Browsing by Author "Thee, Stephanie"
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- ItemPharmacokinetics and safety of first -- and second--line anti-- tuberculosis drugs in children(Stellenbosch : Stellenbosch University, 2015-12) Thee, Stephanie; Schaaf, Hendrik Simon; Hesseling, Anneke Catharina; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child HealthENGLISH 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.