Browsing by Author "Garcia-Prats, Anthony Joseph"

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    Addressing critical knowledge gaps to improve and shorten multidrug-resistant tuberculosis treatment regimens in children
    (Stellenbosch : Stellenbosch University, 2018-12) Garcia-Prats, Anthony Joseph; Hesseling, Anneke Catharina; Schaaf, Hendrik Simon; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
    ENGLISH ABSTRACT: Multidrug-resistant (MDR) tuberculosis (TB), defined as TB disease or infection caused by Mycobacterium tuberculosis with resistance to at least both isoniazid and rifampicin, threatens global TB control, with an estimated 490,000 incident cases of MDR-TB globally in 2016. The burden of paediatric MDR-TB has been poorly characterized to date. However, recent modeling studies estimate that there are approximately 26,000- 32,000 incident MDR-TB cases in children (< 15 years of age) worldwide each year. Traditionally, treatment regimens for adults and children were constructed using a minimum of four second-line antituberculosis drugs likely to be effective, including a second-line injectable medication, for up to 6 months, and a total duration of treatment of up to 18-24 months. In 2016, the World Health Organization (WHO) recommended a shortened (9-12 month) treatment regimen, which still includes an injectable drug for four months. In addition, the development and increasing use of the novel TB drugs bedaquiline and delamanid, are radically altering the MDR-TB treatment landscape, although children have lagged behind in accessing these important developments. Treatment outcomes for adults with MDR-TB have been persistently poor, with 54% successfully treated in 2014 both overall globally, and in South Africa. In contrast, treatment outcomes among children with MDR-TB are generally good, with 78-90% successfully treated under routine clinical conditions. However, current paediatric MDR-TB treatment regimens have important limitations. These current regimens remain long (9-18 months or more), which is costly and burdensome. There are also frequent adverse effects, including from the second-line injectable medications (amikacin, kanamycin, capreomycin) that cause permanent sensorineural hearing loss in up to 24% of children treated long-term. Additionally, the injectables are mainly given by painful daily intramuscular injections, resulting in trauma and distress for patients, their caregivers and healthcare providers. Therefore, it is an urgent priority to develop more optimal treatment regimens for children with MDR-TB that retain their efficacy but are shorter, more child-friendly, are better tolerated, safer and which do not require the use of an injectable medication. The purpose of this doctoral research was to address critical knowledge gaps in paediatric MDR-TB treatment, with the aim of informing more effective, safer, and more child-friendly MDR-TB treatment strategies in children. I identified critical knowledge gaps related to the pharmacokinetics, including the effects of formulation, optimal dosing, safety, and tolerability of key second-line and novel antituberculosis drugs in children, and completed complementary studies on ofloxacin, levofloxacin, linezolid, amikacin and bedaquiline designed to address these knowledge gaps. In an observational study of the pharmacokinetics and safety of ofloxacin in children routinely treated for MDR-TB disease or exposure, exposures after a daily 20mg/kg ofloxacin dose were well below target exposures from adults receiving the routine 800 mg dose. Ofloxacin was safe and well tolerated, with few musculoskeletal complaints or serious adverse events. This data adds to the evidence of the safety of fluoroquinolones in children even with long-term use, and identifies the need to revise ofloxacin paediatric doses. Subsequently, in this large observational study, the population pharmacokinetics of levofloxacin among children with MDR-TB disease or exposure was characterized using non-linear mixed effects modeling. One hundred and nine children treated with the routinely available adult 250 mg tablet formulation of levofloxacin at daily doses of 15 mg/kg or 20 mg/kg were included. Levofloxacin’s apparent oral clearance (CL/F) was higher than expected based on previously published data, possibly due to the formulation studied. Simulations using the final model targeting exposures in adults with TB receiving 750 mg of levofloxacin identified weight-banded doses that were much higher than previously in use (18 mg/kg to nearly 40 mg/kg daily). It was concluded that levofloxacin dosing in children should be reassessed, formulation effects explored further, and that safety should be carefully evaluated if higher levofloxacin doses are used. Building on this data, I completed an evaluation of the safety of long-term levofloxacin in children treated for MDR-TB. Among 70 children, median age 2.1 years, treated for a median of 11.6 months, levofloxacin was generally safe and was well tolerated. There were no Grade 4 or serious adverse events, and few musculoskeletal events. There was no QT-interval prolongation and no association of QT interval with levofloxacin concentration. This study supported the safety of long-term fluoroquinolone treatment in children, and provided novel data on the QT