EO-9 bladder instillations: Formulation selection based on stability characteristics and in vitro simulation studies

Schoot, S. C. van der; Vainchtein, Liia D.; Beijnen, Jos H.; Gore, A.; Mirejovsky, Dorla; Lenaz, Luigi; Nuijen, Bastiaan

doi:10.1016/j.ijpharm.2006.08.031

Cited by 5 publications

(4 citation statements)

References 5 publications

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“…No apaziquone or EO5A were detected in the blood of patients during and after the instillation. In acidified urine, a degradation product known as EO-9-Cl has been reported [31], but the presence of this product was not observed in clinical studies. Pharmacokinetic studies following the intravesical administration of apaziquone to NMIBC patients are therefore limited but in both studies, high levels of apaziquone (4 mg/40 ml) were delivered into the bladder but no detectable levels of drug or known metabolites reached the systemic circulation.…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

“…Despite these disappointing results, it is our opinion that the development of apaziquone should continue and future studies should take several aspects into account such as the instability at acidic conditions and protein binding, as well as timing of the instillation (between 31 and 90 min) after surgery. The stability issue of apaziquone is taken care off by using a buffered formulation (pH 9.2) for the drug, which prolonged stability of apaziquone during instillation, even when mixed with acid urine [31]. Other future applications of apaziquone would be regional treatment for other malignancies, even in the prevention setting.…”

Section: Expert Opinionmentioning

confidence: 99%

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Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer

Phillips

Hendriks²,

Sweeney

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Apaziquone (also known as EO9 and Qapzola TM ) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects. However, phase III clinical trials did not reach statistical significance for the primary endpoint of 2-year recurrence in apaziquone over placebo although improvements were observed. Post-hoc analysis of the combined study data did indicate a significant benefit for patients treated with apaziquone, especially when the instillation of apaziquone was given 30 min or more after surgery. A further phase III study is ongoing to test the hypotheses generated in the unsuccessful phase III studies conducted to date. Expert opinion: Because of its specific pharmacological properties, Apaziquone is excellently suited for local therapy such as NMIBC. Future studies should include proper biomarkers. ARTICLE HISTORY

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Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

Section: Expert Opinionmentioning

confidence: 99%

Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer

Phillips

Hendriks²,

Sweeney

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

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“…Recurrence‐free rates were good in comparison with the results of other ablative studies (Hendricksen et al ., 2009; Jain et al ., 2009). EO9 was reformulated in 2007 (van der Schoot et al ., 2007a; 2008; van der Schoot et al ., 2007b), and it is currently undergoing phase III clinical evaluation in several centres across North America and Europe. Additionally, studies where EO9 was administered within 24 h of TUR, which is the standard recommended treatment for superficial TCC of the bladder (Sylvester et al ., 2004), demonstrated that EO9 was well tolerated and has a good safety profile (Hendricksen et al ., 2008).…”

Section: Pharmacology Of Eo9mentioning

confidence: 99%

EO9 (Apaziquone): from the clinic to the laboratory and back again

Phillips

Hendriks²,

Peters

2012

British J Pharmacology

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EO9 (Apaziquone) is a bioreductive drug that has a chequered history. It underwent clinical trial but failed to show activity in phase II clinical trials when administered i.v. Poor drug delivery to tumours caused by a combination of rapid pharmacokinetic elimination and poor penetration through avascular tissue were the major factors responsible for EO9's poor efficacy. Based upon an understanding of why EO9 failed, a further clinical trial against patients with superficial transitional cell carcinoma of the bladder was conducted. The rationale for this was that intravesical administration directly into the bladder would circumvent the drug delivery problem, and any drug reaching the blood supply would be rapidly cleared thereby reducing the risk of systemic exposure. EO9 was well tolerated, and clinical activity against marker lesions was recorded in both phase I and II clinical trials. This article charts the pharmacological history of EO9 and discusses the potential implications that 'the EO9 story' has for the development of other loco-regional therapies.

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“…Recently, we identified another degradation product of EO9, EO9-CL, where Cl is covalently attached to the aziridine ring-opened EO9 molecule ( Fig. 17) [ [234][235][236]. The administered dose is usually 4 mg of formulated EO9/40 mL of instillation solution.…”

Section: Eo9 (Apaziquone)mentioning

confidence: 99%

Ultrasensitive Bioanalytical Assays for Cytotoxic Drugs: Focus on Locally Administered Anti-Cancer Agents

Vainchtein¹,

Rosing²,

Schellens³

et al. 2008

TOACJ

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Local administration routes have been investigated to reduce the systemic toxicity and to increase the local efficacy of cytotoxic drugs. Some examples of local administration strategies are cutaneous, intraperitoneal, intrathecal and intravesical chemotherapy. When administered locally, high local drug concentrations can be achieved with increased local efficacy and, conditionally that only small amounts of drug are absorbed into the bloodstream, low systemic toxicity. Our main purpose is to make an inventory and to comment on the availability of ultrasensitive bioanalytical assays that could determine traces of the drugs that may have passed into the bloodstream, e.g. after local application, and which may lead to the systemic toxicity. We conclude that in the last years, multiple ultrasensitive assays have been designed capable to quantitatively determine very low levels of cytotoxic agents e.g. systemically reached after local administration. Most methods are based on the hyphenated liquid chromatography with tandem mass spectrometric detection.

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EO-9 bladder instillations: Formulation selection based on stability characteristics and in vitro simulation studies

Cited by 5 publications

References 5 publications

Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer

Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer

EO9 (Apaziquone): from the clinic to the laboratory and back again

Ultrasensitive Bioanalytical Assays for Cytotoxic Drugs: Focus on Locally Administered Anti-Cancer Agents

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