Biomedical subjects

Leon Aarons

Publications and source records attributed to Leon Aarons.

At least 19 recordsLinked to original sources

PubMed2006

Optimum blood sampling time windows for parameter estimation in population pharmacokinetic experiments.

Clinical trials requiring the collection of pharmacokinetic information often specify blood samples to be taken at fixed times. This may be feasible when trial participants are in a controlled environment such as in early phase clinical trials, however it becomes problematic in trials where patients are in an out-patient clinic setting such as in late phase drug development. In such a situation it is common to take blood samples when it is convenient for all involved and may result in data that are uninformative. This paper proposes an approach to pharmacokinetic study design that allows greater flexibility as to when blood samples can be taken and still result in data that allows satisfactory parameter estimation. The sampling window approach proposed in this paper is based on determining time intervals around the D-optimum pharmacokinetic sampling times. These intervals are determined by allowing the sampling window design to result in a specified level of efficiency when compared to the fixed times D-optimum design. Several approaches are suggested for dealing with this design problem.

Blood Specimen Collection↗

PubMed2006

Molecular analysis of the subgingival microbiota in health and disease.

This investigation provides molecular analyses of the periodontal microbiota in health and disease. Subgingival samples from 47 volunteers with healthy gingivae or clinically diagnosed chronic periodontitis were characterized by PCR-denaturing gradient gel electrophoresis (DGGE) with primers specific for the V2-V3 region of the eubacterial 16S rRNA gene. A hierarchical dendrogram was constructed from band patterns. All unique PCR amplicons (DGGE bands) were sequenced for identity. Samples were also analyzed for the presence of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Tannerella forsythensis by multiplex PCR. Associations of patient age, gender, and smoking status together with the presence of each unique band and putative periodontal pathogens with disease were assessed by logistic regression. Periodontal pockets were colonized by complex eubacterial communities (10 to 40 distinct DGGE bands) with substantial individual variation in the community profile. Species diversity in health and disease was determined by the Shannon-Weaver index of diversity and compared by the Mann-Whitney U test. Sequence analyses of DGGE amplicons indicated the occurrence of many nontypical oral species and eubacteria previously associated with this environment. With the exception of T. forsythensis, the putative pathogens were not detected by DGGE. Multiplex PCR, however, detected T. forsythensis, A. actinomycetemcomitans, and P. gingivalis in 9% 16%, and 29% of the patients with disease, respectively. The presence of A. actinomycetemcomitans was significantly associated with disease (P < 0.01). Statistical analyses indicated that the presence of Treponema socranskii and Pseudomonas sp. was a significant predictor of disease (P < 0.05) and that there was no significant difference (P > 0.05) in terms of eubacterial species diversity between health and disease.

Actinobacillus Infections↗

PubMed2006

Diazepam pharamacokinetics from preclinical to phase I using a Bayesian population physiologically based pharmacokinetic model with informative prior distributions in WinBUGS.

Modelling is an important applied tool in drug discovery and development for the prediction and interpretation of drug pharmacokinetics. Preclinical information is used to decide whether a compound will be taken forwards and its pharmacokinetics investigated in human. After proceeding to human little to no use is made of these often very rich data. We suggest a method where the preclinical data are integrated into a whole body physiologically based pharmacokinetic (WBPBPK) model and this model is then used for estimating population PK parameters in human. This approach offers a continuous flow of information from preclinical to clinical studies without the need for different models or model reduction. Additionally, predictions are based upon single parameter values, but making realistic predictions involves incorporating the various sources of variability and uncertainty. Currently, WBPBPK modelling is undertaken as a two-stage process: (i) estimation (optimisation) of drug-dependent parameters by either least squares regression or maximum likelihood and (ii) accounting for the existing parameter variability and uncertainty by stochastic simulation. To address these issues a general Bayesian approach using WinBUGS for estimation of drug-dependent parameters in WBPBPK models is described. Initially applied to data in rat, this approach is further adopted for extrapolation to human, which allows retention of some parameters and updating others with the available human data. While the issues surrounding the incorporation of uncertainty and variability within prediction have been explored within WBPBPK modeling methodology they have equal application to other areas of pharmacokinetics, as well as to pharmacodynamics.

Algorithms↗

PubMed2006

Optimal design for multivariate response pharmacokinetic models.

