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Biomedical subjects

S B Duffull

Publications and source records attributed to S B Duffull.

At least 19 recordsLinked to original sources
PubMed2006

Optimal crossover designs for logistic regression models in pharmacodynamics.

Pharmacodynamics (PD) is the study of the biochemical and physiological effects of drugs. The construction of optimal designs for dose-ranging trials with multiple periods is considered in this paper, where the outcome of the trial (the effect of the drug) is considered to be a binary response: the success or failure of a drug to bring about a particular change in the subject after a given amount of time. The carryover effect of each dose from one period to the next is assumed to be proportional to the direct effect. It is shown for a logistic regression model that the efficiency of optimal parallel (single-period) or crossover (two-period) design is substantially greater than a balanced design. The optimal designs are also shown to be robust to misspecification of the value of the parameters. Finally, the parallel and crossover designs are combined to provide the experimenter with greater flexibility.

Algorithms↗
PubMed2006

Relationships of tacrolimus pharmacokinetic measures and adverse outcomes in stable adult liver transplant recipients.

BACKGROUND AND OBJECTIVES: Alternative measures to trough concentrations [non-trough concentrations and limited area under the concentration-time curve (AUC)] have been shown to better predict tacrolimus AUC. The aim of this study was to determine if these are also better predictors of adverse outcomes in long term liver transplant recipients. METHODS: The associations between tacrolimus trough concentrations (C(0)), non-trough concentrations (C(1), C(2), C(4), C(6/8)), and AUC(0-12) and the occurrence of hypertension, hyperkalaemia, hyperglycaemia and nephrotoxicity were assessed in 34 clinically stable liver transplant patients. RESULTS AND DISCUSSION: The most common adverse outcome was hypertension, prevalence of 36%. Hyperkalaemia and hyperglycaemia had a prevalence of 21% and 13%, respectively. A sequential population pharmacokinetic/pharmacodynamic approach was implemented. No significant association between predicted C(0), C(1), C(2), C(4), C(6/8) or AUC(0-12) and adverse effects could be found. Tacrolimus concentrations and AUC measures were in the same range in patients with and without adverse effects. CONCLUSIONS: Measures reported to provide benefit, preventing graft rejection and minimizing acute adverse effects in the early post-transplant period, were not able to predict adverse effects in stable adult liver recipients whose trough concentrations were maintained in the notional target range.

Adult↗
PubMed2005

Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients.

AIM: To explore relationships between sirolimus dosing, concentration and clinical outcomes. METHODS: Data were collected from 25 kidney transplant recipients (14 M/11 F), median 278 days after transplantation. Outcomes of interest were white blood cell (WBC) count, platelet (PLT) count, and haematocrit (HCT). A naive pooled data analysis was performed with outcomes dichotomized (Mann-Whitney U-tests). RESULTS: Several patients experienced at least one episode when WBC (n = 9), PLT (n = 12), or HCT (n = 21) fell below the lower limits of the normal range. WBC and HCT were significantly lower (P < 0.05) when sirolimus dose was greater than 10 mg day(-1), and sirolimus concentration greater than 12 microg l(-1). No relationship was shown for PLT and dichotomized sirolimus dose or concentration. CONCLUSIONS: Given this relationship between sirolimus concentration and effect, linked population pharmacokinetic-pharmacodynamic modelling using data from more renal transplant recipients should now be used to quantify the time course of these relationships to optimize dosing and minimize risk of these adverse outcomes.

Adult↗
PubMed2003

Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil.

AIM: To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between- and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. METHODS: Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler. RESULTS: The best base model was a two-compartment model with a lag time (apparent oral clearance was 27 l h(-1), and apparent volume of the central compartment 98 l). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. CONCLUSIONS: The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.

Administration, Oral↗
PubMed2001

Optimal design of a population pharmacodynamic experiment for ivabradine.

PURPOSE: To design a parsimonious population pharmacodynamic experiment that has the same or greater efficiency than that provided by two phase I studies. METHODS: The design was based on optimization of the population Fisher information matrix. Options for optimization were (1) determination of the optimal sampling times for each group ("group" represents a group of subjects that have identical design characteristics), (2) determination of the optimal doses for each group, and (3) determination of the optimal group structure. RESULTS: (1) Optimizing the sampling times, while retaining only four unique times per group, provided a more parsimonious experiment with the same efficiency as the original "study" that involved on average 10 samples per subject. Splitting sampling times between the first dose and a steady-state dose gave the most informative design. (2) The optimal dose was the same in all groups and was the upper bound of the dose range. (3) The optimal population design consisted of only one group with four unique sampling times that are the same for all subjects. CONCLUSION: A population pharmacodynamic trial design is presented that is more parsimonious than the original study and would be appropriate for inclusion in a premarketing clinical study.

