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Biomedical subjects

L Aarons

Publications and source records attributed to L Aarons.

At least 19 recordsLinked to original sources
PubMed1996

Practical experience and issues in designing and performing population pharmacokinetic/pharmacodynamic studies.

An expert meeting to discuss issues relating to the design of population pharmacokinetic/pharmacodynamic (PK/PD) studies was held in Brussels in March 1995, under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. The purpose of the meeting was to discuss the experts' experience in designing and performing population PK/PD studies. The topics discussed were current practice, logistical issues, ensuring the accuracy of data, covariate assessment, communication, and protocol design.

Belgium↗
PubMed1996

Lack of interaction between flucloxacillin and methotrexate in patients with rheumatoid arthritis.

1. The aim of the study was to examine the potential pharmacokinetic interaction between methotrexate and flucloxacillin. 2. Ten rheumatoid arthritis patients participated in the interaction study. Subjects were allocated to either methotrexate alone (5-15 mg per week) or methotrexate plus flucloxacillin (500 mg four times a day 48 h prior to sampling) in a random order. 3. There was a statistically, but not clinically, significant decrease in methotrexate AUC (1307 +/- 389 vs 1212 +/- 394 micrograms l-1 h) in the presence of flucloxacillin. Cmax and tmax parameters for methotrexate were not significantly altered in the presence of flucloxacillin. 4. Data from an additional 10 rheumatoid arthritis patients, starting on methotrexate, were added to the data from the placebo arm of the interaction study and a model dependent pharmacokinetic analysis was performed. The plasma concentration profiles were best described by a two-compartment model with a mean clearance of 11.9 (+/- 1.7) l h-1 and an initial volume of distribution of 31.2 (+/- 2.6) l. The pronounced intersubject variability in the pharmacokinetic parameters was not related to any of the available covariate information. 5. Our findings suggest that no important clinical interaction occurs between flucloxacillin and methotrexate in patients with rheumatoid arthritis.

Adult↗
PubMed1995

Effect of norfloxacin on theophylline disposition: a comparison with other fluoroquinolones.

The effects of norfloxacin (NOR), at steady-state plasma concentrations of 0-32 mg.l-1, on the plasma clearance of a 6 mg.kg-1 i.v. bolus dose of theophylline (THEO) in the male Sprague-Dawley rat have been studied. The effects were characterised by a Ki value (Ki = 12 microM), which was comparable with Ki values obtained previously under identical conditions for ciprofloxacin, but higher than that obtained for enoxacin. The distributional characteristics, volume of distribution and liver to plasma concentration ratio, were very similar for the three compounds. The only marked pharmacokinetic differences were in hepatic clearance, where there was a rank order NOR > ciprofloxacin > enoxacin, a reverse of the order in the reduction of THEO clearance seen in clinical studies. The advantages of using the steady-state experimental design described here are that equivalent concentrations are utilised to compare related drugs and differences in pharmacokinetics are accounted for, to allow a direct comparison of potency. This information, together with additional pharmacokinetic considerations, suggests that the different effects on THEO clearance seen in the clinic for NOR, ciprofloxacin and enoxacin are not solely due to differences in inhibitory potency, but also involve differences in hepatic clearance and hence systemic availability of the fluoroquinolones.

Animals↗
PubMed1995

Metabolism of theophylline and its inhibition by fluoroquinolones in rat hepatic microsomes.

1. The effects of beta-naphthoflavone, dexamethasone, phenobarbitone and isosafrole on the metabolism of theophylline by rat liver microsomes have been studied. Only beta-naphthoflavone, a known P4501A inducer, increased the rate of 1-methylxanthine formation (3-fold), whereas all the inducers studied increased the rate of 1,3-dimethyluric acid production (2.5-3-fold). 2. To study the effects of a range of fluoroquinolones on theophylline metabolism, beta-naphthoflavone-induced microsomes were used, as the ratio for metabolite production rates was similar to that of untreated microsomes (4:1,3-dimethyluric acid: 1-methylxanthine at 2 mM theophylline). High concentrations of fluoroquinolones (0.5-1.5 mM) were required to affect microsomal theophylline metabolism. 1-Methylxanthine was more sensitive to fluoroquinolone inhibition by enoxacin, ciprofloxacin, norfloxacin and pipemidic acid than 1,3-dimethyluric acid; CP67015, had a significant effect on 1,3-dimethyluric acid production only; binfloxacin had no effect on either pathway. 3. Ethoxycoumarin, a rapidly metabolized substrate, was also investigated as a surrogate for theophylline in in vitro experiments. Fluoroquinolone inhibition of ethoxycoumarin O-de-ethylation in beta-naphthoflavone-induced microsomes was quantitatively greater but qualitatively similar to theophylline metabolism (IC50s 440-870 microM at 2 microM 7-ethoxycoumarin). 4. These data are comparable with previous rat experiments in vivo, indicating that enoxacin, ciprofloxacin and norfloxacin have similar intrinsic activity in the inhibition of theophylline metabolism.