We address the problem of designing pharmacokinetic experiments in multivariate response situations. Criteria, based on the Fisher information matrix, whose inverse according to the Rao-Cramer inequality is the lower bound of the variance-covariance matrix of any unbiased estimator of the parameters, have previously been developed for univariate response for an individual and a population. We extend these criteria to design individual and population studies where more than one response is measured, for example, when both parent drug and metabolites are measured in plasma, multi-compartment models, where measurements are taken at more than one site, or when drug concentration and pharmacodynamic data are collected simultaneously. We assume that measurements made at distinct times are independent, but measurements made of each concentration are correlated with a response variance-covariance matrix. We investigated a number of optimisation algorithms, namely simplex, exchange, adaptive random search, simulated annealing and a hybrid, to maximise the determinant of the Fisher information matrix as required by the D-optimality criterion. The multiresponse optimal design methodology developed was applied in two case studies, where the aim was to suggest optimal sampling times. The first was a restrospective iv infusion experiment aimed to characterise the disposition kinetics of tolcapone and its two metabolites in healthy volunteers. The second was a prospective iv bolus experiment designed to estimate the tissue disposition kinetics of eight beta-blockers in rat.

Adrenergic beta-Antagonists↗

PubMed2006

Sample size calculations based on generalized estimating equations for population pharmacokinetic experiments.

We present a method for calculating the sample size of a pharmacokinetic study analyzed using a mixed effects model within a hypothesis testing framework. A sample size calculation method for repeated measurement data analyzed using generalized estimating equations has been modified for nonlinear models. The Wald test is used for hypothesis testing of pharmacokinetic parameters. A marginal model for the population pharmacokinetic is obtained by linearizing the structural model around the subject specific random effects. The proposed method is general in that it allows unequal allocation of subjects to the groups and accounts for situations where different blood sampling schedules are required in different groups of patients. The proposed method has been assessed using Monte Carlo simulations under a range of scenarios. NONMEM was used for simulations and data analysis and the results showed good agreement.

Computer Simulation↗

PubMed2006

Pharmacokinetics of a single bolus of propofol in chinese children of different ages.

BACKGROUND: There is no information about the pharmacokinetic profile of propofol in Chinese children younger than 3 yr. This study was designed to determine a complete pharmacokinetic profile of a single dose of propofol in Chinese children of different ages. METHODS: Arterial blood samples were obtained from 35 children with an American Society of Anesthesiologist physical status of I or II at 2, 4, 6, 8, 10, 20, 30, 45, 60, 90, 120, and 180 min after a single bolus intravenous injection of propofol (3 mg/kg). The plasma concentrations of propofol were measured using high-performance liquid chromatography with an ultraviolet detector. A population model was used to estimate the pharmacokinetics of propofol. RESULTS: A three-compartment pharmacokinetic model best described the pharmacokinetics of propofol. Clearance was 0.185 l/min, the volume of distribution of the central compartment was 7.41 l, the peripheral volumes of distribution were 54.6 and 7.2 l, and the intercompartmental clearances were 0.614 and 0.692 l/min for a child of the average weight of 13.7 kg. The half-lives were 2.67, 14.89, and 310.60 min. Covariate models were applied, and weight was found to be significant covariate for the clearance and volume of distribution parameters. No significant age effect could be demonstrated on clearance or volume of distribution parameters after weight was taken into account. CONCLUSIONS: This study supports the case that the pharmacokinetic properties of propofol do not differ substantially across Chinese children of different ages after weight has been accounted for.

Aging↗

PubMed2006

Population pharmacokinetic and pharmacodynamic modelling of the antimalarial chemotherapy chlorproguanil/dapsone.

