PubMed Health⌕ Search

Biomedical subjects

S B Duffull

Publications and source records attributed to S B Duffull.

At least 37 records · Page 2Linked to original sources
PubMed1997

A sequential Bayesian algorithm for dose individualisation of carboplatin.

Carboplatin is associated with significantly less nephrotoxicity and neurotoxicity than is cisplatin. The dose-limiting toxicity of carboplatin is myelotoxicity. A number of dosing methods have been described that allow a value for the area under the concentration-time curve to be targeted on the basis of the patient's renal function. Recently a formalised analysis of the pharmacodynamic response to carboplatin revealed a therapeutic window in which the response rate was maximal and toxicity, tolerable. Optimal therapy would result from targeting this window in the individual patient. The aim of this study was to develop a Bayesian dose-individualisation method for carboplatin. The method involved (1) development of a high-performance liquid chromatography (HPLC) method to measure serum concentrations of carboplatin; (2) a pharmacokinetic study in 12 women receiving carboplatin for ovarian cancer to estimate the population pharmacokinetic values for this group of patients; (3) development of population models to describe the concentration-time course of carboplatin in serum along with associated errors; and (4) development of an algorithm that uses a sequential Bayesian design, which enables estimation of future doses of carboplatin on the basis of feedback from serum concentrations. The results of each of the stages were (1) the coefficient of variation of the assay was 6.3% within day and 8.4% between days (r2 = 0.9993), and the limit of detection was 0.25 mg/l; (2) Patients' ages ranged from 49 to 68 years, their weights varied from 46 to 85 kg, and their glomerular filtration rate ranged from 3.2 to 7.4 l/h. A geometric mean clearance (Cl) of 6.8 L/h and a steady-state volume of distribution (Vss) of 221 were estimated, which are similar to previously published data; (3) and a two-compartment model best described the data. Two error models were developed, the first describing the error associated with the assay and the second, the error of the two-compartment model, i.e. error due to individual variation in pharmacokinetics and error due to model mis-specification. Finally, (4) the development of a sequential Bayesian dose-individualisation method for carboplatin is described. To our knowledge, this is the first sequential design that has been used for dose individualisation of chemotherapy. The program is specific for carboplatin and operates independently of commercially available Bayesian software. Doses predicted by this program are being tested prospectively against conventional dosing methods.

Aged↗
PubMed1997

Comparison of two Bayesian approaches to dose-individualization for once-daily aminoglycoside regimens.

AIMS: Bayesian dose-individualization methods have been shown to have good predictive performance using minimal data points, and are now used widely in clinical practice. This study was designed to compare two computerised Bayesian dose-individualization methods, ABBOTTBASE and SeBA-GEN, in once-daily dosing of aminoglycosides. METHODS: ABBOTTBASE uses the maximum a posteriori estimator (MAP) algorithm which analyses all available serum drug concentration data for individual patients simultaneously, while the prior model remains unchanged. SeBA-GEN analyses each data set sequentially while continually modifying the individual patient's prior model, allowing within-patient variability to be modelled. One hundred consecutive patients who received once-daily dosing of aminoglycosides were prospectively dose-individualized using either of these methods. Retrospectively the alternative dosing method was used to provide comparative data. The ability of the methods to predict subsequent serum aminoglycoside concentration data was assessed in terms of their predictive performance, bias and precision. RESULTS: From the 100 patients, 277 serum aminoglycoside concentrations were available. Ninety-eight patients had serum concentrations available from the first dose and 55 from the second dose. Gentamicin was used in 96 patients. There was no significant bias when predicting peak concentrations from the prior model using either SeBA-GEN or ABBOTTBASE. The prior model used by ABBOTTBASE did, however, significantly underpredict the mid-dose concentration (mean bias = -0.79 mg l-1, 95% Confidence Interval [CI]: -1.3 to -0.3). When using the Bayesian algorithms for prediction of the second set of concentrations neither method was biased when predicting the peak concentration. ABBOTTBASE significantly overpredicted the mid-dose concentration (mean bias = 0.38 mg l-1, 95% CI: 0.03 to 0.74). The prior model used by SeBA-GEN was more precise at predicting both peak and mid-dose concentrations (P < 0.01), indicating better use of covariates. There was no difference between the methods in terms of estimation of the value of volume of distribution, but they differed significantly in the estimation of clearance (mean difference = 0.24 l h-1 for SeBA-GEN-ABBOTTBASE, 95% CI: 0.05 to 0.43). CONCLUSIONS: Bayesian techniques appear to work well with once-daily aminoglycoside dosing. The method of incorporation of individual patient information into the prior model appears to be important in the optimum choice of the first dose. SeBA-GEN has an advantage in this and in the lack of bias related to predicting low concentrations compared with ABBOTTBASE.

