Modeling of Functional Assessment Questionnaire (FAQ) as continuous bounded data from the ADNI database.

An assessment of abilities to function independently in daily life is an important clinical endpoint for all Alzheimer's disease (AD) patients and caregivers. A mathematical model was developed to describe the natural history of change of the Functional Assessment Questionnaire (FAQ) from data obtained in normal elderly, mild cognitive impairment, and mild AD in the AD neuroimaging initiative (ADNI) study. FAQ is a bounded outcome (ranging from 0 to 30), with 0 scored as "no impairment" and 30 as "severely impaired". Since many normal elderly patients had 0 scores and some AD patients had scores of 30 in the ADNI database, a censored approach for handling the boundary data was compared with a standard approach, which ignores the bounded nature of the data. Baseline severity, ApoE4 genotype, age, sex, and imaging biomarkers were tested as covariates. The censored approach greatly improved the predictability of the disease progression in FAQ scores. The basic method for handling boundary data used in this analysis is also applicable to handle boundary observations for numerous other endpoints.

Model-based drug development.

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.

Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors.

AIM: To assess the pharmacokinetics of alosetron, its effect on in vivo enzyme activities, and influence of demographic factors during repeated dosing. METHODS: Thirty healthy men and women received 1 mg oral alosetron twice-daily for 29.5 days and a single oral dose of a metabolic probe cocktail before and on the last day of alosetron dosing. Serum alosetron concentrations were measured on days 1, 8, 15, 22 and 29. Probe-substrate and metabolite concentrations were measured after each cocktail dose. RESULTS: Alosetron accumulation in serum was negligible. Exposure to alosetron did not alter probe-metabolite/substrate ratios associated with CYP2C19, 2E1, 2C9, or 3A4 activity, but modestly decreased those associated with CYP1A2 and N-acetyltransferase activity. Systemic exposure to alosetron was higher in women, positively correlated with age and body mass index, and negatively correlated with CYP1A2 activity. Incidence of constipation was higher in women, but not associated with alosetron concentration. CONCLUSIONS: Single dose data can reliably predict the pharmacokinetics of alosetron after repeated doses. Alosetron exhibits limited potential for inhibition of cytochrome P450-mediated metabolism. Interindividual differences in alosetron pharmacokinetics associated with demographic factors may be related to strong dependence on metabolism by CYP1A2.

Stereospecific pharmacokinetics and toxicodynamics of ketorolac after oral administration of the racemate and optically pure enantiomers to the rat.

To determine the stereospecific pharmacokinetics and gastrointestinal permeability (GI) changes (surrogate measures of toxicity) in the rat following oral administration of S, R, and racemic ketorolac (KT), optically pure enantiomers (S and R 2.5 mg/kg), and racemic KT (5 mg/kg) were administered orally to male Sprague-Dawley rats and plasma samples were collected for 6 h post-dose for pharmacokinetic assessments. KT-induced changes in GI permeability were assessed using sucrose and 51Cr-EDTA as markers of gastroduodenal and distal intestinal permeability, respectively. After the racemate, R-KT was predominant in plasma (AUC S/R, 0.45). No significant differences in pharmacokinetic indices were evident following administration of the racemate as compared with individual enantiomers. In plasma, there was only negligible S-KT after administration of R-KT. After S-KT, on the other hand, AUC of R-KT was found to be 6.7% of that of S-KT. Both permeability markers showed considerable interanimal variability. Gastroduodenal permeability was significantly increased from baseline by the racemate but not by either of the two enantiomers administered alone. Permeability to 51Cr-EDTA was not significantly increased above baseline for any of the treatments. The plasma concentration of R-KT found after administration of S-KT may be from the < 2% chiral impurity which appears magnified due to its slower clearance as compared with its antipode. There is no evidence of a pharmacokinetic interaction between the enantiomers. Since 2.5 mg/kg S-KT is somewhat less toxic on the gastroduodenum than 5 mg/kg racemate, it may be a safer alternative to the latter, at least in the rat model.