AIMS: To determine the population pharmacokinetics of chlorproguanil, dapsone and the active metabolite of chlorproguanil, chlorcycloguanil; and to estimate the duration of parasitocidal activity for chlorpoguanil/dapsone against Plasmodium falciparum isolates of varying sensitivity. METHODS: Rich and sparse pharmacokinetic data were collected prospectively from: healthy volunteers (n=48) and adults (n=65) and children (n=68) suffering from P. falciparum malaria. All subjects received 2.0 mg kg-1 of chlorproguanil and 2.5 mg kg-1 of dapsone. RESULTS: The population pharmacokinetic parameter estimates for chlorproguanil were ka=00.09 h-1 (intersubject variability was 44%), CL/F=51.53 l h-1 (57%), CLD/F=54.67 l h-1, V1/F=234.40 l (50%) and V2/F=1612.75 l; for dapsone were ka=00.93 h-1, CL/F=1.99 l h-1 (72%) and V/F=76.96 l (48%); and for chlorcycloguanil were CLm/Fm=3.72 l h-1 kg-1 (67%) and Vm/Fm=12.76 l kg-1 (64%). For dapsone, CL/F and V/F were both significantly positively correlated with body weight. For a 10-kg child, the mean duration of parasitocidal activity for chlorproguanil/dapsone against the three most susceptible P. falciparum strains was 4.5 days [5th and 95th percentiles 2.4, 7.3] for W282; 5.9 days (3.6, 9.7) for ItG2F6; and 6.1 days (3.7, 10.1) for K39. For an isolate with the ile-164-leu mutation, V1/S, activity ranged from 0.8 days (0.0, 3.3) for a 10-kg child to 1.8 days (0.0, 4.0) for a 60-kg adult. CONCLUSIONS: Plasmodium falciparum malaria has no effect on the pharmacokinetic parameters for chlorproguanil, dapsone or chlorcycloguanil. Chlorproguanil/dapsone will probably prove to be ineffective against parasite strains with the mutation ile-164-leu, were these to become prevalent in Africa.

Adolescent↗

PubMed2005

Propagation of population PK and PD information using a Bayesian approach: dealing with non-exchangeability.

The aim of this work is to implement a conservative prior that safeguards against population non-exchangeability of prior and data likelihood, in the framework of population pharmacokinetic/pharmacodynamic analysis, incorporating multi-level hierarchical modelling. Three different exercises were performed: (i) we investigated the use of parametric priors in the multilevel hierarchical modelling framework; (ii) we assessed the average performance of the multilevel hierarchical model compared to the standard mixed effect model, considering also some interesting extreme cases and (iii) we implemented an application with a small Proof of Principle (PoP) study, which demonstrates the propagation of information across PD studies using multilevel modelling. Fitting with the 4-level model and informative parametric priors performed similar to a meta-analysis of the test datasets combined with the datasets that the priors came from, demonstrating that parametric priors can be used alternatively to meta-analysis. Further, the 4-level model gave posterior distributions which had larger uncertainty but at the same time were unbiased, compared to the 3-level model, and therefore implements a more conservative prior in a formal way, which is appropriate when the prior and the test populations are not exchangeable. For the application with the PoP study, the statistical power of detecting the difference in potency between two drugs, when inter-study variability was present, was greater when an extra level in the hierarchical model to account for it, was used. In conclusion, by applying the prior one hierarchical level above the level of the parameters of interest, we implemented a more conservative prior, compared to applying the prior directly on the parameters of interest. The approach is equivalent to Bayesian individualization, offers a safeguard against bias from the prior and also avoids the danger of the data being overwhelmed by a strong prior.

Bayes Theorem↗

PubMed2005

Uncertainty analysis in pharmacokinetics and pharmacodynamics: application to naratriptan.

PURPOSE: The aim of the study was to predict pain relief of migraine in patients following naratriptan oral (tablet) administration by using uncertainty analysis. The analysis was based on phase I pharmacokinetic naratriptan data, sumatriptan pharmacodynamic data, and naratriptan preclinical (animal) potency information, together with general knowledge as to how migraine affects oral absorption. METHODS: A previously developed pharmacokinetic (PK)/pharmacodynamic (PD) model for naratriptan disposition and effect was used. The uncertain parameters in the model, which were associated with absorption and scaling between first-in-class compound sumatriptan and naratriptan, were modeled using fuzzy sets theory. Global sensitivity analysis was then used to investigate the impact of each PK/PD parameter on the responses. RESULTS: Acknowledging parametric uncertainty did not improve prediction of the probability of pain relief. Global sensitivity analysis demonstrated that predictions were heavily influenced by interindividual variability in pharmacodynamics, as the dose response relationship was relatively insensitive to the pharmacokinetics. CONCLUSIONS: To predict the probability of pain relief following oral (tablet) administration of naratriptan, a simple dose response, instead of the PK/PD model, would have yielded very similar predictions. The naratriptan PK/PD model may be improved by either refining the PD model or better still by specifying the interindividual error by additional data collecting with an improved design.

Algorithms↗

PubMed2005

The use of a modified Fedorov exchange algorithm to optimise sampling times for population pharmacokinetic experiments.

