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Pharmacokinetics and safety of first -- and second--line anti-- tuberculosis drugs in children

Thee, Stephanie (2015-12)

Thesis (PhD)--Stellenbosch University, 2015

Thesis

ENGLISH ABSTRACT : The global burden of tuberculosis (TB) in children is high with a high morbidity and mortality, especially amongst young and HIV-­‐infected children. The emerging epidemic of multidrug-­‐resistant (MDR)-­‐TB is a threat to children, while information on the use of second-­‐line drugs in children is very limited. By reviewing the literature on the first-­‐line anti-­‐tuberculosis agents it is shown that isoniazid (INH) and rifampicin (RMP) exhibit a dose-­‐dependent activity against Mycobacterium tuberculosis. For effective anti-­‐tuberculosis therapy, 2-­‐hour serum concentrations of INH 3-­‐5µg/ml, RMP 8-­‐24µg/ml and pyrazinamide (PZA) >35µg/ml have been proposed. Although not optimal, the major tools at hand to determine desired serum concentrations of an anti-­‐tuberculosis drug in children are comparative clinical data from adults and their pharmacokinetic “optimal” target values. In order to achieve serum concentrations in children comparable to those in adults and which are correlated with efficacy, the existing evidence advocates the use of higher mg/kg body weight doses of INH and RMP in younger children compared to adults. For PZA, similar mg/kg body weight doses lead to PZA maximum concentrations (Cmax) similar to those in adults. In 2009, the World Health Organization (WHO) increased their dosing recommendations and now advises giving INH at 10 mg/kg (range: 7-­‐15 mg/kg), RMP 15 mg/kg (10-­‐20 mg/kg) and PZA 35 mg/kg (30-­‐40 mg/kg). Studies of the pharmacokinetics of the first-­‐line agents in representative cohorts of children especially in younger ages and with different genetic backgrounds are limited; these needed to better define the doses appropriate for children. I performed a pharmacokinetic study on the first-­‐line agents INH, RMP and PZA in 20 children <2 years of age (mean age 1.09 years), following the previous and revised WHO dosing recommendations. Mean (95% confidence interval) Cmaxs [µg/ml], following previous/revised doses, were: INH 3.2 (2.4-­‐4.0)/8.1 (6.7-­‐9.5)µg/ml, PZA 30.0 (26.2-­‐ 33.7)/47.1 (42.6-­‐51.6)µg/ml, and RMP 6.4 (4.4-­‐8.3)/11.7 (8.7-­‐14.7)µg/ml. The mean (95% confidence interval) area under the time-­‐concentration curves (AUC) [µg⋅h/ml] were: INH 8.1 (5.8-­‐10.4)/20.4 (15.8-­‐25.0)µg∙h/ml, PZA 118.0 (101.3-­‐134.7)/175.2 (155.5-­‐195.0)µg∙h/ml, and RMP 17.8 (12.8-­‐22.8)/36.9 (27.6-­‐46.3)µg∙h/ml. This study provides the first evidence for the implementation of the revised WHO guidelines for first-­‐line anti-­‐tuberculosis therapy in children younger than two years of age. Because drug-­‐resistant TB is increasing globally, pharmacokinetic studies to guide dosing and safe use of the second-­‐line agents in children have become a matter of urgency. In this thesis, priority is given to the thioamides (ethionamide [ETH] and prothionamide [PTH]) and the 3 most frequently used fluoroquinolones, ofloxacin (OFX), levofloxacin (LFX) and moxifloxacin (MFX). By reviewing the literature, I have demonstrated that ETH has shown to be effective in in vitro studies against M. tuberculosis and in combination with other drugs had good outcome in MDR-­‐TB and tuberculous meningitis patients, including children. ETH/PTH exhibit dose-­‐dependent activity and are bactericidal at higher doses, although dosing is limited mainly by gastro-­‐intestinal adverse effects. During long-­‐term ETH/PTH therapy hypothyroidism might also occur. An oral daily dose of ETH or PTH of 15-­‐20mg/kg with a maximum daily dose of 1,000mg is recommended in children. No child-­‐friendly formulations of the thioamides exist. Studies on dosing and toxicity of ETH and PTH in childhood TB are needed. With the first study ever conducted on the pharmacokinetics of ETH in 31 children (mean age 4.25 years), supportive evidence for the current dosing recommendation of ETH 15-­‐20mg/kg in children with TB is provided. Mean Cmax was 4.14μg/ml (range 1.48 – 6.99μg/ml) and was reached within two hours (mean tmax 1.29h, range 0.87 – 2.97h). Young children and HIV-­‐infected children were at risk for lower ETH serum concentrations, but the mean drug exposure was still within range of the adult Cmax reference target (2.5µg/ml). In