Addressing critical knowledge gaps to improve and shorten multidrug-resistant tuberculosis treatment regimens in children

Garcia-Prats, Anthony Joseph (2018-12)

Thesis (PhD)--Stellenbosch University, 2018.

Thesis

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.

AFRIKAANSE OPSOMMING: Multimiddel-weerstandige (MMW) tuberkulose (TB), wat gedefinieër word as as TB siekte of infeksie wat veroorsaak word deur Mycobacterium tuberculosis met weerstandigheid teen ten minste isoniasied en rifampisien, bedreig wêreldwye TB beheer, met ‘n geskatte 490,000 nuwe gevalle van MMW-TB wêreldwyd in 2016. Die lading van pediatriese MMW-TB is tot op hede swak omskryf. Onlangse modeleringstudies beraam egter dat daar elke jaar ongeveer 26,000-32,000 nuwe MMW-TB gevalle in kinders (<15 jaar oud) wêreldwyd voorkom. Tradisioneel was die behandelingsregimens vir volwassenes en kinders saamgestel deur ‘n minimum van vier waarskynlik effektiewe tweede-linie antituberkulosemiddels te gebruik, insluitend ‘n tweede-linie inspuitbare middel vir tot 6 maande en totale behandelingsduur van tot 18-24 maande. In 2016 het die Wêreldgesondheidsorganisasie (WGO) ‘n verkorte (9-12 maande) behandelingsregimen, wat steeds ‘n inspuitbare middel vir 4 maande ingesluit het, aanbeveel. Hierby het die ontwikkeling en toenemende gebruik van die nuwe TB middels, bedakwilien en delamanid, gelei tot radikale veranderinge in die MMW-TB omgewing, alhoewel kinders in die toegang tot hierdie belangrike ontwikkelinge agtergebly het. Die uitkomste van behandeling van MMW-TB in volwassenes was aanhoudend swak met 54% suksesvolle behandeling in 2014 beide algeheel globaal, sowel as in Suid- Afrika. In teenstelling hiermee is die uitkomste van behandeling in kinders met MMWTB oor die algemeen goed, met 78-90% suksesvolle behandeling onder roetine kliniese sorg. Huidige pediatriese MMW-TB behandeling het egter belangrike beperkings. Die huidige behandeling bly egter van lange duur (9-18 maande of langer) wat dit duur en moeilik maak. Daar is ook dikwels nadelige gevolge, soos byvoorbeeld permanente sensorineurale gehoorsverlies in tot 24% van kinders wat langtermyn behandeling ontvang en wat deur die tweede-linie inspuitbare middels (amikasien, kanamisien, kapreomisien) veroorsaak word. Daarby word die inspuitbare middels hoofsaaklik per pynlike binnespierse inspuiting toegedien wat trauma en angstigheid in die pasiënt, die versorger en die gesondheidsverskaffers veroorsaak. Daarom is dit ‘n belangrike prioriteit om meer optimale behandelingsregimens vir kinders met MMW-TB te ontwikkel wat hulle effektiwiteit behou, van korter duur en meer kindervriendelik is, wat beter verduur word, veiliger is en wat nie enige inspuitbare middels bevat nie. Die oogmerk van hierdie doktorale navorsing was om kritieke kennisleemtes in die behandeling van pediatriese MMW-TB aan te spreek, met die doel om meer effektiewe, veiliger en meer kindervriendelike MMW-TB behandelingstrategieë in kinders toe te lig. Ek het kritieke kennisleemtes verwant aan die farmakokinetika, insluitend die effek van formulerings, optimale dosering, veiligheid en verdraagsaamheid van sleutel tweedelinie en nuwe antituberkulose middels in kinders geïdentifiseer en het komplimentêre studies oor ofloksasien, levofloksasien, linezolied, amikasien en bedakwilien ontwerp om hierdie kennisleemtes aan te spreek. In ‘n waarnemingstudie oor die farmakokinetika en veiligheid van ofloksasien in kinders wat normaalweg vir MMW-TB siekte of blootstelling behandel is, was die blootstellingsvlakke na ‘n daaglikse dosis van 20 mg/kg ofloksasien duidelik laer as die teikenblootstellingsvlakke wat bereik word deur volwassenes wat ‘n roetine dosis van 800 mg ontvang. Ofloksasien was veilig en is goed verduur met min muskuloskeletale klagtes of ernstige nadelige gevolge. Hierdie inligting dra by tot die bewyse dat die fluorokwinolone veilig is in kinders selfs met