Algorithms↗
PubMed1997

Clinical pharmacokinetics and dose optimisation of carboplatin.

Carboplatin shares some of the therapeutic advantages of cisplatin, but without a significant incidence of the dose-limiting neurotoxicity and nephrotoxicity which is experienced with cisplatin. However, its use is associated with dose-limiting bone marrow suppression. Carboplatin is present in the blood as 3 distinct species. These are total platinum and 2 unbound species, carboplatin itself and a decarboxylated platinum-containing degradation product. The 2 main methods used to assay the unbound species are flameless atomic absorption spectrophotometry and high performance liquid chromatography. The first of these methods assays both unbound platinum species, the second is specific for carboplatin. Both unbound species have similar pharmacokinetic profiles for the first 12 hours post-dose. Carboplatin appears to have a linear pharmacokinetic profile over the doses used clinically and does not interact significantly with drugs that are used commonly in combination chemotherapy. The pharmacokinetics of carboplatin are adequately described by an open 2-compartment model with elimination from the central compartment. Its clearance is proportional to the glomerular filtration rate and the volume of distribution of the central compartment appears to correlate with extracellular fluid volume. The elimination half-life varies with renal function and is typically between 2 and 6 hours in patients with a normal glomerular filtration rate and may be as long as 18 hours in patients with impaired renal function. Relationships between systemic exposure to carboplatin, described as the area under the concentration-time curve (AUC), and both toxicity and response have been described. For toxicity the strongest evidence exists for a relationship between AUC and thrombocytopenia. To a lesser extent the relationship between AUC and neutropenia has also been described. Patients already treated with platinum analogues have been shown to develop a greater degree of myelosuppression from any given AUC. In addition, some evidence suggests a relationship between the shape of the concentration-time curve and myelotoxicity, where constant infusions appear less likely to cause myelosuppression on a mg/m2 dose administration basis. The relationship between AUC and response rate is not as clear, this may be related to the lack of studies describing both the dose and AUC of carboplatin. There appears to be a more clearly defined AUC-response relationship for ovarian cancer than for other malignancies, with an AUC of between 5 and 7 mg/ml.min being associated with the maximal response rate [located at the plateau on an AUC-response curve]. However, new data suggest that higher AUCs may lead to greater response rates. Data from testicular cancer also strongly supports an AUC-response relationship with an increased number of treatment failures with carboplatin AUCs < 5 to 6 mg/ml.min. Given the AUC-effect relationships described above a number of studies have been performed to develop models to describe the relationship between both dose and AUC and dose and platelet nadir. In adults, perhaps the most common method is that of Calvert which describes the relationship between dose and AUC. Paediatric formulas have also been described. More recently a number of limited sampling strategies have been proposed as well as Bayesian dose individualisation techniques.

Adult↗
PubMed1995

Experience of once-daily aminoglycoside dosing using a target area under the concentration-time curve.