a retrospective study on 137 children (median age 2.9 years) receiving anti-­‐ tuberculosis therapy including ETH, abnormal thyroid function tests were recorded in 79 (58%) children. The risk for biochemical hypothyroidism was higher for children on regimens including para-­‐aminosalicylic acid (PAS) and in HIV-­‐infected children. This high frequency of thyroid function abnormalities in children treated with ETH indicates the need for careful thyroid function test monitoring in children on long-­‐term ETH treatment, especially in case of HIV co-­‐infection and concomitant use of PAS. The literature review on the use of fluoroquinolones in childhood TB revealed that the strong bactericidal and sterilizing activity, favourable pharmacokinetics, and toxicity profile have made the fluoroquinolones the most important component of existing MDR-­‐ TB treatment regimens, not only in adults, but also in children. Proposed pharmacodynamic targets for fluoroquinolones against Mycobacterium tuberculosis are AUC0-­‐24/MIC >100 or Cmax/MIC 8-­‐10. In vitro and murine studies demonstrated the potential of MFX to shorten drug-­‐susceptible TB treatment, but in multiple randomized controlled trials in adults, shortened fluoroquinolone-­‐containing regimens have found to be inferior compared to standard therapy. Resistance occurs frequently via mutations in the gyrA gene, and emerges rapidly depending on the fluoroquinolone concentration. Fluoroquinolone resistance occurs in 4-­‐30% in MDR-­‐TB strains depending on the region/country and setting. Emerging data from paediatric studies underlines the importance of fluoroquinolones in the treatment of MDR-­‐TB in children. There is a paucity of pharmacokinetic data especially in children <5 years of age and HIV-­‐infected children. Fluoroquinolone use has historically been restricted in children due to concerns about drug-­‐induced arthropathy. The available data however does not demonstrate any serious arthropathy or other severe toxicity in children. In order to fill the gap in knowledge on fluoroquinolone dosing in children with TB, prospective, intensive-­‐sampling pharmacokinetic studies on OFX, LFX, and MFX including assessment of cardiac effects were conducted. In the study on the pharmacokinetics of OFX and LFX, 23 children (median age 3.14 years) were enrolled; 4 were HIV-­‐infected (all > 6 years of age) and 6 were underweight-­‐ for-­‐age (z-­‐score <-­‐2). The median Cmax [µg/ml], median AUC(0-­‐8) [µg⋅h/ml] and mean tmax [h] for OFX were: 9.67 (IQR 7.09-­‐10.90), 43.34 (IQR 36.73-­‐54.46) and 1.61 (SD 0.72); for LFX: 6.71 (IQR 4.69-­‐8.06), 29.89 (IQR 23.81-­‐36.39) and 1.44 (SD 0.51), respectively. Children in this study eliminated OFX and LFX more rapidly than adults, and failed to achieve the proposed adult pharmacodynamic target of an AUC0-­‐24/MIC >100. Nevertheless, the estimated pharmacodynamic indices favoured LFX over OFX. The mean corrected QT (QTc) was 361,4ms (SD 37,4) for OFX and 369,1ms (SD 21.9) for LFX, respectively and no QTc prolongation occurred. In the study on MFX, 23 children (median age 11.1 years) were included; 6/23 (26.1%) were HIV-­‐infected. The median (IQR) Cmax [µg/ml], AUC(0-­‐8) [µg⋅h/ml], tmax [h] and half-­‐ life for MFX were: 3.08 (2.85-­‐3.82), 17.24 (14.47-­‐21.99), 2.0 (1.0-­‐8.0); and 4.14 (IQR 3.45-­‐6.11), respectively. AUC0-­‐8 was reduced by 6.85μg∙h/ml (95% CI 11.15-­‐2.56) in HIV-­‐ infected children. tmax was shorter with crushed versus whole tablets (p=0.047). In conclusion, children 7-­‐15 years of age have low serum concentration compared with adults receiving 400mg MFX daily. MFX was well tolerated in children treated for MDR-­‐ TB. The mean corrected QT-­‐interval was 403ms (SD 30ms) and as for OFX and LFX, no prolongation >450ms occurred. In conclusion, my research identified and addressed critical gaps in the current knowledge in the management of children with both drug-­‐susceptible and drug-­‐ resistant TB. I provided essential evidence on both the dosing and safety of first-­‐ and second-­‐line anti-­‐tuberculosis agents, informing international treatment guidelines for childhood TB. Nevertheless, more studies in a larger number of children with different genetic backgrounds, HIV co-­‐infection nutritional status and with higher drug doses, novel treatment regimens and child-­‐friendly formulations are needed to further optimize anti-­‐tuberculosis treatment in children.

