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Biomedical subjects

Malcolm Rowland

Publications and source records attributed to Malcolm Rowland.

At least 19 recordsLinked to original sources
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

Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions.

A key component of whole body physiologically based pharmacokinetic (WBPBPK) models is the tissue-to-plasma water partition coefficients (Kpu's). The predictability of Kpu values using mechanistically derived equations has been investigated for 7 very weak bases, 20 acids, 4 neutral drugs and 8 zwitterions in rat adipose, bone, brain, gut, heart, kidney, liver, lung, muscle, pancreas, skin, spleen and thymus. These equations incorporate expressions for dissolution in tissue water and, partitioning into neutral lipids and neutral phospholipids. Additionally, associations with acidic phospholipids were incorporated for zwitterions with a highly basic functionality, or extracellular proteins for the other compound classes. The affinity for these cellular constituents was determined from blood cell data or plasma protein binding, respectively. These equations assume drugs are passively distributed and that processes are nonsaturating. Resultant Kpu predictions were more accurate when compared to published equations, with 84% as opposed to 61% of the predicted values agreeing with experimental values to within a factor of 3. This improvement was largely due to the incorporation of distribution processes related to drug ionisation, an issue that is not addressed in earlier equations. Such advancements in parameter prediction will assist WBPBPK modelling, where time, cost and labour requirements greatly deter its application.

Animals↗
PubMed2006

Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs.

OBJECTIVES: A volunteer trial was performed to compare the pharmacokinetics of 5 drugs--warfarin, ZK253 (Schering), diazepam, midazolam, and erythromycin--when administered at a microdose or pharmacologic dose. Each compound was chosen to represent a situation in which prediction of pharmacokinetics from either animal or in vitro studies (or both) was or is likely to be problematic. METHODS: In a crossover design volunteers received (1) 1 of the 5 compounds as a microdose labeled with radioactive carbon (carbon 14) (100 microg), (2) the corresponding (14)C-labeled therapeutic dose on a separate occasion, and (3) simultaneous administration of an intravenous (14)C-labeled microdose and an oral therapeutic dose for ZK253, midazolam, and erythromycin. Analysis of (14)C-labeled drugs in plasma was done by use of HPLC followed by accelerator mass spectrometry. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentrations of ZK253, midazolam, and erythromycin at therapeutic concentrations, whereas HPLC-accelerator mass spectrometry was used to measure warfarin and diazepam concentrations. RESULTS: Good concordance between microdose and therapeutic dose pharmacokinetics was observed for diazepam (half-life [t((1/2))] of 45.1 hours, clearance [CL] of 1.38 L/h, and volume of distribution [V] of 90.1 L for 100 microg and t((1/2)) of 35.7 hours, CL of 1.3 L/h, and V of 123 L for 10 mg), midazolam (t((1/2)) of 4.87 hours, CL of 21.2 L/h, V of 145 L, and oral bioavailability [F] of 0.23 for 100 microg and t((1/2)) of 3.31 hours, CL of 20.4 L/h, V of 75 L, and F of 0.22 for 7.5 mg), and development compound ZK253 (F = <1% for both 100 microg and 50 mg). For warfarin, clearance was reasonably well predicted (0.17 L/h for 100 microg and 0.26 L/h for 5 mg), but the discrepancy observed in distribution (67 L for 100 microg and 17.9 L for 5 mg) was probably a result of high-affinity, low-capacity tissue binding. The oral microdose of erythromycin failed to provide detectable plasma levels as a result of possible acid lability in the stomach. Absolute bioavailability for the 3 compounds examined yielded excellent concordance with data from the literature or data generated in house. CONCLUSION: Overall, when used appropriately, microdosing offers the potential to aid in early drug candidate selection.

Administration, Oral↗
PubMed2006

The use of isotopes in the determination of absolute bioavailability of drugs in humans.

Absolute bioavailability studies in humans are not routinely performed as part of the drug registration process. They tend to be reasonably demanding, not least because toxicology data are required to support intravenous administration of a drug. Moreover, the classical crossover design of an absolute bioavailability study can suffer from artefacts caused by concentration-dependent pharmacokinetics. Many of the problems associated with absolute bioavailability studies can be alleviated using isotopically labelled drugs. Stable isotopes have been used in the performance of absolute bioavailability studies in humans for > 30 years. More recently, the advantages of using radiolabelled drugs have been expanded by using the ultrasensitive technology of accelerator mass spectrometry. Isotopic labelling not only allows for the accurate and efficient determination of absolute bioavailability, but can also provide information on first-pass effects and other pharmacokinetic parameters.

