Browsing by Author "Boulou, Fanya"

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    Population pharmacokinetics of ethionamide and ethionamide sulfoxide in patients with multidrug-resistant tuberculosis
    (University of the Western Cape, 2025) Boulou, Fanya
    Tuberculosis (TB) remains an infectious disease worldwide and the leading killer of people living with HIV; yet it is curable. One of the challenges faced in TB therapy is the resistance of Mycobacterium tuberculosis to antituberculosis drugs, leading to drug-resistant tuberculosis (DR-TB). Various types of DR-TB resulted from antimicrobial resistance; up-to date, multidrug-resistant tuberculosis (MDR-TB) is the predominant type of DR-TB, thus the focus of the current study. MDR-TB developed following resistance of the Mycobacterium tuberculosis to rifampicin and isoniazid, which are the two most potent first-line antituberculosis drugs. It is currently treated with a choice of regimens: a short, all-oral 6-month regimen, a 9-month all-oral regimen containing ethionamide, and longer individualized regimens. Ethionamide needs to be activated by mycobacterial enzymes to exert its antimicrobial activity. Ethionamide sulfoxide, its active metabolite, displays a similar or greater activity against Mycobacterium tuberculosis; yet there is limited pharmacokinetic literature on ethionamide sulfoxide, unlike ethionamide which has been studied for more than five decades. This study aimed at determining the population pharmacokinetics of ethionamide and ethionamide sulfoxide, assessing the effect of HIV status, antiretroviral drugs, age, weight, gender, and renal and hepatic functions on their respective pharmacokinetic parameters. The study also aimed at determining the amount of ethionamide sulfoxide that emanated from ethionamide metabolism in the body. Methods: After signing an informed written consent, male and female patients with MDR- TB, co-infected or not with HIV, who were on treatment for at least two weeks at Brewelskloof Hospital (Western Cape, South Africa), were involved in the study. On the day of the study, after an 8-hour overnight fast, each patient received his/her medications, including 500 mg or 750 mg dose of ethionamide as determined by the doctor in charge. Blood samples were collected at baseline and 1, 2, 2.5, 3, 3.5, 4, 5, 8 and 24 h post drug administration. Using a developed and validated ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS), ethionamide and ethionamide sulfoxide were simultaneously quantified in patients’ plasma. Ethionamide and ethionamide sulfoxide pharmacokinetic parameters were first determined through non-compartmental analysis (NCA) using PKanalix2023R1 and compared.