Absolute Exposure Research Articles

A Phase 1 Study to Evaluate the Bioavailability and Food Effect of 2 Solid-Dispersion Formulations of the TRPV1 Antagonist ABT-102, Relative to the Oral Solution Formulation, in Healthy Human Volunteers.

ABT-102 is a selective TRPV1 antagonist designed for treatment of nociceptive pain. The objective of this study was to characterize the bioavailability and the food effect of 2 solid-dispersion (melt-extrusion [Meltrex] and spray-dried) tablet formulations of ABT-102 relative to the solution formulation used in initial clinical trials. The study followed a 2-part, single-dose (2-mg), open-label, randomized, 3-period, crossover design in 24 healthy adults, where in each study part, 1 of the 2 solid-dispersion formulations (under fasting and nonfasting conditions) was compared to the solution formulation (under nonfasting conditions). Under nonfasting conditions, the melt-extrusion and spray-dried formulations had 53% and 87% higher Cmax and 42% and 70% higher AUC∞ than the solution formulation, respectively. The 2 solid-dispersion formulations provided comparable absolute ABT-102 exposures (mean ± SD AUC∞ of 116 ± 35 ng·h/mL [melt-extrusion] and 112 ± 55 ng·h/mL [spray-dried]). There was no effect of food (high-fat/high-calorie breakfast) on the bioavailability of the melt-extrusion formulation with the fasting and nonfasting regimens meeting bioequivalence. Food increased Cmax and AUC∞ central values of the spray-dried formulation by an estimated 11% and 17%, respectively. Based on the results of the study, the melt-extrusion formulation of ABT-102 was selected to replace the solution formulation for subsequent clinical development.

Analysis of precipitation-related motor vehicle collision and injury risk using insurance and police record information for Winnipeg, Canada

Introduction Police records are the most common source of data used to estimate motor-vehicle collision risks, understand causal or contributing factors, and evaluate the efficacy of interventions. The literature notes concerns about this information citing discrepancies between police reports and other sources of injury occurrence and severity data. The primary objective of the analysis was to assess the adequacy of police reports for an examination of weather-related injury collision risk. Method Analyses of relative risk were carried out using both police records and comprehensive insurance claim data for Winnipeg, Canada over the period 1999–2001. Results and conclusions Both data sets yielded very similar results—precipitation substantially increases the risk of injury collision (police records: RR 1.76, CI 1.55-2.00; insurance: RR 1.80, CI 1.62-1.99) and risk of injury (police records, RR 1.74, CI 1.55-1.96; insurance, RR 1.69, CI 1.55-1.85) relative to corresponding dry weather control periods. Both rainfall and snowfall were associated with large increases in collisions and injuries. Impact on Industry While relative risks are almost identical, over 64% more injury collisions and 74% more injuries were identified using the insurance data, which is an important difference for evaluating absolute risk and exposure.

Socio-economic differences in exposure to television food advertisements in the UK: a cross-sectional study of advertisements broadcast in one television region

To document socio-economic differences in exposure to food advertising, including advertisements for foods high in fat, salt and sugar (HFSS) as defined by the UK Food Standards Agency's Nutrient Profiling Model. A cross-sectional survey. Information (including product advertised and viewing figures) on all advertisements broadcast in one UK region over one week (6-12 July 2009) was obtained. Food advertisements were identified and linked to nutritional information on the content of advertised foods. UK Tyne-Tees television region. Data were sourced from a UK-wide television viewing panel. Eleven per cent of advertising seen was for food and 63 % of food advertising seen was for HFSS foods. The proportion of all advertising seen that was for food was smaller among viewers in the least v. most affluent social grade (OR = 0·98, 99 % CI 0·95, 1·00). There was no difference in the proportion of food advertising seen that was for HFSS food between viewers in the most and least affluent social grades. Total exposure to both all food advertising and HFSS food advertising was 2·1 times greater among the least v. the most affluent viewers. While the least affluent viewers saw relatively fewer food advertisements, their absolute exposure to all food and HFSS food advertisements was higher than that of the most affluent viewers. Current UK restrictions prohibit advertisements for HFSS foods during programmes with a high proportion of child viewers. Extending these to all programming may reduce socio-economic inequalities in exposure to these advertisements and in diet and obesity.

