Biomedical subjects

B Whiting

Publications and source records attributed to B Whiting.

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↗

PubMed1992

Bayesian parameter estimation and population pharmacokinetics.

The widespread application of Bayesian parameter estimation in the area of therapeutic drug monitoring (TDM) has prompted the need for well conducted population studies to obtain relevant prior pharmacokinetic parameter estimates. In many cases the population has consisted of a relatively small number of subjects. This may be unavoidable for drugs used in cancer chemotherapy or in small, specific populations of patients. In contrast, information about drugs which are used extensively, such as the aminoglycosides, can be obtained by population studies which involve a large number of individuals. Indeed, this technique has proved particularly useful for determining parameter estimates which can be employed in neonatal TDM. Bayesian parameter estimation has been most frequently used for drugs with narrow therapeutic ranges such as the aminoglycosides, cyclosporin, digoxin, anticonvulsants (especially phenytoin), lithium and theophylline. However, the technique has now been extended to cytotoxic drugs, Factor VIII and warfarin. Bayesian methods have also been used to limit the number of samples required in more conventional pharmacokinetic studies with new drugs. Further advances in the use of these methods are likely to include measures of drug response and toxicity requiring population studies which also include relevant pharmacodynamic information.

Bayes Theorem↗

PubMed1991

Cyclosporine pharmacokinetics in liver transplant recipients: evaluation of results using both polyclonal radioimmunoassay and liquid chromatographic analysis.

Pharmacokinetic variables were derived from cyclosporine measurements using liquid chromatography (HPLC) and radioimmunoassay with a non-selective polyclonal antibody (PARIA) in 11 orthotopic liver transplant recipients studied in paired oral and intravenous studies both before and after permanent clamping of the biliary T-tube. After oral drug administration, mean areas under blood cyclosporine concentration versus time curves before clamping were around 5.2-fold greater by PARIA than HPLC but 2.9-fold greater after clamping and closer to comparable values after intravenous cyclosporine (2.5 and 2.3-fold, respectively). Cyclosporine clearance was smaller by PARIA than HPLC (mean 7.3 versus 3.3 ml.min-1.kg-1, respectively, before clamping). Both values decreased by 25% after clamping (to 5.5 and 2.4 ml.min-1.kg-1, respectively), although there was no significant change in distribution or elimination half-lives (around 0.5 and 8 h, respectively). The mean bioavailability of oral cyclosporine increased significantly after clamping in 9 patients (from 10.6% to 28.1% by HPLC and from 14.8 to 35.1% by PARIA) but in two patients who developed the vanishing bile duct syndrome values fell to less than 10% and the proportional overestimation of cyclosporine concentrations by PARIA increased. Clamping had no singificant effect on the mean apparent volumes of distribution but values of Vz were approximately twice those of Vss (around 2.6 and 1.31.kg-1 by PARIA and HPLC respectively). Mean half lives after clamping were shorter following oral than intravenous cyclosporine (t 1/2 lambda 2 around 15 h enterally versus 8 h parenterally).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

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

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↗

PubMed1989

Lisinopril population pharmacokinetics in elderly and renal disease patients with hypertension.

1. The population pharmacokinetics of lisinopril were investigated using data collected from two multicentre trials of lisinopril in the treatment of hypertension in elderly patients (n = 40) and patients with renal disease (n = 20). 2. Lisinopril was started at doses of 2.5-5 mg daily and increased at 2-4 weekly intervals as required for control of blood pressure. Steady-state concentration-time profiles were measured after at least 2 weeks at a constant dose. 3. All concentration-time data were analysed simultaneously using the program NONMEM and the influence of clinical factors on clearance/F and volume of distribution/F was tested. 4. Clearance was significantly influenced by creatinine concentration, age, weight and cardiac failure. No clinical features tested were found to influence volume of distribution. 5. The influence of renal function and cardiac failure on lisinopril clearance has been confirmed using a population pharmacokinetic analysis technique.

Age Factors↗

PubMed1989

Cyclosporin A pharmacokinetics in liver transplant recipients in relation to biliary T-tube clamping and liver dysfunction.