langtermyn gebruik en toon die behoefte aan om die pediatriese dosisse van ofloksasien te hersien. Hierna, in hierdie groot waarnemingstudie, is die populasiefarmakokinetika van levofloksasien in kinders met MMW-TB siekte of blootstelling bepaal deur die nielineêre gemengde-effekte modeleringstegniek te gebruik. Eenhonderd-en-nege kinders wat met die normaalweg beskikbare volwasse-formulering 250mg levofloksasien tablette behandel is met ‘n daaglikse dosis van 15 mg/kg of 20 mg/kg, is ingesluit. Levofloksasien se oënskynlike mondelingse opruiming (CL/F) van levofloksasien was hoër as wat verwag was volgens vorige gepubliseerde inligting, moontlik as gevolg van die formulering wat bestudeer is. Simulasies wat die finale model gebruik het wat blootstellingsvlakke in volwassenes wat 750 mg levofloksasien ontvang, geteiken het, het gewigsgebaseerde dosisse geïdentifiseer wat baie hoër is as wat voorheen gebruik is (18 mg/kg tot byna 40 mg/kg daagliks). Daar is tot die slotsom gekom dat levofloksasiendoserings in kinders hersien moet word, formuleringseffekte verder ondersoek moet word en dat, as hoër doserings van levofloksasien gebruik sou word, veiligheid versigtig nagegaan moet word. Op grond van hierdie inligting het ek die veiligheid van die langtermyngebruik van levofloksasien in kinders met MMW-TB bestudeer en voltooi. In 70 kinders, mediane ouderdom 2.1 jaar, wat behandel is vir ‘n mediane duur van 11.6 maande, was levofloksasien oor die algemeen veilig en is dit goed verduur. Geen Graad 4 of ernstige nadelige effekte het voorgekom nie en net enkele muskuloskeletale effekte het voorgekom. Geen verlenging van QT-interval het voorgekom nie en daar was geen verband waargeneem tussen levofloksasienkonsentrasies en QT-intervalle nie. Hierdie studie het die veiligheid van die langtermyn-gebruik van fluorokwinoloon-behandeling in kinders ondersteun en het nuwe inligting oor die QT-verlengingseffek van levofloksasien verskaf wat baie nodig is, want levofloksasien word toenemend tesame met ander QT-verlengende middels aangewend. Die effekte van middelformulerings in farmakokinetikastudies is van kritiese belang. Tydens ‘n inleidende farmakokinetikastudie vir die TB-CHAMP studie (fase-3 cluster ewekansige studie wat levofloksasien met plasebo vergelyk vir die voorkoming van TB in kinderkontakte van MMW-TB gevalle) het 24 kinders farmakokinetiese monsterneming gehad tydens die gebruik van ‘n nuwe oplosbare tablet van levofloksasien. Die levofloksasien blootstellingsvlakke was baie hoër met hierdie nuwe formulering in vergelyking met dié wat in die vorige studie met die gebruik van die 250 mg volwasse tablette gevind is. Deur hierdie twee inligtingstelle te kombineer deur gebruik te maak van die nie-lineêre gemengde-effekte modeleringstegniek, het dit geblyk dat die verminderde biobeskikbaarheid tussen die volwasse 250 mg tablette en die oplosbare levofloksasien tablette die rede is vir die aansienlike verskil in blootstellingsvlakke. Hierdie studie het die belangrikheid van middelformulerings oorwegings in pediatriese farmakokinetika beklemtoon en het praktiese gewigsgebaseerde doseringsriglyne daargestel vir die gebruik van hierdie formulering wat nou in die veld beskikbaar raak. Linezolied is ‘n sleutelmiddel met ‘n toenemend belangrike rol in die behandeling van MMW-TB stamme met bykomende weerstandigheid sowel as in sentraal senuweestelsel TB siekte. Ek het ‘n gestruktureerde oorsig van die literatuur oor linezolied onderneem om duidelikheid te kry oor die gebruik daarvan in kinders met MMW-TB en om kennisleemtes vir toekomstige navorsing te identifiseer. Slegs enkele kinders wat behandel is vir MMW-TB is in die literatuur opgeteken. Soos in die geval van volwassenes, het linezolied effektief blyk te wees, maar was met gereelde nadelige effekte geassosieer. Daar was geen inligting oor oor die farmakokinetika van linezolied in kinders met TB beskikbaar nie. Praktiese