Comparison of Exposure Controls, Item Pool Characteristics, and Population Distributions for CAT Using the Partial Credit Model

This study investigated item exposure control procedures under various combinations of item pool characteristics and ability distributions in computerized adaptive testing based on the partial credit model. Three variables were manipulated: item pool characteristics (120 items for each of easy, medium, and hard item pools), two ability distributions (normally distributed and negatively skewed data), and three exposure control procedures (randomesque procedure, progressive–restricted procedure, and maximum information procedure). A number of measurement precision indexes such as descriptive statistics, correlations between known and estimated ability levels, bias, root mean squared error, and average absolute difference, exposure rates, item usage, and item overlap were computed to assess the impact of matched or nonmatched item pool and ability distributions on the accuracy of ability estimation and the performance of exposure control procedures. As expected, the medium item pool produced better precision of measurement than both the easy and hard item pools. The progressive–restricted procedure performed better in terms of maximum exposure rates, item average overlap, and pool utilization than both the randomesque procedure and the maximum information procedure. The easy item pool with the negatively skewed data as a mismatched condition produced the worst performance.

Equivalence of using nested buffers and concentric adjacent rings as predictors in land use regression models

Land use regression (LUR) models have been widely used to estimate traffic air pollution within cities taking into account spatial distributions. These prediction models are often built based on multiple linear models that regress concentrations measured at locations spread over the cities on land use characteristics of those locations. Land use variables, as for example total road length, are sometimes calculated in buffers of different radii that are then included simultaneously in the models to account for a distance gradient in the influence of sources. Some authors favour including disjoint concentric ring areas instead. Both approaches have their advantages, and adjacent concentric rings tend to make model interpretation more intuitive. The present paper shows that both approaches lead to identical models and the results achieved from one can be used to calculate the results of the other when absolute continuous exposure measures such as total length of roads are used. It is also shown that this holds as well for relative exposures such as area-weighted total length of streets, inhabitants per area, and % urban area, where the measure of interest is scaled by a constant factor.

Interchangeability of generic anti-epileptic drugs: a quantitative analysis of topiramate and gabapentin

The objective of this study was to determine whether the so-called "shift" or "drift" problem might occur when generic anti-epileptic drugs are interchanged, and thus to assess if generic anti-epileptic drugs are interchangeable and can be used in an efficacious and safe way on the basis of their bioequivalence to one and the same reference product. The bioequivalence of topiramate and gabapentin generics was evaluated. For proper interstudy comparison, individual exposure data (AUC and C(max)) for each bioequivalence study present in the registration dossier was normalized based on the absolute exposure data of one of two innovators. The exposure-normalized plasma concentration curves of the generic product arms between studies were compared, providing indirect evidence of bioequivalence of the different generics. Additionally, comparisons were made for generic-generic as well as innovator-innovator exchange based on absolute exposure data from individual bioequivalence studies. In almost all cases, estimated 90% confidence intervals of the AUC and C(max) ratios for generic-generic interchange were within the routine 80-125% criterion. When absolute, non-corrected exposure data were used for this interstudy comparison, in a number of cases 90% confidence intervals outside the 80-125% criterion were found upon interchanging generics from two studies. However, a similar pattern of 90% confidence intervals outside the 80-125% criterion was observed for the comparison of innovator arms, despite the fact that the innovator was identical in all studies. Our results strongly indicate that the so-called drifting problem upon generic-generic substitution does not result in important differences in exposure upon exchanging topiramate generics or gabapentin generics.