We propose a new algorithm for optimising sampling times for population pharmacokinetic experiments using D-optimality. The algorithm was used in conjunction with the population Fisher information matrix as implemented in MATLAB (PFIM 1.1 and 1.2) to evaluate population pharmacokinetic designs. The new algorithm based on the classical Fedorov exchange algorithm optimises the determinant of the population Fisher information matrix. The performance of the new algorithm has been compared with other existing algorithms including simplex, simulated annealing and adaptive random search. The new algorithm performed better especially when dealing with complex designs at the expense of longer computing times.

Algorithms↗

PubMed2005

Pharmacokinetic studies of linezolid and teicoplanin in the critically ill.

OBJECTIVES: To determine the pharmacokinetic characteristics of linezolid and teicoplanin in critically ill patients. PATIENTS AND METHODS: Serum was collected frequently during day 0 and then pre- and 1 h post-dose on days 1, 2, 3, 5, 7 and every third day thereafter during treatment. Serum linezolid concentrations were analysed using HPLC. Serum teicoplanin levels were analysed by fluorescence polarization immunoassay. RESULTS: A two-compartment model was required to characterize linezolid pharmacokinetics (n=28) and account for the accumulation seen after multiple dosing. The estimated clearance was 0.049 +/-0.016 L/h/kg (+/-s.e.m. of estimate). At steady state (dosing interval 12 h), linezolid serum concentrations exceeded the breakpoint of 4 mg/L for 10.88 h (95% CI 10.09-11.66) after a 600 mg dose with an AUC/MIC of 92.4 (95% CI 57.2-127.7). Teicoplanin was best described by a two-compartment model (n=26). The clearance was 4.97+/-1.58 L/h. Serum levels exceeded the breakpoint of 4 mg/L for the entire dosing interval in all subjects (400 mg dose every 12 h) with an AUC/MIC of 399.3 (95% CI 329.6-469.0). However, only four of 14 exceeded trough serum concentrations of 10 mg/L. For both agents, trough levels were similar in those who survived and those who died. CONCLUSIONS: Linezolid dosage at 600 mg every 12 h was adequate in the critically ill without need for adjustment for renal function. For teicoplanin, further study is needed to confirm if a trough of 10 mg/L is associated with a higher rate of cure than 5 mg/L. If so, serum drug assays would be needed to ensure a therapeutic level.

Acetamides↗

PubMed2005

Optimal blood sampling time windows for parameter estimation using a population approach: design of a phase II clinical trial.

The objective of this paper is to determine optimal blood sampling time windows for the estimation of pharmacokinetic (PK) parameters by a population approach within the clinical constraints. A population PK model was developed to describe a reference phase II PK dataset. Using this model and the parameter estimates, D-optimal sampling times were determined by optimising the determinant of the population Fisher information matrix (PFIM) using PFIM_ _M 1.2 and the modified Fedorov exchange algorithm. Optimal sampling time windows were then determined by allowing the D-optimal windows design to result in a specified level of efficiency when compared to the fixed-times D-optimal design. The best results were obtained when K(a) and IIV on K(a) were fixed. Windows were determined using this approach assuming 90% level of efficiency and uniform sample distribution. Four optimal sampling time windows were determined as follow: at trough between 22 h and new drug administration; between 2 and 4 h after dose for all patients; and for 1/3 of the patients only 2 sampling time windows between 4 and 10 h after dose, equal to [4 h-5 h 05] and [9 h 10-10 h]. This work permitted the determination of an optimal design, with suitable sampling time windows which was then evaluated by simulations. The sampling time windows will be used to define the sampling schedule in a prospective phase II study.

Administration, Oral↗

PubMed2005

Propagation of population pharmacokinetic information using a Bayesian approach: comparison with meta-analysis.

We investigated the propagation of population pharmacokinetic information across clinical studies by applying Bayesian techniques. The aim was to summarize the population pharmacokinetic estimates of a study in appropriate statistical distributions in order to use them as Bayesian priors in consequent population pharmacokinetic analyses. Various data sets of simulated and real clinical data were fitted with WinBUGS, with and without informative priors. The posterior estimates of fittings with non-informative priors were used to build parametric informative priors and the whole procedure was carried on in a consecutive manner. The posterior distributions of the fittings with informative priors where compared to those of the meta-analysis fittings of the respective combinations of data sets. Good agreement was found, for the simulated and experimental datasets when the populations were exchangeable, with the posterior distribution from the fittings with the prior to be nearly identical to the ones estimated with meta-analysis. However, when populations were not exchangeble an alternative parametric form for the prior, the natural conjugate prior, had to be used in order to have consistent results. In conclusion, the results of a population pharmacokinetic analysis may be summarized in Bayesian prior distributions that can be used consecutively with other analyses. The procedure is an alternative to meta-analysis and gives comparable results. It has the advantage that it is faster than the meta-analysis, due to the large datasets used with the latter and can be performed when the data included in the prior are not actually available.