Benzazepines↗
PubMed2001

An identifiability analysis of a parent-metabolite pharmacokinetic model for ivabradine.

The paper considers the structural identifiability of a parent-metabolite pharmacokinetic model for ivabradine and one of its metabolites. The model, which is linear, is considered initially for intravenous administration of ivabradine, and then for a combined intravenous and oral administration. In both cases, the model is shown to be unidentifiable. Simplification of the model (for both forms of administration) to that proposed by Duffull et al. (1) results in a globally structurally identifiable model. The analysis could be applied to the modeling of any drug undergoing first-pass metabolism, with plasma concentrations available from drug and metabolite.

Administration, Oral↗
PubMed2001

Design of clinical pharmacology trials.

1. There are a variety of methods that could be used to increase the efficiency of the design of experiments. However, it is only recently that such methods have been considered in the design of clinical pharmacology trials. 2. Two such methods, termed data-dependent (e.g. simulation) and data-independent (e.g. analytical evaluation of the information in a particular design), are becoming increasingly used as efficient methods for designing clinical trials. These two design methods have tended to be viewed as competitive, although a complementary role in design is proposed here. 3. The impetus for the use of these two methods has been the need for a more fully integrated approach to the drug development process that specifically allows for sequential development (i.e. where the results of early phase studies influence later-phase studies). 4. The present article briefly presents the background and theory that underpins both the data-dependent and -independent methods with the use of illustrative examples from the literature. In addition, the potential advantages and disadvantages of each method are discussed.

Clinical Trials as Topic↗
PubMed2001

An extended interval dosing method for gentamicin in neonates.

Traditional gentamicin dosing every 8-24 h depending on age and weight in neonates does not provide the ideal concentration-time profile to both optimize the concentration-dependent killing by aminoglycosides and minimize toxicity. Fifty-three neonates were audited prospectively while receiving gentamicin 2.5 mg/kg every 8-24 h, aiming for peak concentrations (Cmax) of 6-10 mg/L and trough concentrations (Cmin) <2 mg/L. After the first dose, the mean (+/- s.d.) Cmax was 5.5 +/- 0.7 mg/L with sub-therapeutic concentrations (<6 mg/L) in 62% of patients, while the mean Cmin was >2 mg/L in 15% of the neonates. After the third dose the Cmax was 7.5 +/- 1.5 mg/L, with 17% <6 mg/L, whereas the mean Cmin was 2.2 +/- 1.1 mg/L with 49% of values >2 mg/L. An extended interval dosing method (24, 36 and 48 h) for infant weights of 0.75-5 kg was developed by simulation, and audited prospectively in 51 neonates. Prospective analysis of the extended interval dosing method showed a mean Cmax after the first dose of 13.1 +/- 3.6 mg/L, while the mean Cmin was 0.7 +/- 0.6 mg/L. Seventy-eight per cent had Cmax of >10 mg/L after the first dose. The mean area under the concentration versus time curve AUC0-24 was 93 mg*h/L (target = 100 mg*h/L). The extended interval dosing achieved higher Cmax values while ensuring that overall exposure per 24 h was acceptable. Prospective testing of the method demonstrated good predictive ability.

Anti-Bacterial Agents↗
PubMed2001

Pharmacokinetic software for the health sciences: choosing the right package for teaching purposes.

Computer assisted learning has an important role in the teaching of pharmacokinetics to health sciences students because it transfers the emphasis from the purely mathematical domain to an 'experiential' domain in which graphical and symbolic representations of actions and their consequences form the major focus for learning. Basic pharmacokinetic concepts can be taught by experimenting with the interplay between dose and dosage interval with drug absorption (e.g. absorption rate, bioavailability), drug distribution (e.g. volume of distribution, protein binding) and drug elimination (e.g. clearance) on drug concentrations using library ('canned') pharmacokinetic models. Such 'what if' approaches are found in calculator-simulators such as PharmaCalc, Practical Pharmacokinetics and PK Solutions. Others such as SAAM II, ModelMaker, and Stella represent the 'systems dynamics' genre, which requires the user to conceptualise a problem and formulate the model on-screen using symbols, icons, and directional arrows. The choice of software should be determined by the aims of the subject/course, the experience and background of the students in pharmacokinetics, and institutional factors including price and networking capabilities of the package(s). Enhanced learning may result if the computer teaching of pharmacokinetics is supported by tutorials, especially where the techniques are applied to solving problems in which the link with healthcare practices is clearly established.