prolonging effect of levofloxacin, which is needed, as increasingly levofloxacin is being combined with other QT prolonging medications. The effects of drug formulation in pharmacokinetic studies are critically important. In a lead-in pharmacokinetics study to the TB-CHAMP trial (phase 3 cluster randomized trial comparing levofloxacin vs. placebo for prevention of TB in child contacts of MDR-TB cases), 24 children had pharmacokinetic sampling with a novel dispersible tablet formulation of levofloxacin. The levofloxacin exposures were much higher with this novel formulation compared to those seen in the previously reported study using the adult 250 mg levofloxacin tablet. Combining these two data sets using non-linear mixed effects modeling identified that reduced bioavailability of the adult 250 mg tablet formulation compared to the dispersible levofloxacin tablet was the explanation for the substantial differences in exposures. This study highlighted the importance of formulation considerations to paediatric pharmacokinetic studies and provided practical weight-banded dosing guidelines for use of this formulation now becoming available in the field. Linezolid is a key drug with an increasingly important role in the treatment of MDR-TB strains with additional resistance and in central nervous system TB disease. I performed a structured review of the literature on linezolid to inform its use in children for MDR-TB treatment and identify knowledge gaps for future research. Few children treated with linezolid for MDR-TB were described in the literature. As in adults, linezolid appeared to be effective but was associated with frequent adverse events. There was no data on linezolid pharmacokinetics in children with TB. Practical interim guidance was provided for linezolid use in children. Priority research needs identified included studying linezolid pharmacokinetics in children with TB, characterization of its safety with long-term use, and its optimal dose for TB in MDR-TB regimens going forward. Following on this review, an analysis of linezolid pharmacokinetics and safety from children with MDR-TB was performed with data from 48 children combined from two observational studies using non-linear mixed effects modeling. Seventeen children received long-term linezolid and were monitored longitudinally for safety; 31 children only contributed cross-sectional pharmacokinetic data after a single-dose of linezolid. After accounting for the effects of weight with allometric scaling, no other covariates significantly contributed to the model. Exposures were higher than expected, based on previously reported data. Ten of 17 participants had a linezolid related adverse event, including five Grade 3 or 4 events; anaemia was the most common event. This first data on linezolid pharmacokinetics in children demonstrated higher than expected exposures and frequent, serious linezolid-related adverse events, and will inform the use and future dosing recommendations of this increasingly important antituberculosis medication in children. While drug substitutions for injectable drugs are not yet available for many children, improving the tolerability of the continued use of second-line injectable medications is an important question to address in children. A randomized two-period crossover study was designed to characterize the effect of co-administration of lidocaine on the pain and pharmacokinetics of intramuscular amikacin. Children each received a dose of amikacin with and without additional lidocaine on separate days, and were randomized to the sequence of treatments; pain assessments and pharmacokinetic sampling were performed on each day. Twelve children were enrolled and completed the study. The addition of lidocaine reduced pain immediately after the injection, was safe, and did not affect the pharmacokinetics of amikacin in children, and should be considered as a routine policy in patients with MDR-TB receiving an injectable agent. The novel drug bedaquiline is increasingly used globally and in South Africa for adults with MDR-TB, and ongoing paediatric trials will characterize the pharmacokinetics, safety and optimal dose in children. The paediatric formulation, which is being evaluated in at least one of the ongoing paediatric trials, may not be available for routine care for some time. In order to inform the rational use of the adult bedaquiline formulation in young children, a randomized two-period crossover study in healthy adult volunteers was designed. Adult bedaquiline tablets administered suspended in water were bioequivalent to adult tablets swallowed whole. The suspended tablets were also found to be acceptable and palatable to the majority of participants, an important finding considering that crushing or suspending some tablets, such as the fluoroquinolones, reduces their palatability and acceptability substantially. This data will accelerate access to bedaquiline for young children in research and routine care. In conclusion, this doctoral research has addressed a number of important key knowledge gaps related to more optimal paediatric MDR-TB treatment. This research has raised a number of follow-up questions that have informed subsequent studies that will continue to advance the field towards a goal of effective, safe, shorter MDR-TB treatment for all children.