The Importance of Clinical Pharmacokinetic–Pharmacodynamic Studies in Unraveling the Determinants of Early and Late Tuberculosis Outcomes

McCallum, Alison; Sloan, Derek J.

doi:10.4155/ipk-2017-0004

Cited by 14 publications

(15 citation statements)

References 134 publications

(147 reference statements)

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“…A covariate with inclusion frequency of 50% or more was considered non-spurious and retained in the final conservative model. The antimicrobial effect of rifampicin is concentration dependent, and Cmax is the most frequently used PK parameter for therapeutic drug monitoring (11,13,25). For rifampicin, Cmax correlates well with AUC and has been reported as a suitable functional proxy (26).…”

Section: Pharmacokinetic-pharmacodynamic Modellingmentioning

confidence: 99%

Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB–rifampicin sensitivity among Ugandan patients

Mukonzo

Kengo

Kutesa

et al. 2019

Transactions of the Royal Society of Tropical Medicine and Hygiene

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Background Suboptimal anti-TB drugs exposure may cause multidrug-resistant TB. The role of African predominant SLCO1B1 variant alleles on rifampicin pharmacokinetics and the subsequent effect on the occurrence of Mycobacterium tuberculosis–rifampicin sensitivity needs to be defined. We describe the rifampicin population pharmacokinetics profile and investigate the relevance of SLCO1B1 genotypes to rifampicin pharmacokinetics and rifampicin-TB sensitivity status. Methods Fifty patients with TB (n=25 with rifampicin-resistant TB and n=25 with rifampicin-susceptible TB) were genotyped for SLOC1B1 rs4149032 (g.38664C>T), SLOC1B1*1B (c.388A>G) and SLOC1B1*5 (c.521 T>C). Steady state plasma rifampicin levels were determined among patients infected with rifampicin-sensitive TB. Data were analysed using NONMEM to estimate population rifampicin pharmacokinetics as well as the effect of SLOC1B1 genotypes on rifampicin pharmacokinetics and on rifampicin-TB sensitivity status. Results Overall allele frequencies of SLOC1B1 rs4149032, *1B and *5 were 0.66, 0.90 and 0.01, respectively. Median (IQR) Cmax and Tmax were 10.2 (8.1–12.5) mg/L and 1.7 (1.125–2.218) h, respectively. Twenty-four percent of patients exhibited Cmax below the recommended 8–24 mg/L range. SLOC1B1 genotypes, gender and age did not influence rifampicin pharmacokinetics or TB-rifampicin sensitivity. Conclusions Although SLOC1B1 genotype, age and gender do not influence either rifampicin pharmacokinetics or rifampicin-TB sensitivity status, one in every four Ugandan TB patients achieve subtherapeutic plasma rifampicin concentrations.

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Section: Pharmacokinetic-pharmacodynamic Modellingmentioning

confidence: 99%

Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB–rifampicin sensitivity among Ugandan patients

Mukonzo

Kengo

Kutesa

et al. 2019

Transactions of the Royal Society of Tropical Medicine and Hygiene

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“…3). Specifically, the bacteria were treated with 0 x MIC 90 (green lines), 1 x MIC 90 (blue lines) or the clinically relevant C max (peak levels of antibiotic found in patient serum: 20 x MIC 90 for streptomycin and 5 x MIC 90 for ethambutol 37 – red lines), and the bacterial colony-forming units (CFUs) were quantified at various times during the treatment.…”

Section: Resultsmentioning

confidence: 99%

Modulation of the cAMP levels with a conserved actinobacteria phosphodiesterase enzyme reduces antimicrobial tolerance in mycobacteria

