A5066353718- Tuberculosis Research and Epidemiology
- Antibiotics Pharmacokinetics and Efficacy
- Cancer therapeutics and mechanisms
- Computational Drug Discovery Methods
- Phenothiazines and Benzothiazines Synthesis and Activities
- Antibiotic Resistance in Bacteria
- Long-Term Effects of COVID-19
- Malaria Research and Control
- Pharmacogenetics and Drug Metabolism
- Pneumocystis jirovecii pneumonia detection and treatment
- Pharmacological Receptor Mechanisms and Effects
- Drug Transport and Resistance Mechanisms
- Chronic Myeloid Leukemia Treatments
- PI3K/AKT/mTOR signaling in cancer
- COVID-19 Clinical Research Studies
- Pneumonia and Respiratory Infections
- Synthesis and Biological Evaluation
- HIV, Drug Use, Sexual Risk
- Pharmaceutical studies and practices
- Diagnosis and treatment of tuberculosis
- Chemokine receptors and signaling
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Receptor Mechanisms and Signaling
- Bipolar Disorder and Treatment
- HIV/AIDS drug development and treatment
University of California, San Francisco
2017-2025
Amgen (United States)
2023-2024
University of Cape Town
2015-2020
University of the Western Cape
2019
Imperial College London
2013
Background The sites of mycobacterial infection in the lungs tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach hard-to-treat disease sites, further leading suboptimal concentrations, resulting compromised TB treatment response resistance development. Quantifying lesion-specific uptake pharmacokinetics (PKs) is necessary optimize regimens at all identify risk, improve existing regimens, advance development...
Neutrophils are the most abundant circulating leukocyte and play a fundamental role in innate immune response. Patients with neutropenia, adhesion deficiency syndrome or chronic granulomatous disease particularly prone to bacterial fungal infection. However, highly destructive capacity of these cells also increases potential for neutrophil damage healthy tissues, as seen number inflammatory diseases such rheumatoid arthritis obstructive pulmonary disease. The homeostatic control levels is...
Abstract TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared linezolid in combination with bedaquiline pretomanid (BPaL). We aim optimize the dosing of TBI-223 within BPaL regimen enhanced therapeutic outcomes. investigated preclinical monotherapy, multidrug therapy, lesion penetration experiments describe its versus linezolid. A translational platform incorporating data from 4 clinical trials (NCT00396084, NCT02333799, NCT03086486,...
Accelerated tuberculosis drug discovery has increased the number of plausible multidrug regimens. Testing every combination in vivo is impractical, and varied experimental conditions make it challenging to compare results between experiments. Using published treatment efficacy data from a mouse model treated with candidate regimens, we trained externally validated integrative mathematical models predict relapse mice rank both previously experimentally studied unstudied regimens by their...
Abstract Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse‐to‐human translational pharmacokinetics (PKs) – pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The included Mycobacterium growth function in mice, adaptive immune response effect bacterial growth, relationships among moxifloxacin, rifapentine, and...
Standard treatment for active tuberculosis (TB) requires drug with at least four drugs over six months. Shorter-duration therapy would mean less need strict adherence, and reduced risk of bacterial resistance. A system pharmacology model TB infection, was developed used to simulate the outcome different scenarios. The incorporated human immune response, granuloma lesions, multi-drug antimicrobial chemotherapy, dynamic population pharmacokinetic/pharmacodynamic (PK/PD) simulation including...
Background: Phase 2a trials in tuberculosis typically use early bactericidal activity (EBA), the decline sputum CFU over 14 days, as primary end-point for testing efficacy of drugs monotherapy. However, cost phase can range from USD 7 million to 19.6 on average, while >30% fail progress 3. Better utilising pre-clinical data predict and prioritise most likely succeed will thus help accelerate drug development reduce costs. We aim clinical EBA using vivo pharmacokinetic (PK)-pharmacodynamic...
Tuberculosis (TB) drug, regimen, and vaccine development rely heavily on preclinical animal experiments, quantification of bacterial immune response dynamics is essential for understanding drug efficacy. A mechanism-based model was built to describe
Adherence has been shown to be a major predictor of tuberculosis treatment failure and relapse. The current adherence metrics can improved provide higher resolution patterns identify patients in need alternative interventions. We investigated how affect outcomes, when is likely decrease during which are at risk being nonadherent.Individual-level data were pooled from 3 clinical trials (n = 3724) for drug susceptible where monthly or weekly collected quantified assess the impact clustered...