Cyclosporin A pharmacokinetics were studied after oral (4-14 mg/kg body weight) and intravenous dosing (1.5-3.5 mg/kg) in 13 orthotopic liver transplant recipients before and after permanent clamping of the biliary T-tube. After T-tube clamping, cyclosporin A absorption was faster and more complete with the mean time of peak concentration, tmax, reduced to around three hours from around six hours and mean bioavailability rising from only 16.6% (n = 13) to 30% in the entire group (n = 11 after clamping) or to 35% after excluding two patients who developed severe cholestasis after the preclamping study. Bioavailability in these two patients fell below 8% and to around 1% in a further patient with severe graft dysfunction. Clamping reduced the metabolic clearance of cyclosporin A by only 25% from a mean before clamping of 2.9 ml/min/kg to 2.3 ml/min/kg (n = 11). Oral cyclosporin A becomes a reliable means of maintaining therapeutic drug concentrations only after bioavailability increases in association with T-tube clamping and in the absence of severe liver dysfunction or cholestasis.

Absorption↗

PubMed1989

Rhabdomyolysis and listeria monocytogenes.

Non-traumatic rhabdomyolysis occurs as a complication of a wide variety of infections and is often discovered as a result of the associated renal failure. We report a case of meningitis due to Listeria monocytogenes, an uncommon cause of infection in adults which was associated with rhabdomyolysis. This confirms a recent first case report of this association.

Female↗

PubMed1989

Population pharmacokinetic analysis of bisoprolol.

The technique of population pharmacokinetic analysis was employed to study the variability in the dose concentration relationship of bisoprolol during its clinical development. The influence of demographic factors on the variability of clearance was investigated in 3 different populations: group I, patients (including an elderly group) with essential hypertension receiving multiple oral doses of bisoprolol 10 or 20mg for 3 months; group II, patients with different degrees of renal impairment and healthy controls; and group III, patients with different types of hepatic impairment and healthy controls. Patients and controls in groups II and III received only a single oral dose of bisoprolol 10mg. The 3 data sets were analysed separately, using a non-linear mixed effects model (the NONMEM program). A 2-compartment pharmacokinetic model with first-order absorption described the data adequately. The typical values of volume of central compartment, volume of distribution at steady-state and the absorption rate constant for the 3 populations were: for group I, 68L, 235L, and 0.7h-1; for group II, 28L, 179L, and 0.3h-1; and for group III, 55L, 256L, and 0.4h-1, respectively. Plasma clearance was related to age in group I, to serum creatinine in group II and to aspartate transaminase activity in group III. The 68% confidence limits for clearance and elimination half-life were 8.2 to 21.5 L/h and 7.6 to 19.7h, respectively, for 50-year-old patients in group I. The analysis predicted that progressive increases in serum creatinine or aspartate transaminase activity will result in only a 50% reduction of clearance.

Adrenergic beta-Antagonists↗

PubMed1988

Evaluation of a new Seralyzer assay for carbamazepine.

The performance of a new dry-phase, strip immunoassay technique for the analysis of serum carbamazepine concentrations (Seralyzer), was compared to a standard high performance liquid chromatography (HPLC) method. One hundred blood samples were collected from 87 patients and analysed using both techniques. There was no significant difference between the concentrations measured by either technique, and the results were highly correlated (r = 0.97). The Seralyzer is a rapid and accurate method for use in carbamazepine therapeutic drug monitoring.

Carbamazepine↗

PubMed1987

Who needs molar units for drugs?

The standardisation of units for drug concentration measurement in clinical medicine is an urgent necessity. The obvious choice is mass units based on the litre. A change to molar units for drug concentrations would make no sense unless drugs were also prescribed in moles, which would cause disruption and inconvenience. There would be considerable danger to patients and the change would be expensive. Most importantly, molar units for drugs will not benefit doctors or their patients. Mass units should be retained and proposals for the adoption of molar units should be abandoned.

Humans↗

PubMed1987

Population pharmacokinetics of lisinopril in hypertensive patients.

If optimal dosage administration schedules are to be defined, the factors that influence the disposition of a drug in the population of patients who are likely to receive it should first be determined. Traditionally, separate groups of patients, each with different underlying disease, are given the drug and then detailed studies are performed to assess which groups have significantly different pharmacokinetic parameters and therefore require an adjustment in dose. An alternative approach, utilizing large groups of patients studied less intensively, will be described here. The analysis used the results of two multicenter trials of lisinopril: one in elderly (greater than 65 years) hypertensive patients and one in a group of hypertensive patients with impaired renal function (creatinine clearance rate less than 60 ml/min). Both protocols allowed for a stepwise increase in the dose of lisinopril until optimum control of BP was achieved. Required dosages ranged from 2.5 to 40 mg/day. During the course of therapy, regular trough concentrations were analyzed to assess compliance and a steady-state profile was determined during one dosage interval. Only patients who appeared to be compliant on the basis of multiple trough concentrations were used in the analysis. Data from a total of 53 patients were used, of whom 35 took part in the elderly study, and 18 in the renal study. There were 25 men and 28 women in this combined study group with ages ranging from 21 to 85 years (mean 65 years) and weights from 51 to 115 kg (mean 72 kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

The pharmacokinetics of R- and S-tocainide in patients with acute ventricular arrhythmias.

