Simultaneous modelling of flosequinan and its metabolite.

DESIGN: A randomised, double-blind, prospective, placebo-controlled four-way study of the pharmacokinetics of single oral doses of flosequinan. We do not report the placebo data in this paper. Flosequinan was given at doses of 50, 100 and 150 mg, with a 2-week wash-out between periods. Blood samples were taken at a series of times up to 96 h after dosing. SETTING: Clinical pharmacology unit in a pharmaceutical company. PARTICIPANTS: Eighteen healthy volunteers of both genders, aged from 18 years to 55 years. MAIN OUTCOME MEASURES: Plasma concentrations of flosequinan and of its metabolite, flosequinoxan. RESULTS: We demonstrate that it is possible to model parent and metabolite concentration time profiles simultaneously and, in doing so, to estimate the first-pass effect using data from an oral administration. In our modelling approach, we propose a reasonably wide class of statistical models, allowing for left censoring. CONCLUSIONS: A parent-metabolite model that ignores the first-pass results in misleading predictions in a case where significant first-pass metabolism occurs. Thus, in phase-I studies, the new approach described in this paper can provide additional knowledge that may be useful in future formal studies.

Generalized nonlinear models for pharmacokinetic data.

Phase I trials to study the pharmacokinetic properties of a new drug generally involve a restricted number of healthy volunteers. Because of the nature of the group involved in such studies, the appropriate distributional assumptions are not always obvious. These model assumptions include the actual distribution but also the ways in which the dispersion of responses is allowed to vary over time and the fact that small concentrations of a substance are not easily detectable and hence are left censored. We propose that a reasonably wide class of generalized nonlinear models allowing for left censoring be considered now that this is feasible with current computer power and sophisticated statistical packages. These modelling strategies are applied to a Phase I study of the drug flosequinan and its metabolite. This drug was developed for the treatment of heart failure. Because the metabolite also exhibits an active pharmacologic effect, study of both the parent drug and the metabolite is of interest.

Modeling the covariance structure in pharmacokinetic crossover trials.

Pharmacokinetic studies of drug and metabolite concentrations in the blood are usually conducted as crossover trials, especially in phases I and II. A longitudinal series of measurements is collected on each subject within each period. However, much of the dependence among such observations, within and between periods, is generally ignored in analyzing this type of data. Usually, only a random coefficient model is fitted for the parameters in the nonlinear mean function, along with allowing the variance to depend on the mean so that it changes over time. Here, we develop models to allow more fully for the structure of the crossover study. We introduce two levels of variance components, for the subjects and for the periods within subjects, and also an autocorrelation within periods. We also retain the time-varying variance, using a separate variance function for this, different from that for the mean. We apply this model to a phase I study of the drug flosequinan and its metabolite. This drug was developed for the treatment of heart failure. Because the metabolite also exhibits an active pharmacologic effect, study of both the parent drug and the metabolite is of interest. We find that the autocorrelation is the element in the covariance structure that most improves the fit of the model but that two levels of variance components can also be necessary.

A meta-analysis of nausea and vomiting following maintenance of anaesthesia with propofol or inhalational agents.

A number of prospective randomized comparator studies have suggested that there is a reduction in post-operative nausea and vomiting following maintenance of anaesthesia with propofol compared with inhalational agents. We analysed these studies in more detail by examining the effects of induction agent, choice of inhalation agent, presence/absence of nitrous oxide, age of patient or use of opiate on the incidence of emesis. A search of the Zeneca database MEDLEY was undertaken and prospective randomized comparator studies identified. These were examined individually and independently by two of the authors and log-odds ratios, calculated from the incidence data of each individual trial, were determined and combined using a fixed-effects meta-analysis approach. Patients who received maintenance of anaesthesia with propofol had a significantly lower incidence of post-operative nausea and vomiting in comparison with inhalational agents regardless of induction agent, choice of inhalation agent, presence/absence of nitrous oxide, age of patient or use of opiate.

Relationship between hypoglycaemic response and plasma concentrations of BTS 67 582 in healthy volunteers.

The relationships between blood glucose, plasma insulin and plasma BTS 67 582 concentrations were studied in a randomised, placebo-controlled, four-way crossover study involving 16 healthy male volunteers aged between 19 and 43 years. Single oral doses of 125, 250 and 500 mg BTS 67 582 were studied. Fasting blood samples were taken pre-dose and half-hourly for 8 h post-dose. Mean peak plasma concentrations of BTS 67 582 were 518, 1076 and 2435 ng ml-1 for doses of 125, 250 and 500 mg, respectively. Mean maximum reductions in blood glucose were 1.13, 1.59 and 1.78 mmol l-1, and mean maximum increases in plasma insulin were 26, 14 and 21 muu ml-1 for the three doses, respectively. Changes in incremental area under the curve (AUC) of blood glucose were correlated with changes in plasma BTS 67 582 AUC. The maximum reduction in blood glucose was correlated with the peak plasma BTS 67 582 concentration. No correlations between plasma insulin and plasma BTS 67 582 concentrations were observed. Anticlockwise hysteresis was evident in concentration-effect curves, but less evident following subtraction of placebo data, and was mainly due to an underlying downward trend in fasted blood glucose levels with time evident under placebo treatment. This suggests that hypoglycaemic effects were related to systemic BTS 67 582 concentrations, suggesting that active metabolites of the drug do not make a major contribution to acute hypoglycaemic effects. A log-linear model described the relationship between blood glucose and plasma BTS 67 582 concentrations for 14 of the 16 volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)