Computer Simulation↗
PubMed2000

The effect of body weight on dalteparin pharmacokinetics. A preliminary study.

AIM: To investigate whether there were significant differences in the volume of distribution (V) and clearance (CL) of dalteparin in obese versus normal-weight patients, and thereby determine whether dosing of dalteparin should be based on total body weight, lean body weight or an adjusted body weight in obese patients. METHODS: Patients (ten obese and ten normal weight) treated with dalteparin were matched for age, gender, lean body weight and creatinine CL. Two steady-state plasma dalteparin concentrations were taken from each patient and assayed in duplicate. The pharmacokinetic values of V and CL were estimated, for each patient, using the Bayesian maximum a posteriori method with the program ABBOTTBASE. RESULTS: The mean V in obese patients was approximately 60% larger than in normal-weight patients, but this was not statistically significant (P = 0.11; two-tailed). The mean value of V (8.41) in the normal-weight patients was similar to that reported in the literature. The mean difference in values of CL (18% larger in obese patients) was not clinically or statistically significant. A poor correlation was seen between V and lean body weight (r2 = 0.05). There was a moderate correlation between V and total body weight (r2 = 0.52) and between V and adjusted body weight (r2 = 0.55); adjusted body weight = [lean body weight + 0.4(total body weight - lean body weight)]. Total body weight and adjusted body weight provided a better correlation with CL (r2 = 0.39, 0.32, respectively) than did lean body weight (r2 = 0.01). CONCLUSION: These results suggest that doses of dalteparin in obese patients should be based on total body weight or an adjusted body weight, but not lean body weight. This study highlights some potential differences in the pharmacokinetics of dalteparin in individuals who are obese, and further work is necessary to quantify these differences in more detail.

Anticoagulants↗
PubMed2000

Development of a sequential linked pharmacokinetic and pharmacodynamic simulation model for ivabradine in healthy volunteers.

Ivabradine is a novel bradycardic agent that has been developed for the prevention of angina. Ivabradine has an active metabolite S-18982. The aim of the study was to develop a linked pharmacokinetic-pharmacodynamic simulation model for the description of exercise-induced heart rate. The pharmacodynamic data (heart rate) were pooled from two studies and included a total of 78 healthy subjects. The data consisted of multiple dose oral administration of ivabradine. The multiple dose regimens were administered every 12 h. There were eight active dosing levels and placebo, and a no-dose run in the period before each study. The modelling was performed using the NONMEM software. Both ivabradine and S-18982 possess bradycardic activity, although the extent of the activity of both could not be determined from the data available. A multiple ligand pharmacodynamic model provided the best fit to the data. The model was assessed in terms of its posterior predictive performance and was able to describe the original data adequately when used for simulation purposes.

Benzazepines↗
PubMed2000

A pharmacokinetic simulation model for ivabradine in healthy volunteers.

Ivabradine is a novel bradycardic agent that has been developed for the prevention of angina. Ivabradine has an active metabolite S-18982. The aim of this study is to develop a pharmacokinetic simulation model. Pharmacokinetic data from two studies were pooled and included data from a total of 66 healthy male volunteers. The data were collected following single dose intravenous and multiple dose oral administration of ivabradine. The multiple dose regimens were administered every 12 h and there were seven active dosing levels. The modelling was performed using the NONMEM software. The model was assessed in terms of its ability to describe the original data set used in its construction and also data arising from a different clinical pharmacology study involving 12 additional subjects. The pharmacokinetics of ivabradine and S-18982 were best described by two linked two compartment intravenous bolus and first-order input, with first-pass loss, and first-order output model. When the model was used for simulation it produced an adequate description of both the original data and data arising from a different clinical pharmacology study.

Benzazepines↗
PubMed1999

Development of a general method of limited sampling for the determination of AUC for a drug that displays two-compartment pharmacokinetics.