AFRIKAANSE OPSOMMING : Die globale lading van tuberkulose (TB) in kinders is hoog, met ‘n hoë TB-­‐verwante morbiditeit en mortaliteit, veral onder jong en MIV-­‐geïnfekteerde kinders. Die toenemende epidemie van multimiddel-­‐weerstandige (MMW)-­‐TB hou ‘n bedreiging in vir kinders, terwyl inligting oor die gebruik van tweede-­‐linie middels in kinders tans baie beperk is. Deur middel van ‘n oorsig van die literatuur oor eerste-­‐linie antituberkulose middels is aangetoon dat isoniasied (INH) en rifampisien (RMP) ‘n dosisverwante aksie teen Mycobacterium tuberculosis uitoefen. Vir effektiewe TB behandeling is 2-­‐uur serumkonsentrasies van INH 3-­‐5μg/ml, RMP 8-­‐24μg/ml en pirasienamied (PZA) van >35μg/ml voorgestel. Alhoewel nie optimaal nie, is die voor-­‐die-­‐hand-­‐liggende manier om die verlangde serumkonsentrasies van ‘n antituberkulose middel in kinders te bepaal die vergelykbare kliniese data in volwassenes en hulle farmakokinetiese “optimale” teikenwaardes. Om serumkonsentrasies in kinders gelykstaande aan dié in volwassenes en met ooreenstemmende effektiwiteit te bereik, toon die beskikbare data dat hoër mg/kg liggaamsmassa dosisse vir INH en RMP in jong kinders in vergelyking met volwasse dosisse gegee behoort te word. Met PZA sal soortgelyke mg/kg dosisse per liggaamsmassa in kinders lei tot soortgelyke maksimum konsentrasies (Cmax) in volwassenes. In 2009 het die Wêreld Gesondheidsorganisasie (WGO) hulle dosis-­‐ aanbevelings verhoog, en tans beveel die WGO INH teen 10mg/k (reikwydte 7-­‐15 mg/kg), RMP 15mg/kg (10-­‐20 mg/kg) en PZA teen 35mg/kg (30-­‐40 mg/kg) aan in kinders. Studies oor die farmakokinetika van die eerste-­‐linie antituberkulose middels in verteenwoordigende groepe van kinders, veral in die jonger ouderdomsgroepe en met verskillende genetiese agtergronde is beperk; sulke studies word dringend benodig om toepaslike dosisse vir kinders met TB beter te definieer. Ek het ‘n farmakokinetiese studie van die eerste-­‐linie middels INH, RMP en PZA in 20 kinders <2 jaar oud (gemiddelde ouderdom 1.09 jaar) volgens die vorige en huidige WGO doseringsriglyne uitgevoer. Die gemiddelde (95% vertroue interval) Cmax [μg/ml] volgens vorige/huidige doseringsriglyne was: INH 3.2 (2.4-­‐4.0)/8.1 (6.7-­‐9.5)µg/ml, PZA 30.0 (26.2-­‐33.7)/47.1 (42.6-­‐51.6)µg/ml, and RMP 6.4 (4.4-­‐8.3)/11.7 (8.7-­‐14.7)µg/ml. Die gemiddelde (95% vertroue interval) oppervlakte onder die tyd-­‐konsentrasie kromme (AUC) [µg⋅h/ml] was: INH 8.1 (5.8-­‐10.4)/20.4 (15.8-­‐25.0)µg∙h/ml, PZA 118.0 (101.3-­‐134.7)/175.2 (155.5-­‐195.0)µg∙h/ml, and RMP 17.8 (12.8-­‐22.8)/36.9 (27.6-­‐ 46.3)µg∙h/ml. Hierdie studie voorsien die eerste bewyse vir die toepassing van die hersiene WGO-­‐riglyne vir eerste-­‐linie antituberkulose behandeling in kinders jonger as twee jaar oud. Omdat middelweerstandige TB wêreldwyd aan die toeneem is, het studies oor die farmakokinetika en veiligheid van die gebruik van tweede-­‐linie middels in kinders ‘dringend nodig geword. In hierdie verhandeling word voorkeur gegee aan die tioamiede (etionamied [ETH] en protionamied [PTH]) en die drie mees