Screening for phospholipidosis induced by central nervous drugs: Comparing the predictivity of an in vitro assay to high throughput in silico assays

Mesens, Natalie; Steemans, Margino; Hansen, Poul Erik; Verheyen, Geert R.; Goethem, Freddy Van; Gompel, Jaques Van

doi:10.1016/j.tiv.2010.04.007

Cited by 30 publications

(32 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…characteristics of these compounds. Cationic amphiphilic drugs (CAD) may cause intracellular accumulation of phospholipids in association with drug accumulation (a finding indicative of phospholipidosis), as has been observed for bedaquiline and M2 preclinically, as well as for many marketed drugs (6,12). Upon termination of drug intake, the phospholipidosis is reversible as the drug is eliminated from the tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Both bedaquiline and M2 accumulate in various tissues in preclinical species (12), which is likely a result of the cationic amphiphilic Culture conversion over 24 weeks among subjects who discontinued during the first 24 weeks carried forward as not converting (hazard ratio, 2.253; 95% CI, 1.08 to 4.71; P ϭ 0.031). In the bedaquiline (orange line, above) and placebo (blue line, below) groups, the times to 50% culture conversion were 78 and 129 days, respectively, and 17/21 (81.0%) and 15/23 (65.2%) of the subjects, respectively, submitted negative sputum samples at week 24.…”

Section: Discussionmentioning

confidence: 99%

“…Spot sputum samples to assess the presence or absence of M. tuberculosis by qualitative culture in liquid medium (MGIT 960; Becton Dickinson, Sparks, MD) and by sputum smears to detect acid-fast bacilli on microscopy were collected at baseline and at every visit (weekly up to week 8 and then at weeks 10,12,16,24,36,48,60,72,84, and 104). Susceptibility testing was performed centrally (Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium) on spot sputum samples collected at baseline, at weeks 8, 24, 60, and 72, and shipped in cetyl-pyridinium chloride at room temperature.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance

Diacon

Donald

Pym

et al. 2012

Antimicrob Agents Chemother

342

274

View full text Add to dashboard Cite

The 2-year follow-up results for a randomized placebo-controlled study of 47 patients with multidrug-resistant pulmonary tuberculosis treated with either the new diarylquinoline TMC207, recently renamed bedaquiline, or placebo, added to the first 8 weeks of a background regimen, are presented. Bedaquiline significantly reduced the time to culture conversion over 24 weeks (hazard ratio, 2.253; 95% confidence interval, 1.08 to 4.71; P ‫؍‬ 0.031). With the exception of nausea reported in 26% of patients receiving bedaquiline and none receiving placebo, adverse events occurred at similar frequencies in both groups of patients: bilateral hearing impairment, extremity pain, acne, and noncardiac chest pain occurred in 13 and 21%, 17 and 13%, 9 and 17%, and 4 and 17% of patients, respectively, receiving bedaquiline or placebo. Excluding resistance to ethambutol and ethionamide, only one patient receiving bedaquiline acquired resistance to companion drugs, but five patients receiving placebo (4.8% versus 21.7%; P ‫؍‬ 0.18) acquired resistance to companion drugs, and resistance to ofloxacin was acquired in four patients receiving placebo and none receiving bedaquiline (0% versus 22%; 0 ‫؍‬ 0.066). In all, 23 patients (49%), including 13 receiving placebo (54%) and 10 receiving bedaquiline (44%), discontinued the study prior to its completion, 12 during the first 24 weeks of treatment. Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring. Bedaquiline may contribute to the management of multidrug-resistant tuberculosis by effecting more rapid sputum culture negativity and by preventing acquired resistance to companion drugs. M ultidrug-resistant (MDR) tuberculosis (TB) is a serious form of TB and the term MDR implies resistance to at least the essential first-line agents isoniazid (INH) and rifampin (RMP); because INH and RMP are no longer effective, patients with MDR pulmonary TB must be treated for at least 20 months with potentially toxic, less efficacious drugs (20). MDR Mycobacterium tuberculosis isolates will frequently also be resistant to the other first-line drugs pyrazinamide (PZA), ethambutol (EMB), or streptomycin (or SM) and, at times, other drugs such as ethionamide (Eth), a fluoroquinolone, or injectable drugs such as kanamycin (KAN), amikacin, or capreomycin (CAP). MDR TB with additional resistance to the last two mentioned classes is termed extensively drug-resistant (XDR). The spread of MDR TB, particularly among communities with a high prevalence of human immunodeficiency virus (HIV) infection, is threatening the foundations of TB control programs worldwide (19). TMC207, recently renamed bedaquiline, is a diarylquinoline with a novel mode of action specifically inhibiting mycobacterial ATP synthase (1).The present randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of bedaquiline when it is added to a background regimen (BR) in newly d...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance

Diacon

Donald

Pym

et al. 2012

Antimicrob Agents Chemother

342

274

View full text Add to dashboard Cite

show abstract

“…They incorporate data at several temporal and spatial scales and consider interactions among all relevant elements at different levels (biomolecules, cells, tissues, organs, and organism). These methods have also been widely described in the literature 58, 59, 60, 61, 62…”

Section: Methodsmentioning

confidence: 99%

“…QSP models, in various therapeutic areas, have successfully been used to inform optimal dose selection during the exploratory phase of drug development 58, 59, 60, 61, 62…”

Section: Methodsmentioning

confidence: 99%

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4–5 December 2014)

Musuamba

Manolis²,

Holford

et al. 2017

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late‐stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well‐established and regulatory‐acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4–5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP‐Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)‐based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well‐designed dose‐finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale.

show abstract

High‐Throughput Toxicity Testing in Drug Development: Aims, Strategies, and Novel Trends

Schoonen

Westerink²,

Water

et al. 2013

High‐Throughput Screening Methods in Toxicity Testing

View full text Add to dashboard Cite

Screening for phospholipidosis induced by central nervous drugs: Comparing the predictivity of an in vitro assay to high throughput in silico assays

Cited by 30 publications

References 18 publications

Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance

Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4–5 December 2014)

High‐Throughput Toxicity Testing in Drug Development: Aims, Strategies, and Novel Trends

Contact Info

Product

Resources

About