Bayesian feedback methods for optimising therapy.
Explore the source record for details and available documents.
Antipsychotic Agents↗
Biomedical subjects
A H Thomson
Publications and source records attributed to A H Thomson.
Bayesian estimation of streptomycin pharmacokinetics.
Streptomycin dose requirements were determined in an 83-year-old man with renal impairment who was being treated for miliary tuberculosis. Concentration measurements were interpreted using a Bayesian parameter estimation program. Estimated creatinine clearance (1.1 L/h) was used as a starting value for streptomycin clearance, and volume was initially assumed to be 0.3 L/kg. Bayesian estimates of clearance were close to the starting value and declined from 1.4 L/h to 0.9 L/h during the course of therapy. Volume was higher than the initial estimate (0.4-0.5 L/kg), possibly due to the patient having a low albumin and being underweight. Satisfactory concentrations were maintained for several weeks with doses of 500 mg every 36-48 h.
Aged↗
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↗
Pharmacokinetic optimisation of anticonvulsant therapy.
Changing attitudes towards the use of antiepileptic drugs have led to an emphasis on monotherapy with serum concentration measurement coupled with standard, weight-adjusted starting and maintenance regimens to guide initial therapy and subsequent dosage titration. Currently, the established anticonvulsants are carbamazepine, valproic acid (sodium valproate) and phenytoin. Phenobarbital is now less commonly prescribed due to its propensity to produce sedation and impair cognitive function. The value of pharmacokinetic optimisation with valproic acid is limited by its wide therapeutic index, large fluctuations in the concentration-time profile and concentration-dependent protein binding. Thus, although serum concentrations are often measured, they are rarely subjected to pharmacokinetic interpretation. Carbamazepine has a flatter concentration-time profile than valproic acid. Its target range is more clearly defined and it undergoes autoinduction of metabolism and interacts with other drugs. Pharmacokinetic principles can, therefore, be more readily applied to carbamazepine, although, in general, a simple clinical approach to its use is usually satisfactory. Phenytoin has required the greatest pharmacokinetic input due to its nonlinear pharmacokinetics and narrow target range. Many different graphical methods, equations and computer programs have been reported, some of which demand 2 steady-state, dose-concentration pairs; others function satisfactorily with only 1. Recent attempts have been made to interpret non-steady-state data. In addition, a number of workers have demonstrated the value of altering the population parameter estimates to account for ethnic differences. A pharmacokinetic approach can also be used to tailor the use of phenytoin in the treatment of status epilepticus. Dosage alterations may be needed for specific patient groups. In particular, children generally require higher dosages on a weight-for-weight basis than adults, while equivalently lower dosages should be given to neonates. Most anticonvulsants are principally cleared by hepatic mechanisms, so dosage adjustment is not usually required in renal disease, although care must be taken in interpreting serum concentrations because of changes in protein binding. Close monitoring is required in the elderly and patients with hepatic impairment, while increased dosages may be needed in critically ill patients and during pregnancy. Pharmacokinetic principles can be used in the treatment of treat self-poisoning with anticonvulsants. There are few data available on the pharmacokinetics of vigabatrin, lamotrigine, oxcarbazepine and gabapentin in patients. Due to its mode of action in binding irreversibly to its target enzyme, serum concentration monitoring of vigabatrin plays no role in optimising therapy. The value of applying pharmacokinetic principles with the other 3 drugs remains to be investigated.(ABSTRACT TRUNCATED AT 400 WORDS)
Age Factors↗
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↗
Gentamicin and vancomycin removal by continuous venovenous hemofiltration.
The dispositions and dose requirements for vancomycin and gentamicin were investigated in a 58-year-old man who was receiving long-term continuous venovenous hemofiltration. Estimates of clearance were obtained using a Bayesian parameter estimation program and stayed remarkably consistent throughout the therapy. Single daily doses of both vancomycin and gentamicin generally maintained the profiles for both drugs around the target ranges of peak 5-10 mg/L (gentamicin) and 25-40 mg/L (vancomycin) and trough less than 2 mg/L (gentamicin) and less than 10 mg/L (vancomycin).
Bayes Theorem↗
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↗
Airway function in infants with vascular rings: preoperative and postoperative assessment.
Aortic arch anomalies in infancy often cause intrathoracic airway obstruction. Airway function was assessed as part of the diagnostic evaluation in six symptomatic infants both by plethysmography and using a chest compression technique to obtain partial flow-volume loops. Two infants had normal intrathoracic airway function and their symptoms were unrelated to aortic arch abnormalities. The remaining four had complete vascular rings (three double aortic arch, one pulmonary sling) and had increased expiratory airway resistance (Raw) (mean Raw = 700% predicted) and greatly decreased maximum flow rates at functional residual capacity (VmaxFRC; mean VmaxFRC = 34% predicted) with gross shape abnormalities of the flow-volume loop. Postoperatively airway function was substantially improved (mean Raw = 175% predicted, VmaxFRC = 79% predicted) but some abnormality of flow-volume loop shape remained, suggesting that tracheal dynamics were not completely normal in the early postoperative period.
Airway Obstruction↗
Latent sensitisation to respiratory syncytial virus during acute bronchiolitis and lung function after recovery.
To determine whether latent sensitivity to respiratory syncytial virus antigen(s) occurs after infection, 27 infants with acute bronchiolitis were studied and compared with 15 hospital controls. Blood was collected for whole blood challenge, and histamine release was measured by a high performance liquid chromatography technique with fluorometric detection. There was a significantly greater histamine release to respiratory syncytial virus antigen(s) in those with bronchiolitis than in controls, expressed either in amount (median 154 nmol/l compared with 104 nmol/l) or percentage release (median 20% compared with 3%). There was a significant difference between index and control groups in terms of individual histamine responses. These findings strongly suggest that infants develop latent sensitivity to respiratory syncytial virus antigen(s) during the course of acute bronchiolitis. Serial lung function tests were performed in 15 infants. All infants had abnormalities of lung function at some stage, but the small numbers of subjects precluded comparison between 'sensitised' and 'non-sensitised' infants. Further study is indicated to define the relation of latent sensitisation and subsequent bronchial hyper-responsiveness after respiratory syncytial virus infection in infants.
Acute Disease↗
High-performance liquid chromatographic technique for the rapid determination of histamine in both the plasma and cellular components of blood.
Explore the source record for details and available documents.
Amine Oxidase (Copper-Containing)↗
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↗