tussentydse riglyne vir die gebruik van linezolied in kinders is voorsien. Navorsingsprioriteite wat geïdentifiseer is, het linezolied farmakokinetika in kinders met TB, kenmerke van linezolied se veiligheid met langtermyn gebruik en sy optimale dosering vir TB in MMW-regimens vorentoe, ingesluit. Na hierdie oorsig is ‘n analise van linezolied-farmakokinetika en veiligheid in kinders met MMW-TB gedoen met inligting verkry van 48 kinders saamgevat uit twee waarnemingstudies deur gebruik te maak van nie-lineêre gemengde-effekte modelering. Sewentien kinders het langtermyn linezolied ontvang en is longitudinaal vir veiligheid opgevolg; 31 kinders het slegs deursnit farmakokinetiese inligting na ‘n enkeldosis linezolied verskaf. Na die effek van gewig met behulp van ‘n allometriese skaal in bereking gebring is, het geen ander medevariante betekenisvol tot die model bygedra nie. Blootstellingsvlakke was hoër as wat verwag was in vergelyking met vorige gerapporteerde inligting. Tien van 17 deelnemers het ‘n linezolied-verwante nadelige effek getoon, wat vyf Graad 3 of 4 effekte ingesluit het; anemie was die mees algemene effek. Hierdie eerste inligting oor linezolied-farmakokinetika in kinders het hoër as verwagte blootstellingsvlakke en gereelde, ernstige linezolied-verwante nadelige effekte aangetoon; dit sal die gebruik en toekomstige doseringsaanbevelings van hierdie toenemend-belangrike antituberkulose middel toelig. Terwyl middelvervangings vir die inspuitbare middels vir baie kinders nog nie beskikbaar is nie, is dit belangrik om die verbeterde verduring van die voortgesette gebruik van die tweede-linie inspuitbare middels in kinders aan te spreek. ‘n Ewekansige twee-periode oorkruis-studie is ontwerp om die effek van mede-toediening van lidokaïen op die pyn en farmakokinetika van binnespierse amikasien te bepaal. Kinders het elk ‘n dosis van amikasien met en sonder addisionele lidokaïen op aparte dae ontvang en was ewekansig vir die volgorde van toediening ingedeel; pynevaluering en monsterneming vir farmakokinetika is op beide dae uitgevoer. Twaalf kinders is ingesluit en almal het die studie voltooi. Die toevoeging van lidokaïen het die pyn onmiddelik na die toediening van die inspuiting verlig, was veilig, het nie die farmakokinetika van amikasien beïnvloed nie en behoort as roetine beleid in pasiënte met MMW-TB wat inspuitbare middels ontvang, oorweeg te word. Die nuwe middel bedakwilien word toenemend wêreldwyd en in Suid-Afrika vir die behandeling van volwassenes mt MMW-TB gebruik en voortgesette pediatriese studies sal die farmakokinetika, veiligheid en optimale dosering in kinders toelig. Die pediatriese formulering wat in ten minste een van die voortgesette studies evalueer word, sal moontlik nie binnekort vir roetinegebruik beskikbaar wees nie. Om die rasionele gebruik van die volwasse bedakwilienformulering in jong kinders toe te lig, is ‘n ewekansige twee-periode oorkruis-studie in gesonde volwasse vrywilligers ontwerp. Volwasse bedakwilien-tablette toegedien opgelos in water was bioekwivalent aan volwasse tablette wat heel ingesluk is. Die opgeloste tablette was ook aanvaarbaar en smaakaanvaarbaar vir die meerderheid van die deelnemers wat ‘n belangrike bevinding is as inaggeneem word dat die fyndruk en oplos van sommige tablette, soos byvoorbeeld die fluorokwinolone, die smaak en aanvaarbaarheid aansienlik verminder. Hierdie inligting sal toegang tot bedakwilien vir jong kinders in navorsing en in algemene sorg bespoedig. Ten slotte het hierdie doktorale navorsing ‘n aantal belangrike kennisleemtes aangespreek in verband met die meer optimale behandeling van MMW-TB in kinders. Hierdie navorsing het gelei tot ‘n aantal opvolgvrae wat daaropvolgende studies toegelig het wat op hulle beurt die weg na ‘n doelwit van effektiewe, veilige, korter MMW-TB behandeling vir alle kinders baan.

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