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dc.contributor.authorAl-Otaibi, Faisal Obaid
dc.description.abstractOptimum therapeutic outcomes require not only proper drug selection but also effective drug delivery and monitoring. The aim of this thesis was to A) study drug delivery through the skin with a liquid formulated to promote absorption, B) develop and validate methods to analyze the drug in the samples obtained, C) assess appropriate methods to measure the transdermal delivery of drug, and D) apply to pharmacodynamics. The stability of a rectal formulation of diazepam, Diastat®, and a quality control of a topical form, TDS® diazepam, were studied using high performance liquid chromatography (HPLC) with ultraviolet absorption detection (UV). It was found that diazepam at 10 mg/mL was stable in solution at various temperatures for at least 4 weeks. A pharmacokinetic study of diazepam delivery from the TDS® delivery system was compared with delivery of the drug following rectal administration of Diastat® in 12 healthy volunteers. The TDS® diazepam was evaluated for safety and no adverse effects or events were observed. The preparation was found to be able to deliver diazepam systemically in humans, the confidence interval (CI) of the ratios for Cmax and AUC of diazepam from the two formulations A (TDS®): B (rectal) were not contained within the bioequivalence limit 80–125%, Cmax (0–72h): 7.3–14% and AUC0-72h: 20–38%. In addition, the 90% CI of desmethyldiazepam (A:B) ratio were not contained within the bioequivalence limit, Cmax (0–72h): 38–54% and AUC0-72h: 33–58%. Although not bioequivalent to Diastat® these finding suggest that skin may be an alternative method of diazepam delivery but further developments and studies would be required. The development and validation of fast, high throughput methods to evaluate tetracaine from skin tape samples was another challenge. Sensitive and reliable capillary electrophoresis with UV and HPLC-UV methods were developed and validated to measure tetracaine in skin using tape samples from volunteers given 1 mL Ametop gel (4% w/w of tetracaine) to support a pharmacokinetic drug delivery study of Ametop. The results from these validation studies demonstrated an equal ability of the two methods to measure tetracaine concentrations reproducibly and accurately. The Bland Altman test was in a range of ± 1.96 SD from the mean (SD = ± 8.02, Mean = 2.23), and percentage error (± 20%.), which show an acceptable difference. The assays were found to possess both the sensitivity and specificity necessary to measure the analyte in the skin tape stripping at the concentrations range in these tapes. Finally, observation of appropriate methods to measure the transdermal drug in vivo techniques, such as microdialysis (MD) and tape stripping (TS) have been employed by plotting a concentration time profile to investigate the capability of measuring tetracaine (pharmacokinetics) in local tissue, instead of measuring tetracaine by conventional systemic measurements. The results showed that the tetracaine Cmax concentration was higher in the stratum corneum compared with the major metabolites of tetracaine, 4- butylaminobenzoic acid (BABA) by 3 and 10 times in MD and plasma, respectively. TS samples reached the maximum concentration quicker than BABA in dialysate and plasma samples (p = 0.002). The median tmax was higher in plasma (IQR -53minutes, 95% CI: - 30– -105) compared with tape samples. The AUC and Cmax for tetracaine were higher in TS compared with BABA in MD and plasma (Mean AUC0-4h: 88582, 55594 and 13208 nM.min: Mean Cmax (0–4h), 850, 459, 110 nM, respectively). In addition, the AUC and Cmax values demonstrated that data from the TS study showed less variability compared with the data from plasma. The most variable data were for MD (CV%; AUC0-4h, 24, 63, and 85%: Cmax (0–4h), 42, 60, 80%, respectively). AUC and Cmax (Bartlett’s test, p = 0.004 for AUC; and Levene’s test, p = 0.042, and 0.028, respectively) This thesis has demonstrated that 1) diazepam was successfully delivered through the skin into the systemic circulation by the TDS® system, 2) novel methods have been developed for the measurement of tetracaine and its metabolite, and 3) the methods have been successfully applied to three different sample types employed in pharmacokinetic studies.en_US
dc.titlePharmacokinetic studies of drug absorption into human skinen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author

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  • Theses [3919]
    Theses Awarded by Queen Mary University of London

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