Browsing by Subject "pharmacokinetics"

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    Open Access
    A scoping review on the use of telerehabilitation in physiotherapy in low and middle income countries
    (2025) Ndzamba, Bonginkosi; Denti, Paolo; Resendiz Galvan, Juan Eduardo
    Introduction: Ethambutol is a bacteriostatic drug, administered as part of a fixed-dose combination regimen for the treatment of tuberculosis (TB). Individuals with comorbid HIV have reported reduced serum concentrations of ethambutol. We aimed to evaluate the pharmacokinetics of ethambutol in individuals with both drug-susceptible TB and HIV, identify covariates that influence ethambutol pharmacokinetics, and evaluate the current World Health Organization's (WHO) ethambutol dosing recommendations. Method: We used pharmacokinetic data from the TB-HAART open-label trial that investigated the outcomes of individuals with dual TB and HIV infections treated with first-line anti-TB drugs and antiretroviral therapy (ART). Modelling and simulation was performed using nonlinear mixed-effects modelling in the software NONMEM®. Results: A two-compartment disposition model with transit absorption best fitted the pharmacokinetic data. Allometry using fat-free mass and weight best scaled disposition parameters for body size for the final model. The typical clearance of ethambutol was 34.8 L/h. The Antib-4® formulation of ethambutol showed a 27.8% reduction in bioavailability and a 37.1% increase in mean transit time compared to the e-275 Rifafour® formulation. Creatinine clearance, presence of ART from day 13, and CD4+ T-cell count were also tested but did not improve the model fit. Our simulations showed that, with the current WHO fixed-dose combination regimen, individuals with weight 55 kg weight bands. Therefore, to balance exposures we proposed an additional 275 mg ethambutol dose. Similarly, our simulations suggest that the multidrug-resistant TB WHO 400 mg strength under-exposes patients with weight <54.9 kg had lower exposure to ethambutol 275 mg tablet strength than those in >55 kg weight bands. Therefore, to balance exposures we proposed an additional 275 mg ethambutol dose. Similarly, our simulations suggest that the multidrug-resistant TB WHO 400 mg strength under-exposes patients with weight <46.9 kg, which could be addressed by increasing the dose by 400 mg. Conclusion: We developed a model for ethambutol and observed that different formulations of ethambutol affected its bioavailability and absorption. Our simulation results indicated that individuals weighing less than 55 kg with drug-susceptible TB and those weighing less than 46 kg with multidrug-resistant TB are at risk of being underdosed. To ensure improved therapeutic outcomes for these individuals, a proposed dose optimization is a more effective solution.
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    Open Access
    Pharmacometrics to characterize pharmacokinetics and optimize treatment in understudied populations
    (2025) Gebreyesus, Manna Semere; Denti, Paolo; Wasmann, Roeland E
    Clinical trials frequently exhibit a lack of participant diversity, with underrepresentation of certain demographics, including pregnant women, individuals at the extremes of age (such as children or the elderly), and specific racial or ethnic groups (such as people of African ancestry). Consequently, suitable dose labeling is lacking at the time of drug approval for these groups, leaving healthcare practitioners with a dilemma: either exclude these groups from treatment or make dosing recommendations based on data from a potentially non-representative population, posing a risk of suboptimal or toxic treatment outcomes. Post-marketing pharmacokinetic studies in these populations are challenging due to low consent rates, difficulties with frequent blood sampling, unbalanced study designs resulting from the opportunistic nature of such studies, or resource constraints in developing countries, all contributing to sparse data. Pharmaceutical companies may also lack the incentive to invest in these studies when the medication's market performance is already stable and there is no immediate return on investment. In this thesis, I apply pharmacometrics for understudied populations with limited data across various therapeutic areas, including: optimizing dose of cefazolin, an antibiotic used forsurgical site infection prophylaxis, in children undergoing cardiac surgery with cardiopulmonary bypass; optimizing dose of