Animals↗
PubMed1994

Population approaches in drug development. Report on an expert meeting to discuss population pharmacokinetic/pharmacodynamic software.

An expert meeting to discuss population pharmacokinetic/pharmacodynamic software was held in Brussels in November 1993 under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. Recently developed statistical methods offer the possibility of gaining integrated information on pharmacokinetics and response from relatively sparse observational data obtained directly in patients who are being treated with the drug under development. These methods can minimize the need to exclude patient groups and also allow analysis of a variety of unbalanced designs that frequently arise in the evaluation of the relationships between dose or concentration on the one hand and efficacy or safety on the other relationships that do not readily lend themselves to other forms of statistical analysis. The purpose of the Brussels meeting was to evaluate the state of both existing software and software under development, and to specify the needs and wishes of potential users of such software. It was apparent from the meeting that software development for population data analysis is currently a very active area of investigation and that several very good packages are already available, with more in development. The general consensus of the meeting was that well validated, easy to use software was essential to the implementation of the population approach to drug development.

Humans↗
PubMed1994

Relationship between enoxacin and ciprofloxacin plasma concentrations and theophylline disposition.

Certain fluoroquinolone antibiotics affect theophylline (THEO) disposition by inhibition of its metabolism, yet no studies to date have investigated the relationship between fluoroquinolone plasma concentration and THEO pharmacokinetics. The effects of two fluoroquinolones, enoxacin (ENOX) and ciprofloxacin (CIPRO), have been studied in male Sprague-Dawley rats (n = 33-46) at steady state plasma concentrations of 0-33 mg.l-1, achieved by supplementing an intravenous bolus dose with a constant rate infusion. The effects of steady state ENOX and CIPRO plasma concentrations on the clearance of THEO determined after an intravenous bolus dose of 6 mg.kg-1 were described using a competitive inhibition model. The model consisted of two components, one describing a residual component of THEO clearance, which was unaffected by fluoroquinolone, the other describing the non-linear reduction of THEO clearance by fluoroquinolone. The residual clearance estimated from the model was comparable to renal clearance for THEO in the rat. The potency of each fluoroquinolone was characterised by a Ki value, the concentration reducing THEO clearance by 50% of the maximum change. These values were 4.7 microM and 16.3 microM for ENOX and CIPRO, respectively. Thus, in this study, ENOX was found to be a more potent inhibitor of THEO clearance than CIPRO. The method allowed direct in vivo comparison of potency between different fluoroquinolones, as pharmacokinetic differences, such as clearance, volume of distribution and bioavailability, were 'designed out.'

Animals↗
PubMed1993

Simultaneous assay of fluoroquinolones and theophylline in plasma by high-performance liquid chromatography.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of theophylline in plasma simultaneously with either ciprofloxacin, enoxacin or norfloxacin has been developed. It involves extraction of plasma with chloroform-isopropanol or dichloromethane-isopropanol prior to chromatography on a Spherisorb ODS2 column. The mobile phase is 15% acetonitrile in a phosphate buffer (pH 3.0) containing tetrabutylammonium hydrogen sulphate (4.4 mM) as an ion-pairing agent. Ultraviolet detection is carried out at 280 nm. Run time is less than 10 min for all three separations. The assays have been used to determine the effect of plasma concentrations of fluoroquinolone on theophylline clearance.

Animals↗
PubMed1993

The estimation of population pharmacokinetic parameters using an EM algorithm.