Antiviral Activity, Pharmacokinetics, and Safety of BMS-488043, a Novel Oral Small-Molecule HIV-1 Attachment Inhibitor, in HIV-1-Infected Subjects

BMS-488043 is a novel and unique oral small-molecule inhibitor of the attachment of human immunodeficiency virus type 1 (HIV-1) to CD4(+) lymphocytes. The antiviral activity, pharmacokinetics, viral susceptibility, and safety of BMS-488043 were evaluated in an 8-day monotherapy trial. Thirty HIV-1-infected study subjects were randomly assigned to sequential, safety-guided dose panels of 800 and 1,800 mg BMS-488043 or a matched placebo in a 4:1 ratio, and the drug was administered every 12 h with a high-fat meal for 7 days and on the morning of day 8. Dose-related, albeit less-than-dose-proportional, increases in plasma BMS-488043 concentrations were observed. Mean plasma HIV-1 RNA decreases from the baseline for the BMS-488043 800- and 1,800-mg dose groups on day 8 were 0.72 and 0.96 log(10) copies/ml, respectively, compared with 0.02 log(10) copies/ml for the placebo group. A lower baseline BMS-488043 50% effective concentration (EC(50)) in the active-treatment groups was predictive of a greater antiviral response. Although absolute drug exposure was not associated with an antiviral response, the trough concentration (C(trough)), adjusted by the baseline EC(50) (C(trough)/EC(50)), was associated with antiviral activity. During dosing, four subjects experienced >10-fold reductions in viral susceptibility to BMS-488043, providing further support of the direct antiviral mechanism of BMS-488043. BMS-488043 was generally safe and well tolerated. These results suggest that further development of this novel class of oral HIV-1 attachment inhibitors is warranted.

Three-Dimensional Analysis of Recurrence Patterns in Rectal Cancer: The Cranial Border in Hypofractionated Preoperative Radiotherapy Can Be Lowered

The aim of this study was to determine whether and where the radiotherapy (RT) clinical target volume (CTV) could be reduced in short-course preoperative treatment of rectal cancer patients. Patients treated in the Dutch total mesorectal excision trial, with a local recurrence were analyzed. For 94 (25 who underwent radiation therapy 69 who did not) of 114 patients with a local recurrence, the location of the recurrence was placed in a three-dimensionalthree (3D) model. The data in the 3D model were correlated to the clinical trial data to distinguish a group of patients eligible for CTV reduction. Effects of CTV reduction on dose to the small bowel was tested retrospectively in a dataset of 8 patients with three-field conformal plans and intensity-modulated RT (IMRT). The use of preoperative RT mainly reduces anastomotic, lateral, and perineal recurrences. In patients without primary nodal involvement, no recurrences were found cranially of the S2-S3 interspace, irrespective of the delivery of RT. In patients without primary nodal involvement and a negative circumferential resection margin (CRM), only one recurrence was found cranial to the S2-S3 interspace. With a cranially reduced CTV to the S2-S3 interspace, over 60% reduction in absolute small bowel exposure at dose levels from 15 to 35 Gy could be achieved with three-field conventional RT, increasing to 80% when IMRT is also added. The cranial border of the CTV can safely be lowered for patients without expected nodal or CRM involvement, yielding a significant reduction of dose to the small bowel. Therefore, a significant reduction of acute and late toxicity can be expected.

Quantifying Metrics of External Airport Risk Exposure in Vicinity of Public Use, Nontowered Airports

This paper presents research conducted in modeling specific exposure metrics of communities in the vicinity of public use, nontowered airports to aviation accidents that result in crash sites outside the immediate confines of a runway (termed external airport risk). Two exposure metrics are explored: a relative exposure (termed crash hazard), defined as the probability that a crash site will be located in a specific area if a crash were to occur at an airport, and an absolute exposure (termed crash risk), defined as the expected number of crashes per year within any defined area. Results of this research are presented as a series of choro-pleth maps that define boundaries as contours, within which these metrics exceed some defined threshold. A specific application of this research is presented within the context of a model airport.