The pharmacokinetics of R(-) and S(+)- tocainide were studied in twelve patients requiring intravenous tocainide. In all patients, a progressive increase in the S(+):R(-) ratio was observed during the infusion. Mean +/- s.d. ratios increased from 1.03 +/- 0.05 at 2 min to 1.76 +/- 0.35 at 48.5 h. Data from eight patients were fitted to a two-compartment model and there was a significant difference (Wilcoxon matched-pairs test P less than 0.01) in the clearance estimates for the two enantiomers. The median values were: S(+)-tocainide = 6.25 l h-1 and R(-)-tocainide = 9.31 l h-1. There was no differences in V1 or Vss.

Acute Disease↗

PubMed1979

Alterations of phenytoin protein binding with in vivo haemodialysis in dialysis encephalopathy.

Protein binding of phenytoin was assesed in one patient with dialysis encephalopathy before and after haemodialysis. Phenytoin concentrations were measured by radioimmunoassay and continuous ultrafiltration was used to assess phenytoin binding. At a serum concentration of 60 micromol.1-1 the percentage of phenytoin bound to serum albumin was considerably lower in the patient serum (79.95% predialysis; 92.09% postdialysis) than that in three normal sera (97.90 +/- 0.17%). Analysis of Scatchard plots indicated two classes of binding sites. In class I both the affinity and capacity for binding phenytoin were reduced in the pre and post-dialysis serum, whereas in class II the capacity of the uraemic serum was increased although the intrinsic association constant was greatly reduced. It was concluded that in vivo haemodialysis is associated with large fluctuations in the protein binding of phenytoin, in which the concentration of endogenous dialysible metabolites are strongly implicated.

Adult↗

PubMed1979

Enhancement of methotrexate absorption by subdivision of dose.

A comparison was made in fasting patients between a single 100 mg oral dose of methotrexate formulated as its sodium salt in a palatable syrup and the same total quantity of drug administered in four divided doses of 25 mg taken at 2-h intervals. Allocation to the order of these treatment schedules was on a random basis. The area under the serum methotrexate concentration-time curve until 50 h was found to be considerably greater after the divided dose regimen, the mean ratio AUC 25 mg x 4/AUC 100 mg being 1.86 (+/- 0.90). There was no significant difference in peak serum methotrexate concentrations or methotrexate half-life estimates between the two regimens, however. The results of this study are consistent with saturation of an intestinal transport process when methotrexate is administered orally in a single large dose.

Half-Life↗

PubMed1979

Bioavailability of methotrexate: implications for clinical use.

The absorption of oral methotrexate in syrup form has been compared in six patients with that of an identical IV dose (50 mg/m2). There was variable absorption amongst the group with respect to maximum levels achieved and the time taken to reach those levels. The area under the time-concentration curve was always smaller when the drug was given orally than after IV administration. A total of 33 patients receiving methotrexate for a variety of tumour types were followed for response to treatment and toxicity. A significantly longer methotrexate half-life (t1/2) was found in nine partial responders (9.2 +/- 1.6 h) than in the nonresponders (3.8 +/- 0.7 h). Severe methotrexate toxicity was not seen though occasional mucositis, conjunctivitis, and diarrhoea occurred in seven patients. The side effects could not be predicted from the dose, the bioavailability data, or the serum creatinine. Measurements of serum and urine methotrexate levels are useful in the assessment of absorption and bioavailability of the drug the prediction of tumour response.

Administration, Oral↗

PubMed1979

Correlation of ethanol concentrations in blood and saliva.

1. The concentrations of ethanol in blood, mixed saliva obtained before and after rinsing and drying the mouth and parotid saliva have been monitored in 12 healthy subjects after the ingestion of alcohol. 2. A highly significant linear correlation was found between blood and the three types of saliva examined from 20 min after completion of drinking. 3. Blood and mixed saliva samples were obtained from 20 patients attending the Casualty Department with evidence of ethanol intoxication. A similar correlation was obtained. 4. These results show that salivary ethanol may be used as an index of blood ethanol concentrations, provided that the salivary sample is not obtained within 20 min of the ingestion of alcohol.

Adult↗