PubMed Health⌕ Search

Biomedical subjects

A W Kelman

Publications and source records attributed to A W Kelman.

At least 19 recordsLinked to original sources
PubMed1992

Variability in the pharmacokinetics of epirubicin: a population analysis.

Population pharmacokinetic analysis of the anticancer agent epirubicin was carried out using the program NONMEM. Data were available from 36 patients aged 20-73 years, of whom 23 were women. All subjects exhibited normal liver and renal function. Epirubicin was given as a short-term i.v. infusion over the dose range of 25-100 mg/m2, and an average of 11 plasma samples/subject were taken for a period of up to 72 h after each dose. A Two compartment model was fitted to the data, characterised by the parameters clearance, volume of the central compartment, alpha and beta. Clearance was tested as a linear function of various demographic and/or biochemical features. A significant proportion of the variability in clearance could be attributed to sex, and also to age in women. For example, a 25-year-old man would display an average clearance of 95 l/h, whereas a 70-year-old woman would exhibit an average clearance of 64 l/h. Such differences in clearance might be important in the selection of epirubicin dose regimens.

Adult↗
PubMed1991

The relationships between dose and concentration of tolbutamide and insulin and glucose responses in patients with non-insulin-dependent diabetes.

It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The inter-relationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group). In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration. In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response. In the subset with a fasting blood glucose concentration of less than 8 mmol.l-1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.

Aged↗
PubMed1991

Population pharmacokinetics of rectal theophylline in neonates.

The population pharmacokinetics of theophylline were studied in 35 neonates receiving aminophylline suppositories for the treatment of apnoea of prematurity. Routinely measured theophylline serum concentrations (n = 138, range 3-20 mg/L) were modelled in NONMEM according to a one-compartment model. The influence of a number of clinical and demographic factors, e.g., weight (range 0.8-2.5 kg) and postnatal age (2-80 days), on clearance/bioavailability (CL/F) and volume/bioavailability (V/F) was investigated. Both these parameters were found to significantly correlate to weight alone in a directly proportional manner: CL/F = 40 +/- 2 ml/h/kg and V/F = 1.3 +/- 0.2 L/kg. The absorption was best described by a first-order process, having a half-life of 1.6 +/- 0.7 h. The interindividual variability in CL/F was 25%, whereas the same estimates in V/F and in the first-order absorption rate constant could not be obtained. The residual variability in theophylline concentrations was modelled with additive error with an estimated standard deviation of 1.78 mg/L. From these results, it was concluded that rectal administration of aminophylline in neonates is a therapeutically acceptable alternative to oral administration. The convenience gained by rectal, compared to oral, administrations may compensate, in many instances, for the possibly slightly higher variability in CL/F of the former.

Administration, Rectal↗
PubMed1991

A dose-ranging study of UK-68,798, a novel class III anti-arrhythmic agent, in normal volunteers.

1. UK-68,798, a novel class III anti-arrhythmic agent was administered intravenously to twelve healthy volunteers in a placebo controlled, double-blind, dose-escalating study. 2. Doses of 5 and 10 micrograms kg-1 of UK-68,798 selectively and significantly prolonged the QT interval, with mean maximum changes of 35 and 107 ms respectively, without affecting other ECG intervals. 3. There were dose-related increases in AUC but clearance (23 l h-1), terminal elimination half-life (8 h) and volume of distribution (245 l) were found to be independent of dose with low levels of intra- and inter-patient variability. 4. UK-68,798 has electrophysiological effects indicative of selective class III anti-arrhythmic activity and merits further assessment in clinical studies.

Adult↗
PubMed1990

Experimental design and efficient parameter estimation in population pharmacokinetics.

A computer simulation technique used to evaluate the influence of several aspects of sampling designs on the efficiency of population pharmacokinetic parameter estimation is described. Although the simulations are restricted to the one-compartment one-exponential model, they provide the basis for a discussion of the structural aspects involved in designing a population study. These aspects include number of subjects required, number of samples per subject, and timing of these samples. Parameter estimates obtained from different sampling schedules based on two- and three-point designs are evaluated in terms of accuracy and precision. These simulated data sets include noise terms for both inter- and intraindividual variability. The results show that the population fixed-effect parameters (mean clearance and mean volume of distribution) for this simple pharmacokinetic model are efficiently estimated for most of the sampling schedules when two or three points are used, but the random-effect parameters (describing inter- and intraindividual variability) are inaccurate and imprecise for most of the sampling schedules when only two points are used. This drawback was remedied by increasing the number of data points per individual to three.

