Browsing by Author "Mcilleron, Helen"
Now showing 1 - 3 of 3
Results Per Page
Sort Options
- ItemOpen AccessA pharmacometric approach to optimal use of second line drugs for multidrug-resistant tuberculosis(2023) Court, Richard Gray; Mcilleron, Helen; Maartens, GaryUntil the recent introduction of short course regimens, treatment regimens for multidrug resistant TB (MDR-TB) were long and toxic. Consequently, only approximately half of MDRTB patients completed their treatment. TB dosing guidelines have historically been unrefined with little consideration for pharmacokinetic/pharmacodynamic relationships. Large knowledge gaps therefore exist in the understanding of pharmacokinetic/pharmacodynamic relationships for both efficacy and toxicity in MDR-TB. My PhD used clinical pharmacology approaches to improve the understanding of drug exposures, toxicity, and exposure-toxicity relationships during the first 12 weeks of MDR-TB therapy. Aims and methods 1. Using non-compartmental analyses, describe the pharmacokinetics of cycloserine and, using regression modelling, explore the association of covariates with cycloserine exposure. 2. Using validated screening tools, describe the incidence of neuropsychiatric toxicity in MDR-TB patients, and explore associations with cycloserine pharmacokinetics. 3. Using a validated pain-rating scale in a crossover study design, investigate whether the addition of a local anaesthetic reduces kanamycin-related injection pain, and explore effects on kanamycin pharmacokinetics. 4. Using geometric mean ratios, compare the exposures of crushed versus whole formulations of pyrazinamide, moxifloxacin, ethionamide, ethambutol, cycloserine, and isoniazid. Results and conclusions We found no measurable terizidone in plasma supporting the hypothesis that terizidone is hydrolysed pre-systemically to cycloserine. The cycloserine time-concentration profile supports once daily dosing of terizidone. We describe a high incidence of peripheral neuropathy in MDR-TB patients with both cycloserine clearance and high-dose pyridoxine significantly associated with neuropathy on multivariate analysis. The addition of a local anaesthetic reduced the pain experienced by MDR-TB patients in the first 15 minutes post intramuscular administration of kanamycin, which could improve adherence to MDR-TB treatment. We also found the bioavailability of crushed isoniazid to be approximately 42% less than the whole tablet formulation, and therefore recommend that the crushing of isoniazid be avoided. Although some recent treatment advances have improved MDR-TB outcomes, enhancing the understanding of drugs used to treat MDR-TB, which continues to have an unacceptably high mortality and treatment-related morbidity, is a public health priority. This thesis comprises four peer-reviewed publications, all of which made a pragmatic contribution to the fight against MDR-TB.
- ItemOpen AccessPopulation pharmacokinetic modelling to address the gaps in knowledge of commonly used HIV and TB drugs in children(2021) Tikiso, Tjokosela; Denti, Paolo; Mcilleron, HelenThe epidemiology of HIV and TB are overlapping, particularly in sub-Saharan Africa, and TB infection remains common in HIV-positive children. The combined administration of anti-tubercular and antiretroviral therapies(ART) may lead to drug-drug interactions potentially needing to be addressed with the adjustment of doses. This thesis assessed the pharmacokinetics of abacavir and ethambutol and evaluated the influence of covariates such as age and concomitant medication on the PK parameters across different studies using nonlinear mixed-effects modelling. The models developed were used to estimate area under the concentration-time curve (AUC) and maximum concentrations (Cmax) achieved with the currently-recommended weight-adjusted doses. A web-based paediatric dosing tool, which is meant to be used as a first step in the design of clinical trials for paediatric dosing was also developed. The model describing the pharmacokinetics of abacavir found: a) abacavir exposure to be 18.4% larger (CI:7.50-32.2) after the first dose of ART compared to abacavir co-treated with standard lopinavir/ritonavir for over 7 days, possibly indicating that clearance is induced with time on ART, b) malnourished HIV infected children had much higher exposures but this effect waned with a half-life of 12.2 (CI: 9.87-16.8) days as children stayed on nutritional rehabilitation and recovered, c). during co-administration of rifampicin-containing antituberculosis treatment and super-boosted lopinavir/ritonavir, abacavir exposure was decreased by 29.4% (CI: 24.3-35.8), d) children receiving efavirenz had 12.1% (CI: 2.57-20.1) increased abacavir clearance compared to standard lopinavir/ritonavir. The effects did not result in abacavir exposures lower or higher than those reported in adults and are not likely to be clinically important. The ethambutol model found lower concentrations than those reported in adults. The predicted ethambutol median (IQR) Cmax was 1.66 (1.21-2.15) mg/L for children on ethambutol with or without ART (excluding super-boosted lopinavir/ritonavir) and 0.882 (0.669-1.28) mg/L for children on ethambutol with super-boosted lopinavir/ritonavir, these are below the lower limit of the recommended Cmax range of 2 mg/L. During co-administration with super-boosted lopinavir, ethambutol exposure was decreased by 32% (CI: 23.8-38.9), likely due to drug-drug interaction involving absorption, metabolism or elimination. Bioavailability was decreased in children who were administered ethambutol in a crushed form, with an estimate decrease of 30.8% at birth, and an increase of 9.6% for each year of age up to 3.2 years where bioavailability was now similar to children taking EMB full tablet. The developed paediatric dosing tool contains two major sections. a) the ‘generic module’ which uses allometric scaling -based predictions to explore the expected AUC for a generic drug, b) the ‘drug-specific module’ which can simulate entire pharmacokinetic profiles (concentration over time after dose) by using a drug-specific population pharmacokinetic model. In summary, under the current weight-adjusted doses, abacavir exposure remained within the adult recommended levels. Ethambutol dose adjustment would be required in order to achieve adult exposures. A web-based paediatric dosing tool that uses allometric scaling -based predictions as well as drug specific predictions based on published pharmacokinetic models was successfully developed.
- ItemOpen AccessPopulation/ Nonlinear mixed-effects modelling of pharmacokinetics and pharmacodynamics of tuberculosis treatment(2018) Chirehwa, Maxwell Tawanda; Denti, Paolo; Mcilleron, HelenThe 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.