Browsing by Subject "Drug"

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    Open Access
    Nonlinear mixed-effects modelling of drug-drug interactions between antiretroviral therapy and tuberculosis treatment
    (2025) Kengo, Allan; Denti, Paolo; Resendiz Galvan, Juan Eduardo
    Human immunodeficiency virus (HIV) remains a significant global health challenge that affected approximately 39 million individuals in 2022, with majority residing in Africa. Among people with HIV (PWH), co-infection with tuberculosis (TB) is a leading cause of death. However, the concurrent treatment of HIV and TB often results in drug-drug interactions (DDIs), mediated especially by rifampicin, a key component of the TB regimen and potent enzyme and transporter inducer. These DDIs may compromise treatment safety and efficacy, potentially leading to therapeutic failure and increased risk of drug resistance. In this thesis, we utilized non-linear mixed effects modelling and data from studies in PWH and healthy volunteers to characterize DDIs between first- and second-line antiretroviral (ARV) and anti-TB drugs. Additionally, we performed simulations to assess treatment target attainment following current dosing recommendations in PWH. Our pharmacokinetic model of standard- and high-dose rifampicin in PWH identified lower bioavailability of the top-up capsule formulation as the cause of lower-than-expected drug exposures in participants on high-dose rifampicin. Furthermore, the reduced dolutegravir exposures in participants on concurrent high-dose rifampicin, compared to those on the standard-dose, were attributed to reduced bioavailability rather than enhanced clearance. Notably, our simulations demonstrated that doubling the dosing frequency of dolutegravir effectively counteracted the DDI with both standard- and high-dose rifampicin. Secondly, we characterized the DDI between ritonavir-boosted atazanavir (ATV/r) and rifampicin, both in plasma and within peripheral blood mononuclear cells (PBMCs). Rifampicin increased the clearance of ATV/r by threefold, and doubling the dosing frequency of ATV/r was sufficient to counteract this interaction and restore treatment target attainment. Notably, rifampicin did not affect atazanavir equilibration or accumulation in PBMCs, suggesting that plasma studies can reliably reflect intracellular processes. We also applied our model to an external dataset, estimating a twofold decrease in atazanavir clearance, likely due to ritonavir co-administration. Lastly, we found clofazimine, a second-line drug resistant TB (DR-TB) drug, to increase the clearance of levofloxacin by 15% but not affect the pharmacokinetics of cycloserine, linezolid, or isoniazid. This confirmed that clofazimine can be safely co-administered with other DR-TB drugs, as it poses minimal risk of significant DDIs. In conclusion, non-linear mixed effects modelling can be used to evaluate DDIs, and we recommend its incorporation in routine dose optimization and therapeutic drug monitoring programs to enhance treatment outcomes.
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    Open Access
    Repurposing quinoline-based (metallo) drug leads for the treatment of Leishmania major-induced cutaneous leishmaniasis
    (2025) Murwira, Takudzwa Emmanuel; Hurdayal, Ramona; Smith, Gregory
    Leishmaniasis is a vector-borne neglected tropical disease, of which cutaneous leishmaniasis is the most common form. There is a crucial need to develop new drugs for cutaneous leishmaniasis, as current drugs are sub-optimal due to parasite-specific drug resistance, drug-induced host toxicity and lengthy treatment. Repurposing existing drugs and/or compounds with established biological activity provides an attractive measure for antileishmanial drug development. For instance, N-heterocyclic molecules, such as quinolines and aminoquinolines, are commonly used as privileged scaffolds for developing antimalarial and anticancer drugs, which show enhanced activity when combined with metal complexes. This is exemplified by the iron-containing compound ferrocene, which has been shown to amplify the efficacy of several quinoline-based drug candidates. Accordingly, this study investigates the potential of repurposing ferrocenyl-quinoline compounds as potential drug candidates for the treatment of cutaneous leishmaniasis caused by Leishmania major LV39, focusing on in vitro antiparasitic activity and cytotoxicity, using murine and cell-based models of the disease. Four ferrocenyl-quinoline compounds consisting of the quinoline scaffold bonded to ferrocene via varying linkers (imino-alkyl, amino-alkyl, triazole amine and phenyl-alkene) were synthesised. The synthetic routes used to generate these compounds and their precursors consisted of nucleophilic aromatic substitution, Schiff base condensation, copper(I)-catalysed azide-alkyne cycloaddition and Mizoroki-Heck coupling. All the compounds were fully characterised using standard spectroscopic (1H,13C{1H} NMR and FT-IR spectroscopy) and analytical (mass spectrometry, melting point and elemental analysis) techniques. The four compounds and their precursors were assessed for their antileishmanial activity against the promastigote form of L. major LV39. The amino-alkyl and triazole amine-linked compounds were the most active (IC50 = 0.50 and 4.04 μg/ml, respectively), with the former being more active than the control drug amphotericin B (IC50 = 1.94 μg/ml). Generally, the four ferrocenyl-quinoline compounds had higher antileishmanial activity than their respective precursors. The cytotoxicity of the compounds was also assessed against the murine RAW 264.7 macrophage cell line, and all four compounds were observed to be more cytotoxic than amphotericin B (CC50 < 50 μg/ml). Although the amino-alkyl and triazole amine-linked compounds had the highest cytotoxicities (CC50 = 0.86 and 8.55 μg/ml, respectively), both compounds were more selective toward L. major promastigotes than their imino-alkyl and phenyl-amine counterparts (SI > 1), making them promising antileishmanial agents worthy of further investigation. This study not only delineates structure-based trends on antileishmanial activity but also demonstrates the significance of incorporating metals in drug design to enhance potency.