rifabutin, an antibiotic used for TB, during lopinavir/ritonavir (LPV/r)-co treatment in children with TB-HIV co-infection; showcasing a model-based adherence monitoring tool using enalapril, an angiotensin-converting enzyme inhibitor for hypertension and heart failure, in a small cohort of African heart failure patients, and characterizing pharmacokinetics of esomeprazole, a proton pump inhibitor for hyperacidity and being investigated for preeclampsia, in patients with preterm preeclampsia. Using data contributed by 22 children on cefazolin, Isuggested a continuous infusion regimen for bypass surgeries, which improves the probability of target attainment compared with the intermittent weight-based regimen used in clinical settings. Using data from 28 children on rifabutin, I developed a parent-metabolite model to assess the weight-based dosing used in the studies, proposing a weight-band based regimen for rifabutin without and with LPV/r for controlled exposures across age groups. For enalapril, I devised a model-based adherence assessment method based on data from 30 adults, including 6 African heart failure patients, which improves adherence monitoring since it considers variations in pharmacokinetics and dosing schedules. Finally, I used modelling to identify pharmacokinetic changes in esomeprazole during pregnancy using data from 59 adults(including 10 pregnant) on esomeprazole. In summary, using pharmacometrics, I could interpret limited data from understudied populations to characterize pharmacokinetics, evaluate existing practices and guide the consideration of alternative dosing scenarios
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    Open Access
    Population/ Nonlinear mixed-effects modelling of pharmacokinetics and pharmacodynamics of tuberculosis treatment
    (2018) Chirehwa, Maxwell Tawanda; Denti, Paolo; Mcilleron, Helen
    The pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in TB/HIV coinfected patients recruited in two phase III clinical trials (61 patients in TB-HAART and 222 patients in RAFA study) were described using nonlinear mixed-effects modelling. Concentration-time data for rifampicin (TB-HAART study) was used to develop a semimechanistic pharmacokinetic model incorporating autoinduction and saturable pharmacokinetics. A model describing the pharmacokinetics of pyrazinamide (TB-HAART study) was developed and used to evaluate the 24-hour area under the concentration-time curve (AUC0–24), and maximum concentrations (Cmax) achieved with the currently recommended weight-adjusted doses for drug-susceptible and -resistant tuberculosis. Concentration-time data from the RAFA study were used to characterise the pharmacokinetics of the four drugs of the fixed dose combination (FDC) therapy including desacetyl-rifampicin, and acetyl-isoniazid. Binary recursive techniques were applied in the conditional inference framework to determine predictors including drug exposure of time-to-stable culture conversion and poor long-term treatment outcomes. The model describing the pharmacokinetics of rifampicin predicted that increasing the dose results in a more than proportional increase in exposure. Clearance of rifampicin increased by 90% from baseline to steady-state due to autoinduction and the process takes up to 21 days. Monte Carlo simulations showed that rifampicin doses of at least 25 mg/kg would be required to achieve an AUC0–24/MIC ratio of at least 271. Based on the model describing the pharmacokinetics of isoniazid, co-administration of isoniazid and efavirenz-based antiretroviral therapy results in a 54% reduction in isoniazid exposure only in fast acetylators. There were disparities in exposure across weight bands for all the four drugs: patients with lower weight had reduced exposure. To match drug exposure across the weight bands, we recommend the addition of one FDC tablet to patients with weight less than 55 kg. There is need to explore the use of fat-free mass-adjusted dosing since cumulative evidence shows its superiority over total body weight in driving exposure via allometric scaling for all first-line antituberculosis drugs. Individual drug exposures were not predictive of either time-to-stable culture conversion or long-term tuberculosis treatment outcomes. Baseline X-ray grading, HIV stage as TB diagnosis, and treatment arm were predictive of time-to-stable culture conversion while the presence of cavities, patient’s level of physical activity and CD4 count were the drivers of long-term treatment outcomes.