Heterogeneity in systemic availability of ondansetron and granisetron following oral administration.

This open-label, randomized, two-way crossover study compared the relative heterogeneity in systemic availability of oral ondansetron and granisetron. It was conducted in 10 healthy male and 10 healthy female subjects aged 18 to 50 years. Following an overnight fast, each subject received 8 mg ondansetron and 1 mg granisetron. Treatments were separated by 7 days. Blood samples for drug assay were collected over a period of 36 h and variability in pharmacokinetic parameter estimates were assessed following standardization by their respective means. Granisetron showed significantly more variability than ondansetron in the three primary endpoints of the area under the curve extrapolated to infinite time, the area under the curve to the last quantifiable time point, and maximal concentration (p =.0032,.0037, and.0042, respectively). In one subject, concentrations of granisetron were detectable but below the lower limit of quantitation at any time point. The impact this variability may have on therapeutic efficacy is not clear. An apparent bimodal distribution in granisetron AUC infinite, which appeared to be related to smoking was observed. Because granisetron has been reported to be metabolized primarily by the cytochrome P-450 (CYP) 3A isozyme family in humans, it is possible that cigarette smoke could be an inducer of CYP3A or that CYP1A2, also implicated in the metabolism of granisetron and known to be induced by smoking, is more important in the biotransformation of granisetron than previously thought.

Application of a neural network for gentamicin concentration prediction in a general hospital population.

Neural network (NN) computation is computer modeling based in part on simulation of the structure and function of the brain. These modeling techniques have been found useful as pattern recognition tools. In the present study, data including age, sex, height, weight, serum creatinine concentration, dose, dosing interval, and time of measurement were collected from 240 patients with various diseases being treated with gentamicin in a general hospital setting. The patient records were randomly divided into two sets: a training set of 220 patients used to develop relationships between input and output variables (peak and trough plasma concentrations) and a testing set (blinded from the NN) of 20 to test the NN. The network model was the back-propagation, feed-forward model. Various networks were tested, and the most accurate networks for peak and trough (calculated as mean percent error, root mean squared error of the testing group, and tau value between observed and predicted values) were reported. The results indicate that NNs can predict gentamicin serum concentrations accurately from various input data over a range of patient ages and renal function and may offer advantages over traditional dose prediction methods for gentamicin.

Sucrose urinary excretion in the rat measured using a simple assay: a model of gastroduodenal permeability.

PURPOSE: To develop a non-invasive animal model suitable for studies of altered gastroduodenal (GD) permeability, which is suggested to indicate GD damage; to validate a low cost and convenient assay for sucrose in urine, a permeability marker of GD. METHODS: Control (n = 87) and treated male Sprague-Dawley rats were dosed orally with 1 g of sucrose. Urinary excretion of the sucrose (0-8 h) was measured indirectly by cleavage to glucose and subsequent measurement of glucose in urine using a calorimetric assay. Treated rats were administered single oral doses of 10 and 20 mg/kg indomethacin, or 42 mg/kg aspirin alone or with 0.5 mL 50% ethanol (n = 7 in each group). RESULTS: The assay was linear within the examined range of 10-100 ug/mL sucrose. The inter and intraday variations were 7.63% and 6.89%, respectively. The urinary excretion of sucrose was complete in 8 h. In control rats the urinary excretion of sucrose exhibited a left skewed frequency distribution curve with a mean of 0.6 +/- 0.14% of the dose excreted. All treatment, with the exception of 10 mg/kg indomethacin significantly increased the GD permeability. The GD effect was found to be dose dependent and parallels those reported for humans. CONCLUSIONS: The rat is a suitable model for studies of GD permeability. Combined use of sucrose and 51Cr-EDTA, a marker of intestinal permeability, allows for non-invasive examination of abnormalities of the entire gut. The sucrose assay is convenient and cost effective. The rat model may be useful in the preclinical screening of NSAID formulations and also in the detection of other GI abnormalities.