Population Pharmacokinetics of Levofloxacin and Moxifloxacin, and the Probability of Target Attainment in Ethiopian Patients with Multidrug-Resistant Tuberculosis

Sidamo, Temesgen; Rao, Prakruti; Aklillu, Eleni; Shibeshi, Workineh; Park, Yumi; Cho, Yong-soon; Shin, Jung Woog; Heysell, Scott K; Mpagama, Stellah; Engidawork, Ephrem

doi:10.2147/idr.s389442

Cited by 3 publications

(2 citation statements)

References 50 publications

(58 reference statements)

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“…Like Canouï et al and Sidamo et al ( 40 , 41 ), a one-compartment model adequately described our levofloxacin data. This differs from the two-compartment model found by Denti et al and Garcia-Prats et al ( 42 , 43 ), probably due to different sampling schedules and study populations.…”

Section: Discussionsupporting

confidence: 81%

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Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis

Kengo,

Nabeemeeah,

Denti

et al. 2024

Antimicrob Agents Chemother

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Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring.

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Section: Discussionsupporting

confidence: 81%

“…Our finding of a significant effect of creatinine clearance on levofloxacin clearance is in line with previous reports ( 24 , 25 , 40 ). We also found slower absorption of levofloxacin than has been previously reported ( 41 – 43 ), likely due to a food effect ( 24 , 25 ).…”

Section: Discussionsupporting

confidence: 60%

Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis

Kengo,

Nabeemeeah,

Denti

et al. 2024

Antimicrob Agents Chemother

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Pharmacokinetics of anti-TB drugs in children and adolescents with drug-resistant TB: a multicentre observational study from India

Agibothu Kupparam,

Shah,

Chandrasekaran

et al. 2024

Journal of Antimicrobial Chemotherapy

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Background Drug-resistant tuberculosis (DR-TB) is one of the challenging forms of TB to treat, not only in adults but also in children and adolescents. Further, there is a void in the treatment strategy exclusively for children due to various reasons, including paucity of pharmacokinetic (PK) data on anti-TB drugs across the globe. In this context, the present study aimed at assessing the PK of some of the anti-TB drugs used in DR-TB treatment regimens. Method A multicentre observational study was conducted among DR-TB children and adolescents (n = 200) aged 1–18 years (median: 12 years; IQR: 9–14) treated under programmatic settings in India. Steady-state PK (intensive: n = 89; and sparse: n = 111) evaluation of moxifloxacin, levofloxacin, cycloserine, ethionamide, rifampicin, isoniazid and pyrazinamide was carried out by measuring plasma levels using HPLC methods. Results In the study population, the frequency of achieving peak plasma concentrations ranged between 13% (for rifampicin) to 82% (for pyrazinamide), whereas the frequency of suboptimal peak concentration for pyrazinamide, cycloserine, moxifloxacin, levofloxacin and rifampicin was 15%, 19%, 29%, 41% and 74%, respectively. Further, the frequency of supratherapeutic levels among patients varied between 3% for pyrazinamide and 60% for isoniazid. In the below-12 years age category, the median plasma maximum concentration and 12 h exposure of moxifloxacin were significantly lower than that of the above-12 years category despite similar weight-adjusted dosing. Conclusions Age significantly impacted the plasma concentration and exposure of moxifloxacin. The observed frequencies of suboptimal and supratherapeutic concentrations underscore the necessity for dose optimization and therapeutic drug monitoring in children and adolescents undergoing DR-TB treatment.

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Challenges for global antibiotic regimen planning and establishing antimicrobial resistance targets: implications for the WHO Essential Medicines List and AWaRe antibiotic book dosing

Reza,

Gerada,

Stott

et al. 2024

Clin Microbiol Rev

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SUMMARY The World Health Organisation’s 2022 AWaRe Book provides guidance for the use of 39 antibiotics to treat 35 infections in primary healthcare and hospital facilities. We review the evidence underpinning suggested dosing regimens. Few ( n = 18) population pharmacokinetic studies exist for key oral AWaRe antibiotics, largely conducted in homogenous and unrepresentative populations hindering robust estimates of drug exposures. Databases of minimum inhibitory concentration distributions are limited, especially for community pathogen-antibiotic combinations. Minimum inhibitory concentration data sources are not routinely reported and lack regional diversity and community representation. Of studies defining a pharmacodynamic target for ß-lactams ( n = 80), 42 (52.5%) differed from traditionally accepted 30%–50% time above minimum inhibitory concentration targets. Heterogeneity in model systems and pharmacodynamic endpoints is common, and models generally use intravenous ß-lactams. One-size-fits-all pharmacodynamic targets are used for regimen planning despite complexity in drug-pathogen-disease combinations. We present solutions to enable the development of global evidence-based antibiotic dosing guidance that provides adequate treatment in the context of the increasing prevalence of antimicrobial resistance and, moreover, minimizes the emergence of resistance.

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Population Pharmacokinetics of Levofloxacin and Moxifloxacin, and the Probability of Target Attainment in Ethiopian Patients with Multidrug-Resistant Tuberculosis

Cited by 3 publications

References 50 publications

Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis

Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis

Pharmacokinetics of anti-TB drugs in children and adolescents with drug-resistant TB: a multicentre observational study from India

Challenges for global antibiotic regimen planning and establishing antimicrobial resistance targets: implications for the WHO Essential Medicines List and AWaRe antibiotic book dosing

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