Administration, Intravesical↗
PubMed2005

Reducing whole body physiologically based pharmacokinetic models using global sensitivity analysis: diazepam case study.

There are situations in drug development where one may wish to reduce the dimensionality and complexity of whole body physiologically based pharmacokinetic models. A technique for formal reduction of such models, based on global sensitivity analysis, is suggested. Using this approach mean and variance of tissue(s) and/or blood concentrations are preserved in the reduced models. Extended Fourier amplitude sensitivity test (FAST), a global sensitivity technique, takes a sampling approach, acknowledging parameter variability and uncertainty, to calculate the impact of parameters on concentration variance. We used existing literature rules for formal model reduction to identify all possible smaller dimensionally models. To discriminate among those competing mechanistic models extended FAST was used, whereby we treated model structural uncertainty as another factor contributing to the overall uncertainty. A previously developed 14 compartment whole body physiologically based model for diazepam disposition in rat was reduced to three alternative reduced models, with preserved arterial mean and variance concentration profiles.

Animals↗
PubMed2005

Getting the Dose Right: report from the Tenth European Federation of Pharmaceutical Sciences (EUFEPS) conference on optimizing drug development.

This report highlights the main points emerging from a meeting sponsored on "Getting the Dose Right" in clinical development, jointly sponsored by the European Federation of Pharmaceutical Sciences and the European Center of Pharmaceutical Medicine, as part of the Workshop Series on Frontiers in Drug Development, in Basel, Switzerland on December 9-12, 2002.

Clinical Trials as Topic↗
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

Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases.

Tissue-to-plasma water partition coefficients (Kpu's) form an integral part of whole body physiologically based pharmacokinetic (WBPBPK) models. This research aims to improve the predictability of Kpu values for moderate-to-strong bases (pK(a) > or = 7), by developing a mechanistic equation that accommodates the unique electrostatic interactions of such drugs with tissue acidic phospholipids, where the affinity of this interaction is readily estimated from drug blood cell binding data. Additional model constituents are drug partitioning into neutral lipids and neutral phospholipids, and drug dissolution in tissue water. Major assumptions of this equation are that electrostatic interactions predominate, drugs distribute passively, and non-saturating conditions prevail. Resultant Kpu predictions for 28 moderate-to-strong bases were significantly more accurate than published equations with 89%, compared to 45%, of the predictions being within a factor of three of experimental values in rat adipose, bone, gut, heart, kidney, liver, muscle, pancreas, skin, spleen and thymus. Predictions in rat brain and lung were less accurate probably due to the involvement of additional processes not incorporated within the equation. This overall improvement in prediction should facilitate the further application of WBPBPK modeling, where time, cost and labor requirements associated with experimentally determining Kpu's have, to a large extent, deterred its application.

Animals↗
PubMed2005

Tissue distribution of basic drugs: accounting for enantiomeric, compound and regional differences amongst beta-blocking drugs in rat.

The purpose of this research was to identify the major factors controlling the distribution of beta-blockers (acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol, propranolol and timolol) in rats, across tissues, compounds and enantiomers. Tissue distribution was assessed at steady state by infusing cassette doses of beta-blockers into the jugular vein via an indwelling catheter at a constant rate. Blood was sampled via an indwelling catheter in the carotid artery, and 12 tissues excised at the end of dose infusion (4 or 8 h). Drug concentrations were quantified using a novel chiral LC-MS method and the tissue-to-plasma (Kp) and tissue-to-plasma water (Kpu) values were calculated for each tissue. Differences between Kp were observed between many enantiomeric pairs, and largely explained by enantiomeric differences in plasma protein binding. Across compounds, Kpu values were generally highest in lung and lowest in adipose, and were higher for the more lipophilic drugs betaxolol and propranolol. For any tissue, Kpu differences between the individual beta-blockers correlated well with the corresponding affinity for blood cells. For all compounds, regional tissue distribution correlated well with tissue acidic phospholipid concentrations, with phosphatidylserine appearing to have the strongest influence. This information may be used as the basis for predicting the tissue distribution of basic drugs.

Adrenergic beta-Antagonists↗
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↗
PubMed2004

Physiologically based pharmacokinetics in drug development and regulatory science: a workshop report (Georgetown University, Washington, DC, May 29-30, 2002).