Influence of the dual ABCB1 and ABCG2 inhibitor tariquidar on the disposition of oral imatinib in mice

BackgroundImatinib, a tyrosine kinase inhibitor currently approved for treatment of several malignancies, has been shown to be a substrate for multiple efflux-transporter proteins, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP). The effect of inhibiting these transporters on tissue exposure to imatinib remains unclear.ObjectiveTo assess the role of these transporters on drug disposition, 50 mg/kg imatinib was administered to Balb/C mice, 30 minutes after receiving tariquidar (10 mg/kg), an inhibitor of both ABCB1 and ABCG2, or vehicle, via oral gavage.MethodsQuantitative determination of imatinib in mouse plasma, liver and brain was performed using a newly-developed and validated liquid-chromatography-mass spectrometric method. Results: Exposure to imatinib was 2.2-fold higher in plasma, liver and brain in mice that received tariquidar, as compared to those that received the vehicle (P = 0.001). The peak plasma concentration did not increase substantially, suggesting that tariquidar is affecting the distribution, metabolism and/or excretion of imatinib, rather than absorption. Though tariquidar increased the absolute exposure of imatinib, the brain-to-plasma ratio of imatinib was unaffected.ConclusionThis study suggests that intentional inhibition of ABCB1 and ABCG2 function at the blood-brain barrier is unlikely to significantly improve clinical outcome of imatinib with currently used dosing regimens.

Assessing the age‐weathering correspondence of cosmogenic 21Ne dated Pleistocene surfaces by the Schmidt Hammer

AbstractThe Schmidt Hammer (SH) method is used to quantify the rock weathering degree and has been proposed as a relative dating tool. Terrestrial Cosmogenic Nuclide (TCN) methods provide absolute exposure ages for erosive surfaces. Few works combine both methods for surfaces older than the Holocene. We compare data obtained by both methods for c. 150 ka bp glacial and fluvial erosive granite surfaces from northwest Spain. Rebound values (R) have been firstly compared with the rock density to assess the correlation with the rock strength, independently from influence of factors such as wetness and roughness in the R‐values. For erosive glacial surfaces older than 100 ka R‐values are confined in a narrow range, with no differences within errors. Stepped fluvial surfaces of 700 m to 70 m above present sea level show an inverse correspondence between TCN ages and R‐values, although no age predictions can be done on the basis of the R‐values. Thus, age inferences exclusively based on R‐values may not be realistic, but SH studies could be a useful tool for selecting surfaces for TCN dating. Copyright © 2009 John Wiley & Sons, Ltd.

Metabolites in Safety Testing (MIST): Considerations of Mechanisms of Toxicity with Dose, Abundance, and Duration of Treatment

In previous papers, we have offered a strategic framework regarding metabolites of drugs in humans and the need to assess these in laboratory animal species (also termed Metabolites in Safety Testing or MIST; Smith and Obach, Chem. Res. Toxicol. (2006) 19, 1570-1579). Three main tenets of this framework were founded in (i) comparisons of absolute exposures (as circulating concentrations or total body burden), (ii) the nature of the toxicity mechanism (i.e., reversible interaction at specific targets versus covalent binding to multiple macromolecules), and (iii) the biological matrix in which the metabolite was observed (circulatory vs excretory). In the present review, this framework is expanded to include a fourth tenet: considerations for the duration of exposure. Basic concepts of pharmacology are utilized to rationalize the relationship between exposure (to parent drug or metabolite) and various effects ranging from desired therapeutic effects through to severe toxicities. Practical considerations of human ADME (absorption-distribution-metabolism-excretion) data, to determine which metabolites should be further evaluated for safety, are discussed. An analysis of recently published human ADME studies shows that the number of drug metabolites considered to be important for MIST can be excessively high if a simple percentage-of-parent-drug criterion is used without consideration of the aforementioned four tenets. Concern over unique human metabolites has diminished over the years as experience has shown that metabolites of drugs in humans will almost always be observed in laboratory animals, although the proportions may vary. Even if a metabolite represents a high proportion of the dose in humans and a low proportion in animals, absolute abundances in animals frequently exceed that in humans because the doses used in animal toxicology studies are much greater than therapeutic doses in humans. The review also updates the enzymatic basis for the differences between species and how these relate to MIST considerations.