OBJECTIVES: To develop a method of limited sampling that would enable accurate estimation of the area under the concentration time curve (AUC) when using the log trapezoidal method. METHODS: A series of datasets were simulated. Each dataset comprised 1000 subjects. Each subject was "administered" an intravenous bolus dose of a drug that displays two compartment pharmacokinetics. In the first series of simulations, a variety of combinations of the number of sampling times (K) and number of replicate measurements (R) at each of these times were tested, where K x R = 12 (i.e. N = 12). The times that each of the K samples were taken were chosen to be those that divided the AUC into K - 1 trapezoids of equal area. The concentration-time curves were estimated based on a priori estimates of the population parameters. The best combination of K and R was tested under various conditions of parameter variability and assay variability. The combinations were compared with a conventional sampling strategy, where N = 12, K = 12 (R = 1). RESULTS: The combination K = 4 and R = 3 proved to be the "best". It had similar accuracy to the conventional method. The best limited sampling combination was superior to the conventional method when assay variability was high (CV= 30%), was similar when assay variability was 15%, but the conventional method became statistically superior when assay variability was 7.5% or less. The accuracy of the best limited sampling combination was inversely related to the parameter variability. If K was set to 4 and R allowed to increase to 6 (i.e. N is not equal to 12), there was no further gain in accuracy. CONCLUSION: The proposed method of limited sampling is at least as accurate as the conventional intensive sampling technique, but more efficient in terms of sampling.

Area Under Curve↗
PubMed1999

Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily.

AIMS: 1. To determine the population pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. 2. To see if current starting doses for once daily aminoglycoside dosing are appropriate. 3. To test whether calculating creatinine clearance using an adjusted Cockcroft and Gault method (CLCr,adjusted ) was a better predictor of gentamicin clearance than the standard Cockcroft and Gault method (CLCr,unadjusted ). METHODS: Nine hundred and fifty-seven patients were dose-individualized for gentamicin using SeBA-GEN, a Bayesian dosing method. This method returns estimates of the values of gentamicin CL and V d from which the 24 h AUC can be estimated. The goal of therapy was to attain an AUC of 70-100 mg l-1 h depending on the severity of the infection. The population was divided into four groups of differing renal function. Linear regression analysis was performed to determine the relationship between V d and various indices of weight, and gentamicin CL and either CLCr,adjusted or CLCr,unadjusted. RESULTS: The mean V d (+/-s. d.) and CL (+/-s.d.) of gentamicin in our total population were 17.4 (+/-4.1) l and 4.0 (+/-1.8) l h-1, respectively. There was a decrease in V d with reducing renal function when comparing patients with normal renal function and patients with poor renal function. The lower of total body weight (TBW) and lean body weight (LBW), termed dosing weight (DWT), was a slightly better predictor of V d (r2=0.28) than either TBW (r2=0.21) or LBW (r2=0.21). CLCr,adjusted (r2=0.80) was a better predictor of gentamicin CL than CLCr, unadjusted (r2=0.57). CONCLUSIONS: The mean population values of V d and CL of gentamicin dosed once daily are similar to those described by others in relation to multiple daily dosing. Given that previous methods have been based on population values of V d and CL from multiple daily dosing, the currently recommended starting doses for once daily aminoglycoside dosing would seem appropriate. The V d reduced with decreasing renal function, with a maximum of 23% difference between patients with normal and poor renal function. The Cockcroft and Gault method of calculating creatinine clearance does not appear to perform well at low values of serum creatinine concentration. An adjustment of the Cockcroft and Gault method is proposed to allow for this.

Adult↗
PubMed1999

Paroxetine in human milk.