A 2-day workshop on "Physiologically Based Pharmacokinetics (PBPK) in Drug Development and Regulatory Science" came to a successful conclusion on May 30, 2002, in Washington, DC. More than 120 international participants from the environmental and predominantly pharmaceutical industries, Food and Drug Administration (FDA), and universities attended this workshop, organized by the Center for Drug Development Science, Georgetown University, Washington, DC. The first of its kind specifically devoted to the subject, this intensive workshop, comprising 7 plenary presentations and 10 breakout sessions addressed 2 major objectives: (1) to "define demonstrated and potential contributions of PBPK in drug development and regulatory science," and (2) to "assess current PBPK methodologies with the identification of their limitations and outstanding issues." This report summarizes the presentations and recommendations that emerged from the workshop, while providing key references, software, and PBPK data sources in the appendices. The first day was initially devoted to presentations setting the stage and providing demonstrated applications to date. This was followed by breakout sessions that considered further opportunities and limitations, and which extended into Day 2 to deal with developments in methodologies and tools. Although the primary emphasis was on pharmacokinetics, consideration was also given to its integration specifically with mechanism-based pharmacodynamics.

Animals↗
PubMed2004

Fuzzy simulation of pharmacokinetic models: case study of whole body physiologically based model of diazepam.

The aim of the present study is to develop and implement a methodology that accounts for parameter variability and uncertainty in the presence of qualitative and semi-quantitative information (fuzzy simulations) as well as when some parameters are better quantitatively defined than others (fuzzy-probabilistic approach). The fuzzy simulations method consists of (i) representing parameter uncertainty and variability by fuzzy numbers and (ii) simulating predictions by solving the pharmacokinetic model. The fuzzy-probabilistic approach includes an additional transformation between fuzzy numbers and probability density functions. To illustrate the proposed method a diazepam WBPBPK model was used where the information for hepatic intrinsic clearance determined by in vitro-in vivo scaling was semi-quantitative. The predicted concentration time profiles were compared with those resulting from a Monte Carlo simulation. Fuzzy simulations can be used as an alternative to Monte Carlo simulation.

Animals↗
PubMed2004

Development of a whole body physiologically based model to characterise the pharmacokinetics of benzodiazepines. 1: Estimation of rat tissue-plasma partition ratios.

Three methods for estimation of the equilibrium tissue-to-plasma partition ratios (Kp values) in the presence of tissue concentration time data have been investigated. These are the area method, the open loop (tissue specific) method and the whole body model(closed loop) method, each with different model assumptions. Additionally, multiple imputations, a technique for dealing with deficiencies in data sets (i.e., missing tissues) is used. The estimated Kp values by the three methods have been compared and the limitations and advantages of each approach drawn. The area method, which is essentially model free, gives only a crude estimate of Kp without making any statement of its uncertainty; whereas both the open and closed loop methods provide an estimate of this. The closed loop method, where the most assumptions are made, is the approach that gives the best overall estimates of Kp, which was confirmed by comparing the predicted concentration-time profiles with experimental data. Although the estimates from the closed loop method, as well as the other two methods, are conditioned on the data, they are the most reliable for both propagating parameter variability and uncertainty through a whole body physiologically based model, as well as for extrapolation to human. A series of benzodiazepines, namely alprazolam, chlordiazepoxide, clobazam, diazepam, flunitrazepam, midazolam and triazolam in rat is used as a case study in the current investigation.

Animals↗
PubMed2003

Prediction of in vivo tissue distribution from in vitro data. 2. Influence of albumin diffusion from tissue pieces during an in vitro incubation on estimated tissue-to-unbound plasma partition coefficients (Kpu).

PURPOSE: To determine the extent of albumin diffusion from tissue pieces into medium during in vitro incubations, to develop and assess the utility of mathematical models describing this effect on the estimation of tissue-to-unbound plasma partition coefficients (Kpu) of drug substances and to derive factors to correct for associated errors. METHODS: Twelve separate tissues were obtained from rats sacrificed by cervical dislocation, 48 h after an intravenous dose of 125I-human albumin, and tissue pieces incubated to determine the efflux of albumin into media over 2 to 4 h. A mathematical model was developed to predict and correct for the effect of albumin diffusion on the measured Kpu values of drugs. RESULTS: The model predicted that the effect of albumin diffusion from tissue pieces during in vitro incubation (ranging from 14 to 59% remaining in tissue) on Kpu values was generally minimal, except for compounds that are highly plasma bound and have a low measured Kpu. Under these circumstances, the measured Kpu substantially underestimates the true value. An equation was derived from readily available or measurable parameters to correct for this underestimation. CONCLUSIONS: Albumin diffuses from tissue pieces into protein free media during in vitro incubations until equilibrium is reached, defined by the albumin Kpu. Model predictions indicated that for the majority of compounds albumin diffusion would have a minimal effect on the measured Kpu value and that a correction factor could be calculated to account for any deviation.

Albumins↗