Drug Absorption Modeling as a Tool to Define the Strategy in Clinical Formulation Development

The purpose of this mini review is to discuss the use of physiologically-based drug absorption modeling to guide the formulation development. Following an introduction to drug absorption modeling, this article focuses on the preclinical formulation development. Case studies are presented, where the emphasis is not only the prediction of absolute exposure values, but also their change with altered input values. Sensitivity analysis of technologically relevant parameters, like the drug's particle size, dose and solubility, is presented as the basis to define the clinical formulation strategy. Taking the concept even one step further, the article shows how the entire design space for drug absorption can be constructed. This most accurate prediction level is mainly foreseen once clinical data is available and an example is provided using mefenamic acid as a model drug. Physiologically-based modeling is expected to be more often used by formulators in the future. It has the potential to become an indispensable tool to guide the formulation development of challenging drugs, which will help minimize both risks and costs of formulation development.

Drug Absorption Modeling as a Tool to Define the Strategy in Clinical Formulation Development

The purpose of this mini review is to discuss the use of physiologically-based drug absorption modeling to guide the formulation development. Following an introduction to drug absorption modeling, this article focuses on the preclinical formulation development. Case studies are presented, where the emphasis is not only the prediction of absolute exposure values, but also their change with altered input values. Sensitivity analysis of technologically relevant parameters, like the drug's particle size, dose and solubility, is presented as the basis to define the clinical formulation strategy. Taking the concept even one step further, the article shows how the entire design space for drug absorption can be constructed. This most accurate prediction level is mainly foreseen once clinical data is available and an example is provided using mefenamic acid as a model drug. Physiologically-based modeling is expected to be more often used by formulators in the future. It has the potential to become an indispensable tool to guide the formulation development of challenging drugs, which will help minimize both risks and costs of formulation development.

EU Directive 2004/40: field measurements of a 1.5 T clinical MR scanner

The European Union (EU) Physical Agents (EMF) Directive [1] must be incorporated into UK law in 2008. The directive, which applies to employees working in MRI, sets legal exposure limits for two of the three types of EMF exposure employed in MRI; time-varying gradient fields and radiofrequency (RF) fields. Limits on the static field are currently not included but may be added at a later date. Conservative action values have been set for all three types of exposure including the static field. The absolute exposure limits will exclude staff from the scanner bore and adjacent areas during scanning, impacting on many clinical activities such as anaesthetic monitoring during sedated scans, paediatric scanning and interventional MRI. When the legislation comes into force, NHS Trusts, scanner companies and academic institutions will be required to show compliance with the law. We present results of initial measurements performed on a 1.5 T clinical MRI scanner. For the static field, the proposed action value is exceeded at 40 cm from the scanner bore and would be exceeded when positioning a patient for scanning. For the RF field, the action values were only exceeded within the bore at distances of 40 cm from the scanner ends during a very RF intensive sequence; MRI employees are unlikely to be in the bore during an acquisition. For the time-varying gradient fields the action values were exceeded 52 cm out from the mouth of the bore during two clinical sequences, and estimated current densities show the exposure limit to be exceeded at 40 cm for frequencies above 333 Hz. Limiting employees to distances greater than these from the scanner during acquisition will have a severe impact on the future use and development of MRI.

Exposure of Arctic Field Scientists to Ultraviolet Radiation Evaluated Using Personal Dosimeters