AIMS: The primary aims of the study were to estimate the exposure of infants to paroxetine via breast milk and to determine the maternal milk:plasma ratio (M/P) of paroxetine. Secondary aims were to compare single point and area under the curve (AUC) estimates of M/P, to assess variability of M/P in fore and hind milk, and to compare the observed M/P with that predicted by a model. METHODS: Two studies were performed. In one study, six nursing mothers who were being treated with paroxetine were studied over a 24 h dose interval at steady-state. The total amount of paroxetine in the milk was measured, which represented the 'dose' to the infant. The M/PAUC was calculated and compared with a predicted value. In the second study, four nursing mothers who were being treated with paroxetine, were studied at steady-state, around a normal infant feeding time. A single plasma sample and a prefeed milk sample were taken approximately 3 h after the morning dose of paroxetine, and a postfeed milk sample taken around 1 h later. The dose received by the infant was estimated from the average milk concentrations of the pre and postfeed samples using standard assumptions, and M/P calculated directly. Plasma concentrations of paroxetine were measured in 8 of the 10 infants in the two studies. RESULTS: The mean dose of paroxetine received by the infants in the first study was 1.13% (range 0.5-1.7) of the weight adjusted maternal dose. The mean M/PAUC was 0.39 (range 0.32-0.51). The predicted M/P was 0.22. The mean dose of paroxetine received by the infants in the second study was 1.25% (range 0.38-2.24) of the weight adjusted maternal dose. The mean M/P was 0.96 (range 0.31-3.33) and did not differ between fore and hind milk. The drug was not detected in the plasma of seven of the infants studied and was detected but not quantifiable (<4 microg l-1 ) in one infant. No adverse effects were observed in any of the infants. CONCLUSIONS: Measured M/P and estimated infant dose were similar in the two studies, although the range was wider for the single point study. Paroxetine can be considered 'safe' during breast feeding because the dose transferred to the infant is well below the recommended safety limit of 10% of the weight adjusted maternal dose, concentrations in the infants were generally undetectable, and no adverse effects were reported.

Adult↗
PubMed1998

Experience with heparin dosing at Christchurch Hospital.

AIM: To assess the effectiveness of the conventional dosing regimen for unfractionated heparin as it is used at Christchurch Hospital. METHODS: Dosage regimens and activated partial thromboplastin times (APTTs) were collected prospectively for 100 consecutive patients who received heparin at Christchurch Hospital, the majority being treated for ischaemic heart disease. All patients received the conventional dosing regimen. Parametric and non-parametric descriptive statistics were used to describe the time to therapeutic APTTs (50 to 70 s). RESULTS: The arithmetic and geometric mean time to first therapeutic APTTs were 26.6 and 16 hours respectively, with one patient taking up to 126.5 hours to reach the therapeutic range. After 24 hours of therapy, 20% of patients were below the therapeutic range, 42% were within, and 38% of patients were above the therapeutic range. Similarly, at the end of treatment with heparin or after seven days of treatment, only 44% of patients were within the therapeutic range, with ten patients consistently below the therapeutic range throughout therapy. CONCLUSION: This study shows that the conventional dosing regimen for heparin at Christchurch Hospital was similar in effectiveness to other studies employing the conventional dosing regimen. In addition, this study and those of others suggest that the conventional dosing strategy is not an effective method of dosing heparin with a significant number of patients undertreated at 24 hours. As a result of this research, weight-based dosing guidelines have been introduced at Christchurch hospital. Validation of this new dosing regimen will be performed subsequently.

Anticoagulants↗
PubMed1998

Population analysis of once-daily dosing of gentamicin in patients with neutropenia.

BACKGROUND: Aminoglycoside antibiotics are used as first-line therapy in the treatment of patients with febrile neutropenia. However, there is little information on the pharmacokinetics of aminoglycosides in this specific patient group and whether they differ from the accepted population values. AIM: To determine the population pharmacokinetics of gentamicin for patients with febrile neutropenia, with or without sepsis. METHODS: Data were collected from 26 patients with febrile neutropenia receiving once-daily gentamicin. Patient age, height, weight, estimated lean body weight (LBW), gender, serum creatinine (SCr), creatinine clearance (Cl(Cr)), and serum drug concentration data were collected. Severity of infection and degree of neutropenia were assessed. An initial two-stage population analysis using a Bayesian dose-individualisation programme was performed to estimate likely population values of the parameters. If these were significantly different from typical values then a true population analysis was to be performed. RESULTS: Data for 13 female and 13 male patients were collected. Median age was 57 years (range 19 to 87 years), estimated LBW (kg) = 66 (+/- 10), Cl(Cr) (1/hour) = 5.6 (+/- 2.0) (mean +/- SD). Results of the two-stage approach follow [initial population values in square brackets]: Cl (1/hour) = 0.73 (+/- 0.12) x Cl(Cr) + 0.01 x LBW [0.70 (+/- 0.27) x Cl(Cr) + 0.01 x LBW]; Vd (1) = 0.28 (+/- 0.05) x LBW [0.27 (+/- 0.06) x LBW]. CONCLUSIONS: The population values of Cl and Vd from the two-stage approach do not differ significantly from initial population values of Cl and Vd. Patients receiving gentamicin for febrile neutropenia may be considered pharmacokinetically similar to the general population receiving gentamicin.

Adult↗