BACKGROUND: Many centres are changing to once-daily aminoglycoside administration. However, proposed methods for this practice often have theoretical and practical difficulties. We have developed a method in which a target area under the concentration-time curve (AUC) is used instead of traditional peak and trough serum concentrations. AIMS: To analyse our experience with the target AUC method in the first 100 courses of once-daily aminoglycoside administration in the Christchurch, New Zealand hospitals. METHODS: Following a starting dose of 5-7 mg/kg, administered by 30-minute infusion, the AUC was calculated using two serum aminoglycoside concentrations taken at one and six-14 hours after the start of the infusion. Dose adjustment was made to correct for any difference between the calculated AUC and a target AUC (72-101 mg.1(-1).h). The method was assessed for practicality and precision in 100 courses of treatment. The incidence of aminoglycoside toxicity was documented. RESULTS: The mean final dose of 6.68 mg/kg, and AUC of 92.8 mg.1(-1).h, were significantly different from the mean starting dose and AUC of 5.67 mg/kg and 74.0 mg.1(-1).h, respectively. The method appeared to be more precise than empirical dosing at achieving the target AUC even though the final recommended dose had more variability than the starting dose. Although the study was uncontrolled, observed nephrotoxicity (2%) and ototoxicity (up to 6.9%) were no greater than expected from the results of other studies. There were no deaths related to antibiotic failure. CONCLUSIONS: The AUC method was practical, and more appropriate for once-daily dosing than the conventional method of aiming for target peak and trough concentrations. Dose adjustment can be made before the next dose.

Adolescent↗
PubMed1995

A suggested approach to once-daily aminoglycoside dosing.

1. Once-daily aminoglycoside dosing has many advantages and has been widely advocated. However, existing guidelines for methods of administration and monitoring are non-specific and may lead to excessive dosing. 2. The traditional approach of aiming for target peak and trough concentrations is not appropriate for once-daily dosing. 3. A method is proposed which uses a target area under the concentration-time curve (AUC) for the aminoglycoside based on the 24 h AUC that would result with conventional dosing. This method requires measurement of two drug concentrations, one approximately 0.5 h after the end of the infusion and another at a later time (6-22 h) depending on renal function. 4. A simpler, graphical method is also proposed for patients with normal renal function, which requires the measurement of a single concentration at a time between 6 and 14 h. 5. Both methods are likely to be safer than existing guidelines.

Aminoglycosides↗
PubMed1994

Efficacies of different vancomycin dosing regimens against Staphylococcus aureus determined with a dynamic in vitro model.

A dynamic in vitro model was used to assess four different vancomycin dosing regimens against Staphylococcus aureus. These regimens achieved peak drug concentrations of 48 micrograms/ml (single dose) and 30 micrograms/ml (dosed every 12 h) and constant concentrations of 16 and 8 micrograms/ml. Analysis of the area under the bacterial concentration-time curve, area under the first moment of the bacterial concentration-time curve, and bacterial elimination rate constant showed no difference in the rate or extent of bacterial killing. The optimal dosing method may be that which achieves the lowest area under the curve while concentrations are maintained above the MBC.

Dose-Response Relationship, Drug↗
PubMed1994

Idiosyncratic drug-induced haematological abnormalities. Incidence, pathogenesis, management and avoidance.

Haematological dyscrasias remain important because they are potentially fatal. Their accurate reporting is required to confirm the cause-effect relationship of suspected adverse drug reactions (ADRs); to estimate their incidence; and, by risk-benefit analysis of such events, to introduce preventive measures to reduce their impact. Limitations within the available data on haematological ADRs are reviewed and some suggestions made for improvement. The drugs most commonly associated with haematological dyscrasias are listed. An understanding of the pathogenesis of haematological dyscrasias is essential for their effective management and these are briefly reviewed. Features common to the management of the different types of haematological dyscrasia include the early involvement of a haematologist and drug information pharmacist and the accurate identification and early withdrawal of any likely offending agent. Guidelines for the management of drug-induced aplastic anaemia, agranulocytosis, thrombocytopenia and haemolytic anaemia are presented and the potential value of granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF; GM-CSF) in the management of agranulocytosis is specifically mentioned. Finally, general principles are discussed whereby serious haematological ADRs might be prevented. These include: the importance of continuing education for drug prescribers; policies on the restricted prescribing of likely offending agents; the use of written instructions for patients; and, the use of haematological monitoring. The guidelines presented in this article should be adapted to meet local circumstances and would prove suitable subjects for audit of their effectiveness.