Administration, Oral↗

PubMed2005

The pharmacokinetics of perindoprilat in normal volunteers and patients: influence of age and disease state.

The purpose of the present report was to develop a pharmacokinetic model for perindoprilat based on three phase I studies including administration of oral and intravenous perindopril and administration of intravenous perindoprilat. The model was further refined using additional data collected from four phase II clinical trials including elderly volunteers and patients with hypertension, renal failure and heart failure. A two compartment pharmacokinetic model based on unbound concentration, in which perindoprilat bound to a single saturable binding site was used to analyze the intravenous data, whereas a one compartment model, also with saturable binding, was used for the oral data. The kinetics of perindoprilat were dose dependent with the apparent volume of distribution (V/F) varying from 920 L at a dose of 3.1 mg of perindoprilat to 470 L at a dose of 12.3 mg, in normal volunteers. Apparent unbound clearance (CLu/F) ranged from 59 to 110 L h(-1), showing no systematic trend with dose or from single to multiple dosing. Unbound clearance was strongly related to creatinine clearance in the patient studies and there was also a weak relationship between volume of distribution and creatinine clearance. Unbound clearance was also found to decrease with age. The binding parameters of the model were consistent with a single binding site to a protein having the characteristics of angiotensin converting enzyme (ACE).

Administration, Oral↗

PubMed2005

Retrospective population pharmacokinetics of levocetirizine in atopic children receiving cetirizine: the ETAC study.

AIMS: To evaluate the population pharmacokinetics of levocetirizine in young children receiving long-term treatment with cetirizine. METHODS: Data were available from a randomized, double-blind, parallel group and placebo-controlled study of cetirizine in 343 young children between 12 and 24 months of age at entry, who were at high risk of developing asthma, but were not yet affected (ETAC study). Infants received oral drops of cetirizine at 0.25 mg kg(-1) twice daily for 18 months. Plasma concentration of the active enantiomer levocetirizine was determined in blood samples collected at months 3, 12 and 18 (1-3 samples per child). A one-compartment open model was fitted to the data using nonlinear mixed effects modelling (NONMEM). The influence of weight, age, gender, BSA and other covariates on CL/F and V/F was evaluated. RESULTS: CL/F increased linearly with weight by 0.044 l h(-1) kg(-1) over an intercept of 0.244 l h(-1), and V/F increased linearly with weight by 0.639 l kg(-1). Population estimates in children with weights of 8 and 20 kg were 0.60 and 1.13 l h(-1) for CL/F, and 5.1 and 12.8 l for V/F, respectively, with interpatient variabilities of 24.4% and 14.7%. Weight-normalized estimates of CL/F and V/F were higher than in adults. The estimated relative bioavailability was 0.28 in 12% of instances of suspected noncompliance. Levocetirizine pharmacokinetics were not influenced by severe allergy or aeroallergen sensitization. Results on the effects of concomitant medications or diseases were inconclusive due to limited positive cases. AUC(ss), calculated in compliant subjects using posterior estimates of the final model, was 1952 (1227-3319) microg l(-1) h (mean, min-max), a value similar to that in adults after intake of 5 mg oral solution (2036 (1414-2827) microg l(-1) h. CONCLUSIONS: The model suggests that administration of levocetirizine 0.125 mg kg(-1) twice daily in children 12-48 months of age or weighing 8-20 kg yields the same exposure as in adults taking the recommended dose of 5 mg once daily.

Anti-Allergic Agents↗

PubMed2005

A pharmacokinetic/pharmacodynamic model for a platelet activating factor antagonist based on data arising from Phase I studies.