Computer Simulation↗
PubMed1990

Evaluation of six gentamicin nomograms using a bayesian parameter estimation program.

A new set of guidelines for the administration of gentamicin was developed by estimating steady-state peak and trough gentamicin concentrations for simulated patients with known weights and creatinine clearances. The most appropriate doses to achieve target peak concentrations of 5-10 mg/L and troughs of less than 2 mg/L were then tabulated. The performance of these new guidelines was assessed using data collected from 60 patients who had received gentamicin and had at least two serum concentration measurements. Individual estimates of clearance and volume of distribution were obtained using a Bayesian parameter estimation program and these estimates were used to predict the steady-state peak and trough concentrations that would arise from the new guidelines and five other previously published nomograms (Mawer, Chan, Hull-Sarubbi, Rule of Eight, and Dettli). The new guidelines, the Dettli nomogram, and the Hull-Sarubbi table achieved similar percentages (52-57%) of patients within the target ranges (5-10 mg/L for peak and less than 2 mg/L for trough), although 28% of patients had predicted peak concentrations below 5 mg/L with the new method compared to 15% with the other two. Only 38% of patients were within both ranges when the Mawer nomogram and the Rule of Eight methods were used. Since a large percentage of patients would have achieved concentrations outside of the target ranges no matter which nomogram was used, serum concentration monitoring is still recommended to confirm dose requirements.

Bayes Theorem↗
PubMed1990

Altered pharmacokinetics of cyclosporin in heart-lung transplant recipients with cystic fibrosis.

The cyclosporin dose versus blood concentration relationship for 11 heart-lung transplant recipients with cystic fibrosis was studied retrospectively. Eleven patients, closely matched for age and gender, who received heart-lung transplantation for other diseases were selected as controls. Cystic fibrosis patients received 16.7 (SD 7.2) mg/kg/day of oral cyclosporin compared with 8.2 (SD 1.9) mg/kg/day given to the control patients (p less than 0.01). Nine of the cystic fibrosis patients received higher mean daily doses of cyclosporin. Mean blood cyclosporin concentrations were, however, not significantly different (p = 0.58), and there were no apparent differences in clinical outcome in terms of rejection, infection, and nephrotoxicity in the two groups. The apparent oral clearance of cyclosporin was significantly higher (p less than 0.01) in cystic fibrosis patients. Cyclosporin dosage individualization with the aid of cyclosporin blood concentration measurements is critically important in this subpopulation of heart-lung transplant recipients.

Administration, Oral↗
PubMed1989

Pharmacokinetics of an ACE inhibitor, S-9780, in man: evidence of tissue binding.

Pharmacokinetic data from 20-min constant rate infusions of the ACE inhibitor S-9780 1 mg to 16 subjects were studied for evidence of nonlinearity. A hierarchy of standard compartmental models and of nonlinear binding models was fitted to the data by least squares nonlinear regression and the most appropriate model was chosen on the basis of F-ratio tests, Schwarz criteria, and residual plots. A one-compartment model which included saturable tissue and plasma binding components allowed the best overall description of the data. Median parameter estimates from this model suggest that approximately 308 nmol of plasma binding sites and 572 nmol of tissue binding sites were present and that the total plasma concentration of S-9780 at 50% saturation of binding sites was 16.5 nmol L-1. The elimination half-life for free drug in plasma was only 30 min. This model describes the discrepancy previously noted between accumulation and apparent elimination half-lives for long-acting ACE inhibitors and offers a noninvasive method for assessment of tissue-bound ACE inhibitor in vivo.

Adult↗
PubMed1988

Effects of nadolol on arrhythmias during laparoscopy performed under general anaesthesia.