During July 2000 we used an electronic personal dosimeter (X-2000) and a biological dosimeter (Deutsches Zentrum fur Luft- und Raumfahrt: Biofilm) to characterize the UV radiation exposure of arctic field scientists involved in biological and geological fieldwork. These personnel were working at the Haughton impact structure on Devon Island (75°N) in the Canadian High Arctic under a 24 h photoperiod. During a typical day of field activities under a clear sky, the total daily erythemally weighted exposure, as measured by electronic dosimetry, was up to 5.8 standard erythemal dose (SED). Overcast skies (typically 7–8 okta of stratus) reduced exposures by a mean of 54%. We estimate that during a month of field activity in July a typical field scientist at this latitude could potentially receive ∼80 SED to the face. Because of body movements the upper body was exposed to a UV regimen that often changed on second-to-second timescales as assessed by electronic dosimetry. Over a typical 10 min period on vehicle traverse, we found that erythemal exposure could vary to up to 87% of the mean exposure. Time-integrated exposures showed that the type of outdoor field activities in the treeless expanse of the polar desert had little effect on the exposure received. Although absolute exposure changed in accordance with the time of day, the exposure ratio (dose received over horizontal dose) did not vary much over the day. Under clear skies the mean exposure ratio was 0.35 ± 0.12 for individual activities at different times of the day assessed using electronic dosimetry. Biological dosimetry showed that the occupation was important in determining daily exposures. In our study, scientists in the field received an approximately two-fold higher dose than individuals, such as medics and computer scientists, who spent the majority of their time in tents.

Relationships Between Personal, Indoor, and Outdoor Levels of Sulfate, Elemental Carbon, and PM2.5 for a Cohort of Individuals With Cardiopulmonary Disease

SM4-PD-14 Background: Previous exposure studies have validated the use of ambient fine particulate matter (PM2.5) measurements as surrogates of exposure in PM time-series epidemiologic studies. It is uncertain, however, whether ambient measurements of specific PM components are equally good surrogates. Panel exposure assessment studies provide a direct means of exploring the strength of the relationships between personal, home indoor, home outdoor, and ambient particulate levels. For this study, we conducted a panel study measuring personal, home indoor, home outdoor, and ambient site concentrations of PM2.5 as well as its components, sulfate, and elemental carbon (EC), for individuals with cardiopulmonary disease. We examined particulate pollutant associations among the microenvironments by season and subject. Methods: Simultaneous 24-hour integrated personal, home indoor, and home outdoor PM2.5, SO42−, and EC concentrations were measured in 25 single-family homes during the summer and winter. All homes and subjects were measured for 7 consecutive days. Integrated 24-hour PM2.5, sulfate, and EC samples were also measured at a central monitoring site. Results: A total of 210 person-days of exposure data were collected. We found ambient sulfate to be strongly correlated with personal and home indoor sulfate for all individuals without an indoor source of sulfate in the home. Outdoor or ambient sulfate accounted for approximately 80% of the variability in personal and indoor sulfate concentrations, despite the fact that absolute exposure to sulfate was at times considerably lower than outdoor levels. In contrast to the results for sulfate, personal/indoor, and outdoor/ambient associations for EC and PM2.5 were weaker, likely due to indoor and/or local sources of EC and PM2.5. There were relatively weak EC outdoor-ambient associations, especially during the summer (mean home-specific Spearman's correlation coefficient = 0.26), indicating a greater degree of spatial heterogeneity for this pollutant. Discussion and Conclusions: These findings provide further evidence that ambient sulfate monitors may serve as good indicators of correlations, but not absolute exposures, to particles of ambient origin for particle health effects studies. The spatial variability of EC was notable in this study, although our results did not show stronger personal-outdoor associations compared with personal-ambient associations. These findings suggest that, for this metropolitan area, locating monitors closer to participants’ homes may not be effective when trying to assess personal EC exposure in future studies. Our results also indicate that housing characteristics are likely the central driving factor determining the strength of the personal-outdoor or personal-ambient relationships for PM2.5 and these 2 components.

Concentrations of Polychlorinated Biphenyls in Indoor Air and Polybrominated Diphenyl Ethers in Indoor Air and Dust in Birmingham, United Kingdom: Implications for Human Exposure

Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) were measured in air (using PUF disk passive samplers) in 31 homes, 33 offices, 25 cars, and 3 public microenvironments. Average concentrations of sigmaBDE (273 pg m(-3)) and sigmaPCB (8920 pg m(-3)) were an order of magnitude higher than those previously reported for outdoor air. Cars were the most contaminated microenvironment for sigmaBDE (average = 709 pg m(-3)), but the least for sigmaPCB (average = 1391 pg m(-3)). Comparison with data from a previous spatially consistent study, revealed no significant decline in concentrations of sigmaPCB in indoor air since 1997-98. Concentrations in indoor dust from 8 homes were on average 215.2 ng sigmaBDE g(-1), slightly higher than other European dust samples, but twenty times lower than Canadian samples. Inhalation makes an important contribution (between 4.2 and 63% for adults) to overall UK exposure to sigmaPCB. For sigmaBDE, dust ingestion makes a significant but--in contrast to Canada-a not overwhelming contribution (up to 37% for adults, and 69% for toddlers). Comparison of UK and Canadian estimates of absolute exposure to sigmaBDE suggest that differences in dust contamination are the likely cause of higher PBDE body burdens in North Americans compared to Europeans.

A simple measure for precautionary assessment of organic chemicals with respect to global cold condensation

The paper presents a new approach to assessing the cold condensation risk of chemicals. Cold condensation is related to disproportionate exposure levels in the water or soil compartments of cold regions compared to moderate temperature regions. The present contribution starts with a two-box model for transport and degradation with one box representing the polar regions and a second box for the non-polar regions. The ratio of absolute exposure in the two boxes is the basis for the definition of the cold condensation potential P cc,w which is shown to be an analytical function of four substance-related chemical constants. P cc,w is then calculated for a first group of chemicals commonly assumed to exhibit cold condensation, a second group of unsuspected substances, and a third set of chemicals of special interest. It turns out that P cc,w in combination with the absolute exposure in the water compartment of the polar region, e 2w/ c 0 s, fairly well separates group 1 and 2 ( c 0 is the initial concentration in the non-polar box, s is seconds). As the main result of the paper it is shown that values of log( P cc,w) ≥ −0.5 in combination with log( e 2w/ c 0 s) ≥ 8 can be used to identify cold condensating chemicals. This outcome is compared to related results by other authors. The risk of aggregation at this extreme level is briefly discussed.

Pharmacokinetics of Terbinafine in Young Children Treated for Tinea Capitis

Dermatophytes are the most common cause of human fungal infections. Response rates to existing therapy are lower than optimal, but newer agents like terbinafine hold promise for improved management of such infections. This investigation was designed to evaluate the single dose and steady state pharmacokinetics of terbinafine in young children with tinea capitis. Twenty-two otherwise healthy children (4-8 years) with tinea capitis were eligible for enrollment. Children were treated with terbinafine once daily according to body weight (<25 kg, 125 mg; 25-35 kg, 187.5 mg), and pharmacokinetic sampling was conducted after the first dose, at the midpoint of treatment and at steady state. Plasma terbinafine concentrations were quantitated, and the pharmacokinetic indices compared with adult data. Absolute estimates of Cmax and area under the concentration curve (AUC)0-24 were comparable between children and adults for the administered dose; however, children demonstrated significantly lower estimates of exposure when dose was corrected for weight (Cmax SS 200 +/- 104 versus 454 +/- 185 ng/mL per mg/kg dose, P < 0.01; AUCSS: 1110 +/- 640 versus 2756 +/- 1775 ng*h/mL per mg/kg dose, P < 0.01). When examined along a continuum, age accounted for approximately 50% of the variability observed in dose-normalized Cmax and AUC (P < 0.01). A slight but significant reduction in apparent oral clearance was observed with increasing age (0.02 L/h/kg per yr) that likely accounts for the lesser degree of accumulation observed in children at steady state (accumulation ratio, 1.5 +/- 0.8 versus 2.3 +/- 0.6, P < 0.01). Adverse events consisted principally of headache (n = 3) and gastrointestinal complaints (altered eating habits n = 3, loss of appetite n = 3, stomachache n = 4, diarrhea n = 2). A reduction in neutrophil count was observed in 5 children and thought to be related to study drug in 2. Children require significantly larger weight-normalized doses to approximate the exposure estimates observed in adults. The dosing scheme used in this investigation results in absolute exposure estimates at steady state and a safety profile that are not appreciably different from adults.