Saudi Cultural Missions Theses & Dissertations
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Item Restricted Pharmacokinetics And Tissue Distribution of a Lipid-Based Extended-Release Nano-Formulation Of MO-OH-Nap Tropolone to Enhance Pulmonary Delivery for the Treatment of Pulmonary Metastatic Osteosarcoma(University of Nebraska Medical Center, 2024-08) Aldhafiri, Wafaa Nasser; Murry, DJOsteosarcoma is the most common primary bone tumor in children and adolescents. Metastasis is prevalent in 25% of patients, at diagnosis, with the lungs being the most common metastatic site. Pulmonary metastatic osteosarcoma is a significant therapeutic challenge with a 5-year survival rate of ≤30%. Patients with pulmonary metastatic disease at diagnosis receive the same standard of care as patients with local disease, which hasn’t changed over the past 30 years. The treatment and prevention of pulmonary metastatic osteosarcoma represents a significant critical and unmet need. MO-OH-Nap tropolone is a novel small molecule with cytotoxic activity across multiple human osteosarcoma cell lines, yet poor solubility limits its clinical development. We developed a MO-OH-Nap tropolone liposomal nanoparticle formulation to enhance delivery to pulmonary tissue for the treatment of pulmonary metastatic osteosarcoma. The nanoparticle formulation was prepared using a lipid film hydration method. Dynamic light scattering and ultra-centrifugation were used to determine the average particle size and encapsulation efficiency. The pharmacokinetics and biodistribution of MO-OH-Nap tropolone were determined in CD-1 mice following a single intraperitoneal dose of MO-OH-Nap tropolone aqueous solution or MO-OH-Nap tropolone liposomes nanoparticle formulation (5 mg/kg). Serial plasma and tissue samples were collected over 48 hours. MO-OH-Nap tropolone concentrations were determined utilizing a validated LC-MS/MS method. Phoenix® software was used to determine pharmacokinetic parameters utilizing non-compartmental analysis and a 3-compartment pharmacokinetic model to better characterize the MO-OH-Nap tropolone liposomes nanoparticle plasma and tissue concentrations. The finalized model was used to simulate different dosing regimen responses utilizing Monte Carlo simulations. The liposomes nanoparticle average particle size was 188.3 ± 54 d.nm with 99% encapsulation efficiency. Following single dose administration in mice, MO-OH-Nap tropolone systemic drug exposure was significantly increased (~10 fold) for the nanoparticle formulation (28229 hr*ng/mL) compared to the MO-OH-Nap (2846 hr*ng/mL). The observed clearance was 184.4 mL/hr/kg for the nanoparticle formulation and 1738.6 mL/hr/kg for the drug in aqueous solution. Drug concentrations in lung tissue 24 hours post dose (165.5 ng/g) were significantly increased following nanoparticle formulation administration compared to drug in aqueous solution (1.20 ng/g, student t-test, p-value < 0.001). The developed pharmacokinetic model accurately described the plasma concentration time profile and pulmonary drug accumulation. The model revealed a biphasic absorption pattern with a rapid initial drug release followed by a sustained drug release phase, indicating the controlled release properties of the nanoparticle formulation. Monte Carlo simulation for multiple dosing scenarios identified that the 7.5 mg/kg twice-weekly regimen would significantly improve lung coverage while moderately enhancing plasma levels, aligning better with the goal of maintaining pulmonary concentrations above the IC50 for a 75% of the dosing interval of 28 days. The model's fit was validated through bootstrap analysis, confirming the reliability of the pharmacokinetic parameters. Overall, this pharmacokinetic model provides critical insights into the behavior of MO-OH-Nap tropolone nanoparticle formulation, facilitating the development of effective dosing strategies for enhanced treatment of pulmonary metastatic osteosarcoma. The developed formulation substantially increased systemic exposure and pulmonary delivery of MO-OH-Nap tropolone. Further studies will assess the safety profile of 7.5 mg/kg IP dose twice weekly, as well as evaluate efficacy in mouse models of metastatic OS.17 0Item Restricted Acute arterial hypoxaemia and its impact on drug pharmacokinetics in humans; clinical and in-vitro investigation.(Cardiff University, 2024-06-13) Alablani, Dalal; Gumbleton, Mark; Coulson, James; Bailey, DamianArterial hypoxaemia ultimately leads to the formation of systemic and localised free radicals, activating pathways of oxidative-inflammatory-nitrosative stress. The physiological adjustments, encompassing redox and haemodynamic responses, have the potential to influence the pharmacokinetics (PK) and pharmacodynamics (PD) of both acutely and chronically administered medications. Sildenafil, a drug that acts through phosphodiesterase-5 inhibition and is clinically used for pulmonary hypertension, also serves as a short-term treatment to prevent or mitigate altitude-induced pulmonary vasoconstriction, a key factor in the development of high-altitude pulmonary oedema (HAPE). This thesis aims to simulate the PK/PD outcomes of sildenafil under acute hypoxaemia and identify the underlying mechanistic pathway that drives PK/PD alterations under hypoxia. The PK/PD profile of a single oral 100 mg sildenafil oral tablet was simulated using R V.3.6.3 with the IQRtools package. A Monte Carlo method was employed, involving 1000 subjects, with a one-compartment first-order elimination and absorption model. The HepaRG cell line served as an in-vitro model to predict the intrinsic clearance (Clint) of sildenafil under hypoxia (1% O2). This was accomplished by evaluating CYP3A4 and CYP2C9 turnover activities and investigating the associated mechanistic pathway. Hypoxia resulted in a significant decrease in the turnover activity of both CYP3A4 and CYP2C9, leading to a 29% reduction in Clint compared to the normoxic control. Monte Carlo simulations revealed that acute hypoxia increased the maximum concentration (Cmax), half-life (t1/2), area under the curve (AUC 0-∞), as well as AUC above the inhibitory concentration 50% (IC50). Hypoxia stimulated stressors such as cytokine and superoxide production, had exerting a negative regulatory effect on CYP3A4/2C9. The preservation of CYP3A4/2C9 activity under hypoxia was achieved by employing reactive oxygen species (ROS) scavengers like Tiron. Furthermore, hypoxia may regulate CYP3A4/2C9 through the modulation of the pregnane x receptor (PXR). The MAPK/ERK signalling pathway appears to be the target pathway for this regulation. In conclusion, hypoxia has the capacity to alter the PK/PD profile of drugs, warranting dosage regimen adjustments, particularly for drugs with narrow therapeutic indices. Further mechanistic studies focusing on the PXR pathway are necessary to fully comprehend the mechanisms underlying hypoxia-induced alterations.14 0