algemeen gebruikte fluorokwinolone, ofloksasien [OFX], levofloksasien [LFX] en moksifloksasien [MFX]. Deur ‘n oorsig van die literatuur het ek aangetoon dat ETH in in vitro studies teen M. tuberculosis effektief is en in kombinasie met ander middels goeie uitkomste in MMW-­‐ TB en tuberkuleuse meningitis, insluitend kinders, het. ETH/PTH toon dosisverwante aktiwiteit en is bakteriedodend teen hoër dosisse, alhoewel dosering hoofsaaklik deur gastrointestinale newe-­‐effekte beperk word. Tydens langtermyn behandeling met ETH/PTH kan hipotireose ook voorkom. ‘n Daaglikse mondelingse dosis van ETH of PTH van 15-­‐20mg/kg met ‘n maksimum daaglikse dosis van 1,000 mg word vir kinders aanbeveel. Daar bestaan tans geen kindervriendelike formulerings vir die tioamiedes nie. Met die eerste studie ooit wat handel oor die farmakokinetika van ETH in 31 kinders (gemiddelde ouderdom 4.25 jaar), verleen ek ondersteunende bewys vir die huidig aanbevole dosis van ETH van15-­‐20mg/kg in kinders met TB.. Die gemiddelde ETH Cmax was 4.14μg/ml (reikwydte 1.48-­‐6.99μg/ml) en hierdie konsentrasie was binne twee ure (gemiddelde tmax 1.29h, reikwydte 0.87-­‐2.97h) bereik. Jong en MIV-­‐geïnfekteerde kinders het geneig om laer ETH konsentrasies te toon, maar die gemiddelde middelblootstelling was steeds binne die reikwydte van die volwasse Cmax teiken (2.5μg/ml). In ‘n retrospektiewe studie van 137 kinders (gemiddelde ouderdom 2.9 jaar) wat antituberkulose behandeling insluitende ETH ontvang het, is abnormale tiroïedfunksietoetse in 79 (58%) kinders gedokumenteer. Die risiko vir biochemiese hipotireose was hoër in kinders op behandeling wat para-­‐aminosalisielsuur (PAS) ingesluit het, asook in MIV-­‐geïnfekteerde kinders. Hierdie hoë voorkoms van tiroïedfunksie abnormaliteite in kinders wat ETH behandel ontvang het, dui op die belang van die versigtige monitering van tiroïedfunksietoetse in kinders op langtermyn ETH behandeling, veral in die geval van MIV ko-­‐infeksie en met meegaande gebruik van PAS. Die literatuuroorsig oor die gebruik van fluorokwinolone in kindertuberkulose het dit duidelik gemaak dat die sterk bakteriedodende effek, gunstige farmakokinetika en toksisteitsprofiel die fluorokwinolone die belangrikste deel van die huidige MMW-­‐TB behandeling gemaak het, nie alleen in volwassenes nie, maar ook in kinders. Voorgestelde farmakodinamiese teikens vir die fluorokwinolone teen M. tuberculosis is AUC0-­‐24/MIC >100 of Cmax/MIC 8-­‐10. In vitro en muisstudies het die potensiaal van MFX om die behandeling van middelsensitiewe TB te verkort, aangetoon, maar in veelvuldige ewekansig-­‐gekontroleerde studies in volwassenes het verkorte fluorokwinoloon-­‐ bevattende regimens egter geblyk om minderwaardig te wees in vergelyking met huidige standaardbehandeling. Weerstandigheid kom dikwels via mutasies in die gyrA-­‐ gene voor en kom vining na vore afhangend van die fluorokwinoloonkonsentrasie. Fluorokwinoloon-­‐weerstandigheid kom voor in 4-­‐30% van MMW-­‐TB stamme, afhangend van die konteks en streek. Data van kinders wat na vore kom versterk die belang van die