A nonlinear mixed-effects modelling approach was used to analyse pharmacokinetic and pharmacodynamic data from two Phase I studies of a platelet activating factor (PAF) antagonist under development for the treatment of seasonal allergic rhinitis. Data for single-dose (8 subjects) and multiple-dose (9 subjects) administration were available for analysis with a program based on an EM algorithm. Pharmacokinetic analyses of plasma drug concentrations were performed using a biexponential model with first-order absorption. PAF response data were modelled with a hyperbolic Emax model. The drug showed nonlinear pharmacokinetics, with the clearance decreasing from 46.0 to 27.1 L h(-1) over a dose range of 160-480 mg. There was an apparent dose dependency within the C50 (concentration producing 50% of the maximum effect) but at higher doses most of the data was above the estimated C50 and when the data was analysed simultaneously a value of 17.57 ng mL(-1) was obtained for C50, with considerable intersubject variability (103%). Consistent results were obtained from the two studies and the population and individual pharmacodynamic parameter estimates from the analyses provided predicted responses that were in good agreement with the observed data. The results were used to simulate a 320-mg twice-daily dosing regimen.

Administration, Oral↗

PubMed2004

Population pharmacokinetic model for daunorubicin and daunorubicinol coadministered with zosuquidar.3HCl (LY335979).

PURPOSE: The impact of zosuquidar.3HCl, an inhibitor of P-glycoprotein, on the pharmacokinetics of daunorubicin and daunorubicinol was examined in a phase I trial using a population approach. Pharmacokinetic and pharmacodynamic properties of zosuquidar.3HCl were also determined. METHODS: The pharmacokinetics of daunorubicin and daunorubicinol were studied following daunorubicin administration on day 1 (50 mg/m2 i.v. infusion over 10 min) alone and on day 3 concomitantly with zosuquidar.3HCl (i.v. 200 or 300 mg/m2 over 6 h or 400 mg over 3 h). Of a total of 18 patients entered, 16 with acute leukemia completed the study. RESULTS: A three-compartment pharmacokinetic model adequately described daunorubicin concentration-time profiles. Five- and four-compartment models adequately described the daunorubicin-daunorubicinol pharmacokinetics in the absence and presence of zosuquidar.3HCl, respectively. The impact of zosuquidar.3HCl on coadministered daunorubicin was minimal, with a 10% reduction in daunorubicin clearance. The model predicted a 50% decrease in daunorubicinol apparent clearance in the presence of zosuquidar.3HCl. A direct concentration-effect relationship between zosuquidar.3HCl concentrations and inhibition of rhodamine 123 (Rh123) efflux in CD56 lymphocytes was defined by a sigmoid E(max) model. The IC(50) was 31.7 microg/l. The zosuquidar.3HCl dosing regimen led to concentrations in excess of the IC(90) (169.6 microg/l) and provided maximal P-glycoprotein inhibition during the distribution phases of daunorubicin. CONCLUSIONS: The decrease in daunorubicin and daunorubicinol clearance in the presence of zosuquidar.3HCl likely reflects inhibition of P-glycoprotein in the bile canaliculi impeding their biliary excretion. The results need to be interpreted carefully due to the sequential nature of daunorubicin administration and analysis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Pharmacodynamics of controlled release verapamil in patients with hypertension: an analysis using spline functions.

AIMS: To use a nonparametric approach involving longitudinal splines to model the baseline blood pressure profile and investigate the impact of this modelling on the pharmacodynamic analysis for verapamil in patients with angina or hypertension. METHODS: Dose ranging studies were conducted in patients with hypertension and with angina. Subjects received doses of 120, 180, 360 or 540 mg racemic verapamil. Pharmacodynamic data were created by subtracting the (systolic) blood pressure following active drug from the placebo response, either by direct subtraction or after modelling the baseline with a longitudinal spline model fitted to the placebo data by nonlinear mixed effects modelling. An Emax model was then used to describe the relationship between change in blood pressure and (R-)verapamil plasma concentration. RESULTS: The maximum decrease in systolic blood pressure was found to be 57.6 (+/- 26.1) mm and the C50 was 420 (+/- 349) microg/l for the data obtained by direct subtraction of the placebo data. Similar results were obtained when a cubic spline model was used to describe each individual's placebo response. However, the use of a population spline model only allowed a linear pharmacodynamic model to be fitted to the resulting data. Sparse data were created by randomly removing 66% of the data from the placebo and active phases. The population spline model gave very similar parameter estimates for the linear model applied to the sparse data to those obtained from the complete data set. CONCLUSIONS: The use of a longitudinal spline model together with nonlinear mixed effects modelling to account for baseline blood pressure response can be very powerful in a sparse data environment.

Adult↗