Adolescent↗
PubMed1993

How vancomycin is used in Australasia--a survey.

BACKGROUND: Vancomycin serum concentrations have been monitored over the last 30 years in an attempt to avoid dose-dependent toxicity and enhance efficacy. Current literature recommendations for peak and trough concentrations are usually in the range of 20-40 mg/L and 5-10 mg/L, respectively. Literature recommendations regarding the time at which peak concentrations are measured are highly variable, ranging from immediately after the end of the infusion to three hours post-dose. AIMS: To identify how vancomycin dosing is being monitored and assess variability in the current practice. METHODS: A survey of microbiology departments and infectious disease physicians in major Australasian hospitals was undertaken. The variability in the current practice was assessed by fitting mean recommendations to a two compartment Bayesian model. RESULTS: Of the 83 (70%) who replied 71 (86%) monitored vancomycin concentrations. Fifty-four percent targeted peak concentrations within the range of 20-40 mg/L, and 73% targeted trough concentrations < or = 10 mg/L. The time of sampling of peak concentrations varied considerably ranging from immediately (12%) to 120 minutes (12%) post-infusion (median 30 minutes [40%]). The concentration-time curves resulting from three sets of mean recommendations ('peaks' drawn at: 0, 30 and 120 minutes aiming for a concentration of 35 mg/L with a trough concentration of 10 mg/L) were modelled using a two compartment Bayesian programme. The predicted true peak (maximum) concentrations ranged from 30 to 86 mg/L, despite aiming for identical target concentrations, indicating marked variation in the actual dosing practice. CONCLUSIONS: There is thus considerable variation in the practice of vancomycin therapeutic monitoring which has a major effect on dosing. The main contributing factor is the variable timing of sampling peak concentrations.

Australia↗
PubMed1992

Pharmacokinetics and efficacy of rectal versus oral sustained-release morphine in cancer patients.

Sustained-release morphine (MST) given by the rectal route was compared with oral MST in an open randomised cross-over trial in ten patients with cancer who received stable doses of MST. No significant difference was found in the areas under the curve of the concentration-time profiles (AUC) following oral or rectal administration for parent morphine. The AUCs determined for morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) after oral administration were approximately twice those obtained following rectal administration. The maximal concentration achieved was lower and the time to maximal concentration was longer following rectal administration for morphine, M6G and M3G. The relative mean arrival times following rectal administration were significantly longer for morphine and M3G but not for M6G. These findings suggest slower absorption but less first-pass metabolism of MST after rectal administration. No significant difference was noted between the oral and the rectal route in measurements on visual-analogue scales for pain or side effects. We recommend the rectal route as being suitable for MST administration when the oral route is no longer available. In changing from oral to rectal administration, the same dose and dose interval may be used, but dose adjustment may be needed.

Administration, Oral↗
PubMed1992

Prospective evaluation of a model for the prediction of milk:plasma drug concentrations from physicochemical characteristics.

1. Milk:plasma (M/P) drug concentration ratios predicted by a model utilizing pKa, plasma protein binding and octanol:water partition coefficients have been compared with actual M/P values for 10 basic drugs. 2. There was a close relationship between predicted and observed M/P ratios with a coefficient of determination r2 of 0.97. However, there was a proportional error. 3. The data were transformed by taking logs of predicted and observed (M/P + 1) values. Regression analysis resulted in an r2 of 0.95, an intercept on the Y-axis not significantly different from zero and a slope not significantly different from one. 4. The 95% confidence interval around a single prediction revealed an error between 150% for the lowest and 23% for the highest M/P ratios. The error is therefore lowest for the drugs likely to have the greatest transfer into milk. 5. There was no significant bias in the predictions. 6. The model was refined by multiple linear regression analysis utilising the observed M/P ratios for the 10 basic drugs in addition to those of the original drugs. The revised equation resulted in an improvement in the explained variance. 7. Protein binding was the most important single predictor. 8. The results confirm that M/P ratios for basic drugs can be predicted accurately from their physicochemical characteristics.

Algorithms↗