fluorokwinolone in die behandeling van kindertuberkulose. Daar is veral ‘n tekort aan farmakokinetiese data in kinders <5 jaar oud en in MIV-­‐geïnfekteerde kinders. Die gebruik van fluorokwinolone in kinders is geskiedkundig beperk as gevolg van besorgdheid oor middel-­‐geïnduseerde gewrigsaantasting. Die beskikbare inligting dui egter nie op enige erge gewrigsaantasting of enige ander erge toksisiteit in kinders nie. Ten einde die gaping in kennis oor die dosering van fluorokwinolone in kinders met TB te vul, is ‘n prospektiewe, intensiewe-­‐monsterneming farmakokinetiese studies oor OFX, LFX en MFX, insluitend evaluering van kardiotoksiese effekte, uitgevoer. In die studie oor die farmakokinetika van OFX en LFX is 23 kinders (mediane ouderdom 3.14 jaar) ingesluit; 4 was MIV-­‐geïnfekteer (almal >6 jaar oud) en 6 was ondergewig-­‐vir-­‐ ouderdom (z-­‐telling <-­‐2). Die mediane Cmax [μg/ml], mediane AUC0-­‐8 [µg⋅h/ml] en gemiddelde tmax [h] vir OFX was: 9.67 (interkwartielreikwydte IKR 4.69-­‐8.06), 43.34 (IKR 36.73-­‐54.46) en 1.61 (SD 0.72); vir LFX: 6.71 (IKR 4.69-­‐8.06), 29.89 (IKR 23.81-­‐ 36.39) en 1.44 (SD 0.51), onderskeidelik. Kinders in hierdie studie het OFX en LFX vinniger as volwassenes uigeskei en het nie daarin geslaag om voorgestelde volwasse farmakodinamiese teikens van AUC0-­‐24/MIC >100 te behaal nie. Nogtans was die berekende farmakodinamiese indekse ten gunste van LFX bo OFX. Die gemiddelde gekorrigeerde QT-­‐interval (QTc) was 361.4ms (SD 37.4) vir OFX en 369.1ms (SD 21.9) vir LFX, onderskeidelik, en geen verlenging van QTc-­‐interval het voorgekom nie. In die studie oor MFX was 23 kinders (mediane ouderdom 11.1 jaar) ingesluit; 6/23 (26.1%) was MIV-­‐geïnfekteerd. Die mediane (IKR) Cmax [μg/ml], AUC0-­‐8 [µg⋅h/ml], tmax [h] en half-­‐lewe van MFX was: 3.08 (2.85-­‐3.82), 17.24 (14.47-­‐21.99), 2.0 (1.0-­‐8.0) en 4.14 (3.45-­‐6.11), onderskeidelik. Die AUC0-­‐8 was met 6.85µg⋅h/ml (95% vertrouensinterval 11.15-­‐2.56) verminder in MIV-­‐geïnfekteerde kinders. Die tmax was korter met fyngemaakte teenoor heel tablette (p=0.047). Ter samevatting, kinders 7-­‐15 jaar oud het lae serumkonsentrasies in vergelyking met volwassenes wat 400mg MFX per dag ontvang, getoon. MFX was goed verdra in kinders met MMW-­‐TB. Die gemiddelde QTc-­‐interval was 403ms (SD 30ms). Soos in die geval van OFX en LFX, het geen verlenging >450ms voorgekom nie. Ter samevatting spreek my navorsing kritiese gapings in die hudige kennis oor die hantering van kinders met middelsensitiewe en middelweerstandige TB aan.. Ek verskaf belangrike bewyse oor beide die dosering en veiligheid van eerste-­‐ en tweede-­‐linie antituberkulose middels, wat internasionale behandelingsriglyne vir kindertuberkulose toegelig het. Nogtans is verdere studies met groter getalle kinders uit verskillende genetiese agtergronde, MIV ko-­‐infeksie, voedingstatus, en met hoër doserings van antituberkulose middels, nuwe behandelingsregimens en kindervriendelike formulerings nodig om die behandeling van tuberkulose in kinders verder te verbeter.

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