3. Electronic Theses and Dissertations (ETDs) - All submissions

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    The nonstandard finite difference method applied to pharmacokinetic models
    (2018) Egbelowo, Oluwaseun Francis
    A good understanding of pharmacokinetic-pharmacodynamic can shed light on situations where one or the other needs to be optimized in drug discovery and development. As a result of this, pharmaceutical companies aim to develop new tools to support drug discovery and e cacious dose for clinical use. Drugs take a complicated journey through the body before they produce their desired therapeutic e ects. Ultimately, these processes are usually best described by compartment pharmacokinetic-pharmacodynamics models. Pharmacokinetic (PK) models are commonly used to predict drug concentrations that drive controlled intravenous (I.V.) transfers (or infusion and oral transfers) while pharmacokinetic and pharmacodynamic (PD) interaction models are used to provide predictions of drug concentrations a ecting the response of these clinical drugs. These PK/PD models leads to di erential equations. Few of these di erential equations can be solved exactly. Therefore, a lack of exact solutions to many of these di erential equations leads to numerical approximation been used to determine the possible solution or behaviour of the di erential equations. The aim of this thesis is to apply standard nite di erence (SFD) and nonstandard nite di erence (NSFD) methods to continuous-time pharmacokinetic- pharmacodynamic models. Another aim of this thesis is to provide a rigorous analysis of these models to gain insight into the dynamical features. This will allow us to also comment on the impact of certain key parameters. The NSFD method was shown to be dynamically consistent with the original continuous-time models. Also, the NSFD method is able to predict the concentration{time pro le of a drug when there are alterations in the dosing regimen|this would not be possible were one to consider non-compartment analysis. Furthermore, the NSFD method preserves signi cant properties of the analogous models and consequently gives reliable numerical results even when analytical solutions are not possible. The standard approaches to multi-compartment models assume linear dynamics over the duration of each time step, whereas the NSFD method assumes exponential dynamics. Thus, in the case of a linear model the NSFD method recovers the model dynamics exactly. This thesis illustrates the ability of the NSFD method to solve compartment PK models in a stable and robust fashion.
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    A comparison of classical bioequivalence analysis techniques with simulated annealing algorithm optimised sampling times and population pharmacokinetic modelling
    (2017) Cudjoe, Senyo Frank Kofi
    Bioequivalence (BE) studies are conducted to demonstrate that two drug for- mulations produce similar bioavalabilities or therapeutic e ect and safety when used. During this study, drug concentrations are obtained several times over a given period of time and a concentration vs. time graph is constructed. For a generic drug to be approved, this BE studies are conducted and the generic drug must be demonstrated to be therapeutically equivalent to the innovator drug. This study utilised a standard 2 2 crossover design to randomly assign sub- jects to each of the two sequences. Statistical methods such as con dence in- tervals, Schuirmann's two one-sided and Wilcoxon-Mann-Whitney tests were used to assess average bioequivalence (ABE). However, there are concerns that the use of ABE alone is not appropriate for drugs with high intra-subject and inter-subject variabilities. Under such a circumstance, population bioequiv- alence (PBE) and individual bioequivalence (IBE) are proposed. This study employs the PBE approach but not the IBE as it is not possible to perform IBE on the available data. Results indicated that the generic drug is average bioequivalent to the innovator drug although Cmax was outside the regulatory range set by the Food and Drug Administration (FDA). Most biological data are modelled using nonlinear xed e ect models. Popula- tion pharmacokinetic (PK) modelling has been used in clinical pharmacology to identify the sources of PK variability in the target population. This study was conducted to determine the characteristics of the PK parameters of the orally administered antibiotic given to pigs using a population approach. A population PK model was developed using a nonlinear mixed e ects model (NLMEM) with a one-compartment model using di erent residuals. For the NLMEM, the stochastic approximation expectation maximisation (SAEM) al- gorithm was implemented in MONOLIX. The models were used to estimate the population PK parameters and diagnostic plots obtained for model eval- uation. The results showed that the combined residual error model tted the data better than the constant error model. In addition, this study sought to nd optimal sampling times which will min- imise the number of blood samples required for pharmacokinetic study. The optimal sampling times were generated from a one compartment model and implemented in MATLAB. The parameters used in the optimisation were es- timated from the population PK model. These sampling times were generated using the simulated annealing (SA) algorithm. Keywords: Bioavailability, Bioequivalence, generic drugs, reference drugs, average bioequivalence, population bioequivalence, individual bioequivalence, pharmacokinetics, pharmacodynamics, therapeutic window, con dence inter- val, nonlinear xed e ects model, two one-sided tests, maximum likelihood, population parameters, optimal sampling design, concentration-time curve, model evaluation, Visual predictive checks (VPC), Normalised prediction dis- tribution errors (NPDE), Stochastic approximation expectation maximisation (SAEM) algorithm.
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    Lithium - A general overview of its uses
    (1985-08) Vermeulen, Raymond A
    This dissertation consists of a review of the literature, past and present, pertaining to the metal lithium. An overview is presented of its actions, its adverse effects, and its use in medicine particularly in psychiatry. As it is not irregular for many patients to receive two or more drugs concomitantly and often in a combination which has the potential to interact adversely, an overview of these interactions is also presented.
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    The effects of miglitol on the pharmacokinetics of phenytoin in healthy volunteers
    (1996-12-22) Richardt, Denise
    The interaction between miglitol, an a-glucosidase inhibitor used as an adjunct therapy in diabetes, and phenytoin, an anticonvulsant primarily used in the treatment of epilepsy, was studied over 26 days. Twenty-four healthy male volunteers took part in a placebo controlled, double blind, cross-over study in two phases, to determine the effects of multiple 100mg doses of miglitol on a single 400mg dose of phenytoin sodium. Miglitol or placebo was administered three times daily from Day 1 to Day 5. Phenytoin was administered as a single dose on Day 3 of each phase, after which blood samples were taken at regular intervals. A washout period of 14 days separated the two phases.
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