An EM algorithm was used to analyse data arising from non-linear mixed-effects models. The fixed parameters were determined by maximum likelihood using simplex minimization, and the random effects were estimated using the EM algorithm after linearization with respect to the random effects. Applications to a simple linear model and population pharmacokinetics are described. The use of posterior parameter estimates to investigate covariate relationships is briefly described. The implementation of the estimation-maximization (EM) algorithm described here has proved in practice to be robust but slow. We intend to use a Newton-Raphson minimization routine in place of the simplex method to hasten convergence. The alternative linearization of the non-linear mixed effects model suggested by Lindstrom and Bates (Biometrics 46 (1990) 673-687) is much more unstable than the usual linearization, especially during the initial iterations. In the case of indomethacin the two linearizations produced very similar results. The individual posterior parameter estimates provided by the program are very useful for the detection of covariate relationships in population pharmacokinetic studies. In addition, the posterior means can be used in the estimation of pharmacokinetic-pharmacodynamic relationships from sparse pharmacokinetic data where individual modelling is impossible.

Algorithms↗
PubMed1993

Time-dependent disposition of beta-naphthoflavone in the rat.

The pharmacokinetics of beta-naphthoflavone (BNF) have been investigated in rats following various modes of intravenous administration. From intravenous bolus studies it was established that BNF showed a high blood clearance (130 ml/min/kg) and no detectable excretion of unchanged compound in the urine. The volume of distribution for BNF was large (6 L/kg), and binding to plasma proteins extensive (96%). Intravenous infusion studies where the length of infusion was increased from 1 to 8 hr showed marked signs of time-dependent pharmacokinetics. During continuous infusions the plasma concentrations accrued for approximately 1 hr, after which plasma concentrations declined in an apparent exponential fashion to a plateau value. In the short infusion studies the postinfusion half-life (27 min) was significantly shorter than the terminal half-life after bolus administration (40 min). Time-dependent clearance of BNF resulting from enhancement/induction of P450IA enzymes is proposed as the mechanism for these unusual pharmacokinetic features. The use of antipyrine as an independent probe for P450 activity gave similar trends in antipyrine clearance for various modes of BNF administration. Computer simulations based on an autoinduction model for time-dependent clearance were consistent with the observations on BNF in the rat.

Animals↗
PubMed1992

A comparison of the relative sensitivities of factor VII and prothrombin time measurements in detecting drug interactions with warfarin.

We have studied the comparative abilities of the prothrombin time and factor VII clotting activity, measured using a chromogenic assay, to detect drug interactions with warfarin. Pharmacokinetic and pharmacodynamic data were collected from studies involving the single administration of 25 mg of warfarin in the absence and presence of fengabin, cimetidine, ranitidine, and enoxacin. Fengabin caused changes in both the pharmacokinetics and pharmacodynamics of warfarin, whereas cimetidine and enoxacin only caused changes in its pharmacokinetics. Ranitidine had no effect on either the pharmacokinetics or pharmacodynamics of warfarin. In general, factor VII clotting activity showed greater sensitivity but also greater variability than the prothrombin time to changes in clotting activity. Consequently, factor VII clotting activity did not have greater discriminatory power than the prothrombin time in detecting drug interactions involving warfarin.

Adult↗
PubMed1992

Population pharmacokinetics.

Traditionally pharmacokinetic studies have been performed in small homogenous groups of subjects, often normal healthy, young male volunteers. These studies are well controlled and generate meaningful baseline data. However, concern has been expressed that insufficient data is collected at an early state in the target population during a drug's development. Logistically studies during Phase III are difficult, control is lacking and what data that is generated is very sparse. In recent years there has been a growing interest in techniques capable of analyzing sparse data and there is now pressure on manufacturers to obtain more kinetic and dynamic information from Phase III studies. The issues, problems and the current status of population based studies will be discussed.

Animals↗
PubMed1991

A population analysis of the pharmacokinetics and pharmacodynamics of midazolam in the rat.

The concentration-EEG effect relationship of midazolam in the rat was studied from a population perspective. Plasma concentration and EEG effect data from 27 rats were available for analysis. Effect parameters derived from aperiodic EEG analysis were used as effect parameters. The population analysis gave results that were similar to the sample theory estimates (means s and SDs) obtained from the fits to individual data sets. Reanalysis of the EEG data using mean population pharmacokinetic parameters as input to the pharmacodynamic model led to poorer estimation of the pharmacodynamic parameters: particularly EC50. Inclusion of one observed plasma concentration per individual significantly improved the estimation of the pharmacodynamic parameters and led to results that were virtually indistinguishable from those obtained using complete pharmacokinetic data.