Nunta

Cheyne

Liu

et al. 2020

Preprint

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Antimicrobial tolerance (AMT) is the gateway to the development of antimicrobial resistance (AMR) and is therefore a major issue that needs to be addressed.The second messenger cyclic-AMP (cAMP), which is conserved across all taxa, is involved in propagating signals from environmental stimuli and converting these into a response. In bacteria, such as M. tuberculosis, P. aeruginosa, V. cholerae and B. pertussis, cAMP has been implicated in virulence, metabolic regulation and gene expression. However, cAMP signalling in mycobacteria is particularly complex due to the redundancy of adenylate cyclases, which are enzymes that catalyse the formation of cAMP from ATP, and the poor activity of the only known phosphodiesterase (PDE) enzyme, which degrades cAMP into 5’- AMP.Based on these two features, the modulation of this system with the aim of investigating cAMP signalling and its involvement in AMT in mycobacteria id difficult.To address this pressing need, we identified a new cAMP-degrading phosphodiesterase enzyme (Rv1339) and used it to significantly decrease the intrabacterial levels of cAMP in mycobacteria. This analysis revealed that this enzyme increased the antimicrobial susceptibility of M. smegmatis mc2155. Using a combination of metabolomics, RNA-sequencing, antimicrobial susceptibility assays and bioenergetics analysis, we were able to characterize the molecular mechanism underlying this increased susceptibility.This work represents an important milestone showing that the targeting of cAMP signalling is a promising new avenue for antimicrobial development and expands our understanding of cAMP signalling in mycobacteria.

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“…39,40 Since the existing anti-tubercular regimens made before the current advance in pharmacokinetic-pharmacodynamic (PK-PD), we are lacking evidence of exposure-response relationships even in today's tuberculosis pharmacotherapy. 41 Owing to this gap WHO developed a technical report on the PK and PD of drugs used for tuberculosis treatment. 13 This review examined the literature published over the last ten years reporting pharmacokinetics in particular plasma concentration of first-line anti-tubercular drug association with treatment outcome.…”

Section: Discussionmentioning

confidence: 99%

The Impact of First-Line Anti-Tubercular Drugs’ Pharmacokinetics on Treatment Outcome: A Systematic Review

Sileshi¹,

Tadesse²,

Makonnen³

et al. 2021

CPAA

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Background: Tuberculosis remains the major public health problem besides tremendous efforts to combat it. Most tuberculosis patients are treated with a standard dose of first-line anti-TB drugs. The cure rate, however, varies from patient to patient. Various factors have been related to anti-TB treatment failure. In recent years, studies associating lower plasma concentrations of anti-TB drugs with poor treatment outcomes are emerging although the results are inconclusive. Objective: Investigate the impact of first-line anti-tubercular drugs pharmacokinetics on treatment outcome. Methods: A systematic search of Pubmed, EMBASE, Web of Science, and the Cochrane Library for articles published in the English language between January 2010 to June 2020 was conducted to identify eligible studies describing associations of first-line anti-tubercular drug pharmacokinetics with treatment outcomes. The primary outcomes considered were pharmacokinetics parameter results and its association with treatment outcome. Results: The search identified 1754 articles of which twelve articles; ten prospective observational studies and two controlled clinical trials fulfilled the eligibility criteria. The majority of the studies showed target concentrations for the first-line anti-tubercular drugs below the current standard range. Among the twelve studies, eleven studies assessed rifampicin pharmacokinetics of which eight reported association of drug concentration and treatment outcomes. Similarly, four out of eight and three out of seven reported drug concentration and treatment outcome association for isoniazid and pyrazinamide, respectively. Despite the low plasma concentration, a favorable treatment outcome was achieved for the bulk of the patients. Irrespective of the inconsistency, an increase in exposure to rifampicin improved the outcome, and lower rifampicin, isoniazid, and pyrazinamide concentration are associated with poor outcome. No data are available for ethambutol associating its pharmacokinetics with treatment outcomes. Conclusion: The pharmacokinetics of first-line antitubercular drugs can influence treatment outcomes. Further controlled clinical studies are, however, required to establish these relationships.

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The Importance of Clinical Pharmacokinetic–Pharmacodynamic Studies in Unraveling the Determinants of Early and Late Tuberculosis Outcomes

Cited by 14 publications

References 134 publications

Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB–rifampicin sensitivity among Ugandan patients

Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB–rifampicin sensitivity among Ugandan patients

Modulation of the cAMP levels with a conserved actinobacteria phosphodiesterase enzyme reduces antimicrobial tolerance in mycobacteria

The Impact of First-Line Anti-Tubercular Drugs’ Pharmacokinetics on Treatment Outcome: A Systematic Review

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