Students
Mgambi Gideon Gamba
MSc Development of Drugs and Health Products / Paris Saclay University, France
PharMetrX Research+ Program
PhD student year: 2024
University of PhD: Freie Universität Berlin
Supervisor: Prof. Charlotte Kloft
Co-Supervisor: Prof. Wilhelm Huisinga
Mentoring I-Partner: Boehringer Ingelheim
PhD Project
Towards optimisation of anti-infective therapy: Leveraging complementary pharmacometric pproaches to unravel complex pharmacokinetics and its link to efficacy and safety in special populations
Invasive fungal infections (IFIs) remain one of the major causes of morbidity and mortality among critically ill and immunocompromised patients. Fungal pathogens pose a significant public health risk due to their increasing prevalence and resistance to treatment. Currently, there are only four classes of antifungal medications available, and there are limited new treatments in development.
Voriconazole (VRC) is a second-generation triazole with broad-spectrum antifungal activity. VRC works against clinically significant fungal pathogens, including invasive and pulmonary aspergillosis, as well as fluconazole-resistant candidiasis caused by Candida albicans, C. glabrata, and C. krusei. Additionally, VRC demonstrates efficacy against emerging pathogens, such as Scedosporium and Fusarium species. VRC is indicated for use in both adults and children aged 2 years and older. VRC is recommended as prophylaxis and first-line treatment for invasive aspergillosis in immunocompromised children with haematologic malignancies and allogeneic hematopoietic stem cell transplantation among other diseases. However, its use is associated with several adverse reactions, among which photosensitivity is particularly concerning, especially in paediatrics patients.
VRC exhibits nonlinear pharmacokinetics (PK), along with large inter- and intraindividual variability, and a narrow therapeutic index. Nonlinearity of VRC PK is largely caused by CYP3A4- , CYP2C19- and CYP2C9-mediated metabolism. VRC is an intensely metabolised drug, 98% of the administered dose undergoes mainly oxidative metabolism, while only 2% is excreted unchanged in the urine. However, the PK properties of the main metabolites of VRC, voriconazole N-oxide (NO) and hydroxy-voriconazole (OH-VRC), and their contributions to the efficacy and safety profile of VRC are not well characterised. In addition, VRC and its metabolites are both substrate and inhibitor of CYP3A4 and CYP2C19 and thus inhibiting their own metabolism. However, the extent and clinical implications of these inhibitory effects remain to be fully elucidated. As these isoenzymes are involved in the main metabolic pathways of many drugs, there is a considerable potential for drug interactions, including both inhibition and induction of VRC metabolism by other drugs.
There are significant differences between the PK of VRC in paediatric and adult populations, e.g., the reduced oral bioavailability of 44.6% in paediatric patients compared to 96.0% bioavailability observed in healthy adults. Moreover, VRC plasma exposure exhibits substantial intra- and interindividual variability, which is even more pronounced in paediatrics than in adults. Factors contributing to the large inter- and intra-patient variability of VRC PK include nonlinear PK, age, body size, cytochrome P450 2C19 polymorphisms, and variable oral bioavailability. Consequently, there is a growing need for additional paediatric PK investigations considering these factors using ontogeny functions.
Pharmacometric approaches, such as physiologically-motivated pharmacokinetic nonlinear mixed-effects (NLME) modelling, integrate data and knowledge from various sources, such as clinical trials, observational studies, in vitro or ex vivo or nonclinical investigations and literature in a coherent mathematical framework to represent the relevant processes in the body. Physiologically-based pharmacokinetic (PBPK) modelling is a powerful tool for exploring, and quantitatively predicting the PK of drugs and the magnitude of drug‐drug interactions (DDIs). This project will utilise a combination of “bottom-up” PBPK modelling and “top-down” NLME modelling and simulation techniques leveraging the so called “middle-out approach”, to (i) elucidate the PK characteristics of VRC and its main metabolites NO and OH-VRC, (ii) evaluate the safety profile of VRC by linking its complex PK to the observed pharmacodynamic photosensitivity effect, (iii) develop a comprehensive CYP219 and CYP3A4 drug-drug-gene-interaction (DDGIs) network for VRC, and (iv) extrapolate VRC PK to paediatric populations. Combining in vitro, in silico and in vivo data through complementary pharmacometrics approaches, the project will contribute to elucidate significant knowledge gaps in VRC PK and pharmacotherapy for special populations, e.g., paediatrics.
Publications
Please see the list of all publications and PhD theses.
Education
- 03/2024: Entering PharMetrX
- 02/2023-07/2023: Master thesis in the Clinical Pharmacology and Therapeutic group at University College London, UCL
- 05/2022-07/2022: Translational Research Intern at the National Institute of Health and Medical Research, INSERM
- 09/2021-07/2023: International Master’s in Development of Drugs and Health Products, D2HP at Paris Saclay University
- 07/2020-08/2021: Pharmacist at Abacus Pharma Africa, Tanzania
- 01/2019-06/2020: Regulatory officer at Tanzania Medicine and Medical Devices Authority, TMDA
- 11/2017-11/2018: Pharmacist Intern at Muhimbili National Hospital and Jakaya Kikwete Cardiac Institute
- 10/2013-09/2017: Bachelor of Pharmacy at Muhimbili University of Health and Allied Sciences