inhibitors, a 14% decrease in CL/F was estimated. Only body weight was found to significantly (P0.001) influence V/F (a 6% increase in V/F for every 10-kg increase).The pharmacokinetics of, and covariate influences on, sildenafil in patients with erectile dysfunction were shown to be consistent with those demonstrated in phase I volunteer studies.

Aim: Tumor growth inhibition (TGI) metrics estimated with longitudinal tumor size (TS) models have been shown to be predictive of overall survival (OS) in a variety of tumor types. Methods: TS data from 2490 patients with 1st line or refractory RCC who received temsirolimus, interferon, sunitinib, sorafenib or axitinib in 10 Phase 2 or Phase 3 studies were used. TGI metrics (Early tumor shrinkage (ETS) at week 8, 10, 12, time to growth (TTG)) as well as baseline prognostic factors were tested in a multivariate log-normal model of OS. Model performances were evaluated by posterior predictive check of the OS and hazard ratio distributions. Results: TTG was the best TGI metric to predict OS (days), but Week 8 ETS, an earlier measure, had satisfactory performance, and was employed due to its ease of clinical utility. The parameter estimates of the model with Week 8 ETS are: Parameter Estimate (SE) p-value Intercept 8.07 (0.270) TS ratio at week 8 -1.99 (0.135) Baseline hemoglobin (g/L) 0.133 (0.111) Baseline ECOG = 1 -0.400 (0. 048) Baseline ECOG = (2, 3) -0.163 (0.077) 0.033 Log(# baseline metastases) -0.209 (0.032) Baseline cor. calcium (mg/dL) -0.104 (0.019) Time from diagnosis (day) 8.0E-5 (1.7E-5) Baseline LDH (U/L) -3.7E-4 (9.2E-5) Lung metastases (yes) -0.138 (0.046) 0.002 Log(scale) -0.107 (0.020) This model was then used in simulation mode to define a clinically relevant ETS target for future Phase II studies with investigational treatments. Conclusions: A TGI-based OS model is proposed for patients with RCC. The model demonstrates good performance when fitted to data from 10 different Phase II and Phase III clinical trials. Simulations with this model help with identification of relevant ETS targets in clinical trial design. Disclosure: F. Mercier:is employed by Pharsight Consulting Services (a division of Certara, L.P.), a company that received financial support from Pfizer to complete this work; B. Houk: is employed by Pfizer; L. Claret: is employed by Pharsight Consulting Services (a division of Certara, L.P.), a company that received financial support from Pfizer to complete this work; P. Milligan: is employed by Pfizer; R. Bruno: is employed by Pharsight Consulting Services (a division of Certara, L.P.), a company that received financial support from Pfizer to complete this work.

A modeling framework relating exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor (sVEGFR)-2, -3, soluble stem cell factor receptor (sKIT)), and tumor growth to overall survival (OS) was extended to include adverse effects (myelosuppression, hypertension, fatigue, and hand-foot syndrome (HFS)). Longitudinal pharmacokinetic-pharmacodynamic models of sunitinib were developed based on data from 303 patients with gastrointestinal stromal tumor. Myelosuppression was characterized by a semiphysiological model and hypertension with an indirect response model. Proportional odds models with a first-order Markov model described the incidence and severity of fatigue and HFS. Relative change in sVEGFR-3 was the most effective predictor of the occurrence and severity of myelosuppression, fatigue, and HFS. Hypertension was correlated best with sunitinib exposure. Baseline tumor size, time courses of neutropenia, and relative increase of diastolic blood pressure were identified as predictors of OS. The framework has potential to be used for early monitoring of adverse effects and clinical response, thereby facilitating dose individualization to maximize OS.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e85; doi:10.1038/psp.2013.62; advance online publication 4 December 2013.