Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs

Rousseau, Annick; Marquet, Pierre

doi:10.1046/j.1472-8206.2002.00086.x

Cited by 87 publications

(43 citation statements)

References 66 publications

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“…It has been suggested that TDM should be reserved for only a proportion of patients, depending on factors such as tumor type, anticancer drug, and patient characteristics [74]. However, despite its limitations, more and more research is being done on the use of TDM in oncology [73][74][75]. For example, Ratain et al [17] introduced a (complex) formula to dose etoposide based on pretreatment WBC, among others, whereas a populationbased Bayesian methodology to routinely adjust etoposide therapy when given as a 5-day infusion, based on its pharmacokinetic profile as determined on the first day, was proposed by others [76].…”

Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

Flat-Fixed Dosing Versus Body Surface Area–Based Dosing of Anticancer Drugs in Adults: Does It Make a Difference?

et al. 2007

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LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Describe how and why BSA-based dosing was implemented into oncology. 2. Discuss if flat-fixed dosing of adults has advantages over BSA-based dosing in terms of interpatient pharmacokinetic variation of anticancer drugs, efficiency, and costs. 3. Explain which alternative dosing strategies for BSA-based dosing may have potential, leading to a minimum of adverse events and superior therapeutic outcome.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTThe current practice of using body-surface area (BSA) in dosing anticancer agents was implemented in clinical oncology half a century ago. By correcting for BSA, it was generally assumed that cancer patients would receive a dose of a particular cytotoxic drug associated with an acceptable degree of toxicities without reducing the agent's therapeutic effect. More recently, doubt has arisen to this hypothesis, and for many drugs, the effects of BSA on the pharmacokinetics of these agents have therefore been studied retrospectively. In (by far) most cases, use of BSA does not reduce the interindividual variation in the pharmacokinetics of adults, and thus, a logical rationale for further use of this tool in dosing adults is lacking. As a result, alternative dosing strategies have been proposed in order to replace BSA-based dosing. Flat-fixed dosing regimens have been suggested, thereby avoiding potential dose calculation mistakes. As flat-fixed dosing does not typically lead to greater pharmacokinetic variability, it does not seem worse than using BSA-based dosing. While it provides a simplification, it can, however, be questioned whether to call this an improvement or not. Classic cytotoxic agents are known for their relatively narrow therapeutic window. This means that "low" doses of these drugs may not be effective, while "high" doses may be (very) toxic for the patient. Therefore, the optimal dose should be somewhere in between, thereby leading to the best possible treatment, which means yielding maximal therapeutic effect given tolerable and manageable toxicities. Based on the theory that large patients have a larger volume of distribution and a higher metabolizing capacity, it is assumed that those patients need to be dosed higher than smaller patients to reach equal drug concentrations. For this reason, traditionally, the administered dose is typically adjusted to the body-surface area (BSA) of the individual patient. BSA was originally calculated using a formula based on length and weight developed by DuBois and DuBois in 1916 [1] from an investigation that involved only nine individuals (Table 1) [1][2][3][4][5]. Although validation of the derived formula was not performed initially [3, 4], the use of BSA was incorporated into animal studies for the purpose of allometric scaling, and in the 1950s, BSA-based dosing was introduced into pediatric oncology [6,7]. Without further study, its use was also incorporated int...

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Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

Flat-Fixed Dosing Versus Body Surface Area–Based Dosing of Anticancer Drugs in Adults: Does It Make a Difference?

et al. 2007

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“…Of the many challenges, ensuring that optimal exposures of drug are achieved in tumor versus normal tissues is one of the most important (reviewed in refs. [1][2][3]. The field of pharmacokinetics, which is concerned with the absorption, distribution, metabolism, and excretion of drugs, is instrumental to the drug development process and is applied to both preclinical and clinical investigations.…”

Section: Introductionmentioning

confidence: 99%

“…The nonradioactive plasma data were convolved with the group average human PET temozolomide IRF to calculate tissue concentrations of the drug under different clinically used dosing schedules. The short elimination half-life of temozolomide ensures that there is minimal drug accumulation NOTE: VD (1) , K 1 , and MRT (mean residence time) were calculated using spectral analysis (12) and averaging over m slices from scans of n patients; VD (2) was calculated using the rank-shaped estimator (28). Tissue pharmacokinetic parameters derived with and without contribution of regional blood volume are presented.…”

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confidence: 99%

A New Model for Prediction of Drug Distribution in Tumor and Normal Tissues: Pharmacokinetics of Temozolomide in Glioma Patients

et al. 2008

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Difficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m 2 /d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 Mg/mL in human glioma tumors and from 1.8 to 3.7 Mg/mL in normal brain, with the total drug exposure, as indicated by the tissue/ plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules. [Cancer Res 2009;69(1):120-7]

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“…The serious adverse effects of anticancer drugs in the clinical setting are often mentioned in the literature. [3][4][5] Site-specific targeting of anticancer drugs to tumor tissues remain a major challenge in cancer chemotherapy. [5][6][7] To overcome these drawbacks, nanomaterials, nanoparticles, polymer-drug conjugates, and nanodevices have been extensively investigated in the last 2 decades.…”

Section: Introductionmentioning

confidence: 99%

Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery

Lee¹,

Jeong²,

Park³

et al. 2015

IJN

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Background Since cancer cells are normally over-expressed cathepsin B, we synthesized dendrimer-methoxy poly(ethylene glycol) (MPEG)-doxorubicin (DOX) conjugates using a cathepsin B-cleavable peptide for anticancer drug targeting. Methods Gly-Phe-Leu-Gly peptide was conjugated with the carboxylic acid end groups of a dendrimer, which was then conjugated with MPEG amine and doxorubicin by aid of carbodiimide chemistry (abbreviated as DendGDP). Dendrimer-MPEG-DOX conjugates without Gly-Phe-Leu-Gly peptide linkage was also synthesized for comparison (DendDP). Nanoparticles were then prepared using a dialysis procedure. Results The synthesized DendGDP was confirmed with 1 H nuclear magnetic resonance spectroscopy. The DendDP and DendGDP nanoparticles had a small particle size of less than 200 nm and had a spherical morphology. DendGDP had cathepsin B-sensitive drug release properties while DendDP did not show cathepsin B sensitivity. Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an in vivo CT26 tumor xenograft model, ie, the volume of the CT26 tumor xenograft was significantly inhibited when compared with xenografts treated with doxorubicin or DendDP nanoparticles. The DendGDP nanoparticles were found to be relatively concentrated in the tumor tissue and revealed stronger fluorescence intensity than at other body sites while doxorubicin and DendDP nanoparticles showed strong fluorescence intensity in the various organs, indicating that DendGDP has cathepsin B sensitivity. Conclusion DendGDP is sensitive to cathepsin B in tumor cells and can be used as a cathepsin B-responsive drug targeting strategy. We suggest that DendGDP is a promising vehicle for cancer cell targeting.

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Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs

Cited by 87 publications

References 66 publications

Flat-Fixed Dosing Versus Body Surface Area–Based Dosing of Anticancer Drugs in Adults: Does It Make a Difference?

Flat-Fixed Dosing Versus Body Surface Area–Based Dosing of Anticancer Drugs in Adults: Does It Make a Difference?

A New Model for Prediction of Drug Distribution in Tumor and Normal Tissues: Pharmacokinetics of Temozolomide in Glioma Patients

Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery

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