Fusidic acid (FA) has previously been shown to be rapidly metabolized in rodents its C-3 epimer, which significantly lower antimycobacterial activity relative FA. This was part hypothesized account for FA's lack of vivo efficacy a mouse model tuberculosis despite potent vitro activity. In the current work, we that alkyl ester prodrugs FA would deliver higher levels drug and prevent rapid metabolism observed upon administration original form. Pharmacokinetic analysis 3-ketofusidic metabolite...
Moxifloxacin (MOX) is used as a first-choice drug to treat multidrug-resistant tuberculosis (MDR-TB); however, evidence-based dosing optimization should be strengthened by integrative analysis. The primary goal of this study was evaluate MOX efficacy and toxicity using model-based approaches in MDR-TB patients. In total, 113 patients from 5 different clinical trials were analyzed for the development population pharmacokinetics (PK) model. A final PK model merged with previously developed...
Abstract Background Current TB treatment for children is not optimized to provide adequate drug levels in lesions. Dose optimization of first-line antituberculosis drugs increase exposure at the site disease could facilitate more optimal and future treatment-shortening strategies across spectrum with pulmonary TB. Objectives To determine concentrations intrathoracic Methods We quantified tissue samples from 13 children, median age 8.6 months, complicated forms requiring bronchoscopy or...
Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use few decades. However, its pharmacokinetic (PK) profile remains unclear. This study aimed to develop population PK model prothionamide and then apply the determine optimal dosing regimen MDR-TB patients. Multiple plasma samples were collected from 27 patients who had treated with at 2 different hospitals. Prothionamide was administered according weight-band dose (500 mg/day weight <50 kg 750 >50...
Abstract Sotorasib exhibits pH‐dependent solubility, making it susceptible to altered exposures when coadministered with acid‐reducing agents (ARAs). Several clinical studies were conducted investigate the impact of ARAs on sotorasib pharmacokinetics under different clinically relevant scenarios and identify potential mitigation strategies. Upon coadministration 960 mg 40 omeprazole fasted conditions, area concentration‐time curve (AUC) maximum observed plasma concentration (C max )...
Introduction: Recent research points to the Sigma Receptor (σR) as a possible neuromodulatory system with multi-functional action and σ 1 Rs have been suggested drug target for number of CNS conditions. Hexacyclododecylamines shown R activity provide an advantageous scaffold design that can improve blood-brain barrier permeability privileged structures. Methods Materials: A series oxa- aza- hexaxcyclododecylamines were synthesised evaluated sigma-1 receptor voltage-gated calcium channel...
The World Health Organization recommends pre-exposure prophylaxis (PrEP) for individuals at substantial risk of HIV infection. aim this analysis is to quantify the individual infection over time, using a large database high-risk (n = 5583). We used data from placebo recipients in five phase III PrEP trials: iPrEx, conducted men who have sex with and transgender women; VOICE, young women high sexual risk; Partners PrEP, serodiscordant heterosexual couples; TDF2, BTS, persons inject drugs....
Phase 2a trials in tuberculosis typically use early bactericidal activity (EBA), the decline sputum colony forming units (CFU) over 14 days, as primary outcome for testing efficacy of drugs monotherapy. However, cost phase can range from 7 to 19.6 million dollars on average, while more than 30% fail progress 3. Better utilizing preclinical data predict and prioritize most likely succeed will thus help accelerate drug development reduce costs. We aim clinical EBA using vivo...
Abstract The solubility of KRASG12C inhibitor sotorasib is pH dependent and coadministration with a proton pump (omeprazole) decreased maximum concentration (Cmax) by 56.9% the area under curve from time zero to last quantifiable (AUClast) 42.4% fasted conditions. This study in healthy volunteers evaluated if taking an acidic beverage such as Coca Cola would alter absorption when coadministered omeprazole improve exposure. Two separate phase 1, open-label, fixed sequence, 2-period studies...