Cardiac arrhythmias are a well recognized complication of anaesthesia for laparoscopy. The effect of nadolol, given by mouth 12 h before operation, was compared with placebo on arrhythmias in 86 females undergoing laparoscopy. All types of arrhythmia were documented; there was a 97% incidence in the placebo group, but in the nadolol group there was a smaller incidence of supraventricular tachycardia, ventricular ectopics and atrioventricular dissociation (P less than 0.01). There was no significant difference in the incidence of sinus bradycardia. Nadolol may be recommended as a safe agent to be given by mouth before laparoscopy to reduce the frequency of cardiac arrhythmias during anaesthesia.

Adult↗
PubMed1988

Naproxen dose and concentration: response relationship in rheumatoid arthritis.

Information on the relationship between the plasma concentration of nonsteroidal anti-inflammatory drugs (NSAIDs) and clinical response in rheumatoid arthritis is sparse. As a result treatment is often relatively empirical. Standard doses are prescribed and an apparent lack of response leads either to the prescription of another drug, or an increase in the dose beyond that recommended. This study investigated 18 patients given three doses (500, 1000 and 1500 mg/day) of naproxen in a randomized double-blind design for 12 days at a time. Using a linear modelling approach we found that three out of four clinical response measurements improved linearly with increasing naproxen trough concentrations, suggesting that most patients will achieve an improvement in symptoms if the dose of naproxen is increased up to 1500 mg/day. However, since trough naproxen concentrations show a less than proportional increase with increasing dose (due to saturation of binding sites on plasma albumin), the improvement in response will be less dramatic as the dose is increased.

Arthritis, Rheumatoid↗
PubMed1988

Population pharmacokinetics of gentamicin in neonates.

The influence of a number of clinical characteristics on the population pharmacokinetics of gentamicin were examined using routine drug-monitoring data from a group of 113 neonates. The data were analyzed using the programme NONMEM. Clearance was 0.053 litres.h-1.kg-1 and was reduced in neonates with postconceptional age less than or equal to 34 weeks (X 0.83) and 5-min Apgar score less than 7 (X 0.82). Volume of distribution was 0.47 litres.kg-1. These population mean parameter estimates were used to generate dosage regimens to achieve concentrations within the therapeutic range.

Aging↗
PubMed1988

Nifedipine: individual responses and concentration-effect relationships.

Dynamic and kinetic variability account for the large intersubject differences in the antihypertensive response to nifedipine, and a clear concentration-effect relationship has not been established. The effects of placebo, first dose, and chronic (1 and 6 weeks) treatment with nifedipine were studied in 14 subjects with essential hypertension using an integrated kinetic-dynamic model to calculate individual subject responsiveness in terms of fall in blood pressure per unit change in drug concentration. Nifedipine concentrations were well correlated with the fall in systolic blood pressure in individual subjects, and the mean responsiveness was -0.48 mm Hg/ng/ml after the first dose, -0.45 mm Hg/ng/ml after 1 week, and -0.49 mm Hg/ng/ml after 6 weeks. The responsiveness to the first dose of nifedipine was significantly correlated with the responsiveness after 1 (r = 0.83) and 6 weeks (r = 0.78) of therapy and with the height of the pretreatment blood pressure (r = 0.6). This study incorporated kinetic as well as dynamic information to characterize the antihypertensive response to nifedipine and identify nifedipine concentration-effect relationships in individual hypertensive subjects.

Adult↗
PubMed1988

Population analysis of the pharmacokinetic variability of high-dose metoclopramide in cancer patients.

Metoclopramide infusions are used to prevent nausea and vomiting in cancer patients during chemotherapy. 47 patients received metoclopramide during 109 chemotherapeutic treatments as a loading (dose range = 0.55 to 4.5 mg/kg over 15 minutes) and maintenance (dose range = 0.57 to 4.8 mg/kg over 8 hours) infusion. During and up to 24 hours after the end of the maintenance infusion between 4 and 10 blood samples were collected per treatment. Metoclopramide was analysed in plasma by liquid chromatography. Pharmacokinetic and demographic data of 83 treatments were analysed by the NONMEM program using a linear 2-compartment model. It was found that bodyweight and serum alkaline phosphatase activity explain some of the interindividual variability in clearance (CL). The typical pharmacokinetic parameters for an average individual (70kg, alkaline phosphatase = 100 IU/L) were: CL = 20 L/h; volume of distribution at steady state (Vdss) = 190L; terminal half-life = 8h. The interindividual variabilities in clearance, volume of central compartment and Vdss were 50%, 35% and 35%, respectively. The residual variability in plasma concentrations was estimated as 13%.