Animals↗
PubMed1991

The kinetics of flurbiprofen in synovial fluid.

Steady state plasma and synovial fluid flurbiprofen concentrations obtained from 26 rheumatoid arthritis patients receiving 100 mg of flurbiprofen b.i.d. were analyzed using the NONMEM program. Only one synovial fluid sample per patient was available. Population estimates for the plasma parameters, clearance, volume of distribution, and elimination half-life were 1.75 L hr-1, 11.9 L, and 4.8 hr, respectively, and the corresponding interindividual variances in these parameters were 29, 19 and 23%, respectively. The apparent elimination half-life from synovial fluid was 7.1 hr. After accounting for interindividual variability there was a residual variability of approximately 40% in both the plasma and synovial fluid concentrations.

Adolescent↗
PubMed1991

The pharmacokinetics of the enantiomers of flurbiprofen in patients with rheumatoid arthritis.

Plasma and synovial fluid concentrations of the enantiomers of flurbiprofen were measured in 15 rheumatoid patients receiving 100 mg racemic flurbiprofen twice daily. Pharmacokinetic parameters showed considerable variability within the group of patients, although differences in S(+)/R(-) plasma concentration ratios were small. The average values (+/- s.d.) of oral plasma clearance, volume of distribution and elimination half-life for R(-)-flurbiprofen were 0.075 (+/- 0.066) l min-1, 12.47 (+/- 5.79) l and 138 (+/- 61) min, respectively. The average values (+/- s.d.) of oral plasma clearance, volume of distribution and elimination half-life for S(+)-flurbiprofen were 0.057 (+/- 0.035) l min-1, 12.81 (+/- 4.43) l and 155 (+/- 49) min, respectively. S(+)/R(-) ratios (+/- s.d.) rose from 1.06 (+/- 0.12) to 1.75 (+/- 0.61) at the end of the 12 h interval in plasma and from 1.18 (+/- 0.13) to 1.47 (+/- 0.24) over the measured time course in synovial fluid. Increases in S(+)/R(-) ratios may be clinically important as they demonstrate accumulation of the pharmacologically active species.

Aged↗
PubMed1990

Investigations into the potential effects of multiple dose ketorolac on the pharmacokinetics and pharmacodynamics of racemic warfarin.

1. The potential interaction between racemic warfarin given as a 25 mg single oral dose and chronically administered ketorolac was studied in 12 young healthy male volunteers. 2. Ketorolac produced no major change in the pharmacokinetics of (R)- or (S)-warfarin. 3. Ketorolac did not alter the pharmacodynamic profile of racemic warfarin. 4. Ketorolac increased template bleeding time by a factor of 1.35 as compared with placebo. 5. The results suggest that the ketorolac-warfarin interaction is unlikely to be of major clinical significance; however, combined use of ketorolac and warfarin in patients should be undertaken with due caution and appropriate monitoring.

Adult↗
PubMed1989

Design and analysis of protein binding experiments.

The design and analysis of protein binding experiments for obtaining precise parameter estimates for a one-site and a two-site model treating fu, the fraction unbound as the experimentally determined quantity was investigated. Total drug concentrations were chosen at which the binding isotherm is determined to yield the most information about the parameters under study. The D-optimization information criterion was used to achieve this although other criteria are also discussed. For both the one-site and the two-site models the number of design points was always equal to the number of parameters being estimated. The results arrived at when dealing with constant variance and unconstrained total drug concentration were rather unique in that in most of the cases studied, all the optimal design points were away from the boundary conditions. For constant relative variance and unconstrained total drug concentrations, one of the design points was always placed at the smallest possible value of fu, the fraction unbound. For the one-site model the second point was always given by K(-1) + nP. The optimal designs arrived at lead to lower theoretical coefficients of variation in the parameters than the corresponding conventional ones. Simulated experiments supported these theoretical findings for both the one-site and the two-site models. For the one-site model, results from nonlinear regression were compared with Scatchard analysis and the optimal designs were also optimal in Scatchard space. We also show that using Scatchard analysis with the conventional strategy leads to poorly determined estimates particularly when the number of observations is low.

Binding Sites↗