A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979)

Callies, Sophie; Alwis, Dinesh P. de; Wright, James G.; Sandler, Alan; Burgess, Michael; Aarons, Leon

doi:10.1007/s00280-002-0542-3

Cited by 38 publications

(54 citation statements)

References 22 publications

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“…Determination of the optimal PK sampling time points for the trial was based on a model derived from adult data [14]. An initial population pharmacokinetic model for doxorubicin and doxorubicinol in children was set up from datasets of three earlier studies (two adults and one child) using NONMEM ® 7.2.…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial

Krischke

Hempel

Völler

et al. 2016

Cancer Chemother Pharmacol

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PurposeDoxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited.MethodsWe conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited. Doses of doxorubicin ranged from 10.4 to 57.7 mg/m2. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after two administrations, with five samples collected in children <3 years and eight in children ≥3 years. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. Natriuretic peptides and cardiac troponins were measured to evaluate their role as early indicators of cardiotoxicity.ResultsAge dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a statistically significant lower clearance (21.1 ± 5.8 l/h/m2) than older children (26.6 ± 6.7 l/h/m2) (p = 0.0004) after correcting for body surface area. No effect of the investigated genetic polymorphisms on the pharmacokinetics could be observed. Although natriuretic peptides were transiently elevated after each doxorubicin administration and troponin levels increased with increasing doxorubicin exposure, only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics.ConclusionIn the European framework of funding and regulatory support, an add-on study to existing therapeutic trials was developed. The pediatric need concerning missing PK data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were generally found to be justified based on our PK analyses.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3174-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial

Krischke

Hempel

Völler

et al. 2016

Cancer Chemother Pharmacol

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“…The development of population PK models for doxorubicin and doxo'ol have been reported in previous studies [34,[40][41][42]. Doxorubicin is typically described by a threecompartment model.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic modelling of acute N‐terminal pro B‐type natriuretic peptide after doxorubicin infusion in breast cancer

Liang

Brundage

Jacobson

et al. 2016

Brit J Clinical Pharma

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AIMSThe aim of the present study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to characterize the relationship between plasma doxorubicin and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations within 48 h of doxorubicin treatment. METHODSThe study enrolled 17 female patients with stages 1-3 breast cancer and receiving adjuvant doxorubicin (60 mg m -2 ) and cyclophosphamide (600 mg m -2 ) every 14 days for four cycles. In two consecutive cycles, plasma concentrations of doxorubicin, doxorubicinol, troponin and NT-proBNP were collected before infusion, and up to 48 h after the end of doxorubicin infusion. Nonlinear mixed-effects modelling was used to describe the PK-PD relationship of doxorubicin and NT-proBNP. RESULTSA three-compartment parent drug with a one-compartment metabolite model best described the PK of doxorubicin and doxorubicinol. Troponin concentrations remained similar to baseline. An indirect PD model with transit compartments best described the relationship of doxorubicin exposure and acute NT-proBNP response. Estimated PD parameters were associated with large between-subject variability (total assay variability 38.8-73.9%). Patient clinical factors, including the use of enalapril, were not observed to be significantly associated with doxorubicin PK or NT-proBNP PD variability. CONCLUSIONThe relationship between doxorubicin concentration and the acute NT-proBNP response was successfully described with a population PK-PD model. This model will serve as a valuable framework for future studies to identify clinical factors associated with the acute response to doxorubicin. Future studies are warranted to examine the relationship between this acute response and subsequent heart failure. Should such a relationship be established, this model could provide useful information on patients' susceptibility to doxorubicin-induced long-term cardiotoxicity. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Doxorubicin is a first-line cytotoxic agent used for treating patients with malignancies, including breast cancer. However, total lifetime doses, and thus efficacy, are capped to limit the associated cardiomyopathy and congestive heart failure.• Despite limited total doses, cardiotoxicity can develop in 2-7% of patients months or even years after treatment, and angiotensin-converting enzyme (ACE) inhibitors are often prescribed to prevent and reduce severity.• Early predictive markers of susceptibility are needed, so patients at greatest risk could be identified and personalized approaches to treatment developed. WHAT THIS STUDY ADDS• N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin are commonly measured cardiac biomarkers, and we observed that plasma NT-proBNP concentrations dramatically increased 24-48 h after doxoburicin infusion, but troponin did not.• A population pharmacokinetic-pharmacodynamic model was developed to describe the relationship between doxorubicin exposure and the plasma acute NT-proBNP response.• High (...

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“…In clinical trials, co-administration of the multi-drug resistance (MDR) modulators, such as zosuquidar, with DOX, led to increased exposure to DOX and DOXol [12]. When applying the classic MDR modulator, cyclosporine, the AUC of DOX and DOXol increased by 55 and 350%, respectively.…”

Section: Doxorubicinol Formation and Pharmacokineticsmentioning

confidence: 99%

“…Cancer cell resistance is a significant problem among patients treated with ANT [12, 13, 30]. A major mechanism found to play a dominant role in this phenomenon is the active transport of drugs across the cell membrane.…”

Section: Significance Of Doxol Formation In Cancer Resistancementioning

confidence: 99%

Metabolic carbonyl reduction of anthracyclines — role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents

et al. 2017

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SummaryAnthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in cancer therapy, their usefulness is greatly limited by their cardiotoxicity. Possible mechanisms of ANT cardiotoxicity include their conversion to secondary alcohol metabolites (i.e. doxorubicinol, daunorubicinol) catalyzed by carbonyl reductases (CBR) and aldo-keto reductases (AKR). These metabolites are suspected to be more cardiotoxic than their parent compounds. Moreover, overexpression of ANT-reducing enzymes (CBR and AKR) are found in many ANT-resistant cancers. The secondary metabolites show decreased cytotoxic properties and are more susceptible to ABC-mediated efflux than their parent compounds; thus, metabolite formation is considered one of the mechanisms of cancer resistance. Inhibitors of CBR and AKR were found to reduce the cardiotoxicity of ANT and the resistance of cancer cells, and therefore are being investigated as prospective cardioprotective and chemosensitizing drug candidates. In this review, the significance of a two-electron reduction of ANT, including daunorubicin, epirubicin, idarubicin, valrubicin, amrubicin, aclarubicin, and especially doxorubicin, is described with respect to toxicity and efficacy of therapy. Additionally, CBR and AKR inhibitors, including monoHER, curcumin, (−)-epigallocatechin gallate, resveratrol, berberine or pixantrone, and their modulating effect on the activity of ANT is characterized and discussed as potential mechanism of action for novel therapeutics in cancer treatment.

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A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979)

Cited by 38 publications

References 22 publications

Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial

Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial

Pharmacokinetic–pharmacodynamic modelling of acute N‐terminal pro B‐type natriuretic peptide after doxorubicin infusion in breast cancer

Metabolic carbonyl reduction of anthracyclines — role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents

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