Antineoplastic Agents↗
PubMed1988

Pharmacokinetic and pharmacodynamic modelling of the alpha adrenoceptor antagonist doxazosin.

1. The pharmacokinetic and pharmacodynamic profiles of intravenous and oral doxazosin were investigated in 6 normotensive volunteers. 2. The pharmacokinetics of i.v. and oral doxazosin were fitted simultaneously and independently. The parameters derived were in good agreement with a mean elimination half-life of 539 +/- 75 min, bioavailability of 0.65 +/- 0.11 and clearance of 140 +/- 26 ml/min. 3. Pharmacokinetic-pharmacodynamic modelling indicated that the sensitivities to oral and i.v. doxazosin in individual subjects were in good agreement. 4. Based on these findings it is unlikely that doxazosin metabolites contribute significantly to the pharmacodynamic profile of doxazosin.

Administration, Oral↗
PubMed1988

Indirect assessment of tissue angiotensin II converting enzyme inhibition in vivo in man.

The pharmacokinetics of long-acting angiotensin converting enzyme (ACE) inhibitors show features which are consistent with saturable binding of the drugs to ACE. Their pharmacokinetics may thus be used to assess the extent and affinity of plasma and tissue binding of the drug. For 16 subjects, a hierarchy of pharmacokinetic models was fitted by weighted, least squares, non-linear regression analysis to the concentration-time profile during and after an intravenous infusion of S-9780. A one-compartment model which included saturable tissue and plasma binding gave the best description of the data. The median parameter estimates from this model suggested that total binding capacity for drug was 333 micrograms, of which 62% was in tissue sites, and that the total plasma concentration of drug at half maximum saturation was 6.3 ng/ml. Thus the extent and affinity of ACE inhibitor binding to tissue ACE may be estimated from appropriate analysis of pharmacokinetic data in man.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Comparison of a Bayesian forecasting technique with a new method for estimating phenytoin dose requirements.

A simple, novel approach to phenytoin dose adjustment recently proposed by Wagner has been compared with an established Bayesian method. A data set comprising a minimum of two steady-state concentration/dose pairs from each of 43 adult epileptic patients was used. Prediction error analysis demonstrated that the two methods were equally precise but that the Wagner method tended to underpredict concentrations. The slope of the semilogarithmic relationship between concentration and dose was found to be 54% higher than originally reported by Wagner. It may therefore be necessary to adjust Wagner's equation for different patient populations before this method is used in routine clinical practice.

Adult↗
PubMed1987

The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects.

Lignocaine clearance declines during continuous intravenous infusion in man and in vitro studies suggest that this may partly be due to inhibition by MEGX, a metabolite of lignocaine. MEGX is pharmacologically active in animals, but this is not yet proven in man. This study examined the pharmacokinetics and pharmacodynamics of lignocaine and MEGX in eight healthy male volunteers given lignocaine HCl 120 mg, MEGX HCl 120 mg, lignocaine HCl 120 mg + MEGX HCl 120 mg, and placebo, administered according to a randomized double-blind protocol. One-, two-, or three-compartment models were fitted to drug and metabolite blood concentration-time profiles and clearance, volume (Vss), and half-life values were calculated and compared by paired t-test. Systolic time intervals and QT interval were recorded and compared by repeated measures ANOVA. When administered in combination with MEGX, lignocaine clearance was significantly reduced from 58 +/- 18 to 48 +/- 13 L hr-1 (p less than 0.02). The Vss was unchanged and there was a trend toward an increase in terminal half-life. Lignocaine, MEGX, and the combination significantly reduced QT interval up to 30 min after injection and this was maintained to 2 hr with the lignocaine and the combination. Transient side effects were experienced with all active treatments, but were most pronounced with the combination. Thus, lignocaine clearance was inhibited by MEGX, which was pharmacologically active in man.

Adult↗