2004
DOI: 10.1038/sj.bjc.6601469
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Factors affecting pharmacokinetic variability of oral topotecan: a population analysis

Abstract: The aim of this study was to characterise the pharmacokinetics of the anticancer agent topotecan, and explore the influence of patient covariates and interoccasion variability on drug disposition. Data were obtained from 190 patients who received the drug as a 30-min infusion (N ¼ 72) or orally (N ¼ 118). The population model was built with the use of NONMEM to identify candidate covariates, and obtain models for clearance (CL) and volume of distribution. The final models were based on first-order absorption w… Show more

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Cited by 31 publications
(24 citation statements)
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“…Due to the GLS method used here, our quantitative estimate should be less biased and additionally corresponded to preclinical data of a highly synergistic pharmacodynamic interaction between both drugs (39). A pharmacokinetic interaction has been excluded by others (20,40). Overall, both significant and nonsignificant relations on SLOPE of all drugs were in good agreement with published data and can be regarded as a quality control of our analyses.…”
Section: Discussionsupporting
confidence: 74%
“…Due to the GLS method used here, our quantitative estimate should be less biased and additionally corresponded to preclinical data of a highly synergistic pharmacodynamic interaction between both drugs (39). A pharmacokinetic interaction has been excluded by others (20,40). Overall, both significant and nonsignificant relations on SLOPE of all drugs were in good agreement with published data and can be regarded as a quality control of our analyses.…”
Section: Discussionsupporting
confidence: 74%
“…First, the median (range) transient time (4/k bp ) was 2.5 (1.4-5.4) days for blasts to proceed though the various differentiation stages and to enter the circulation. Whereas this time was shorter than the range of 4 to 10 days in normal bone marrow (24, 28 -30), it was reflective of the shortened transition time associated with increased endogenous G-CSF due to decreased ANC as a result of topotecan therapy (31,32). Second, the median (range) IC 50 was 0.54 (0.001-2.4) ng/mL, which was consistent with the in vitro determination of the IC 50 of 1.2 ng/mL in human granulocyte-macrophage colony-forming unit cells (33).…”
Section: Resultsmentioning
confidence: 98%
“…Pharmacokinetic studies were repeated each day until the patient's AUC was within the target range. The second cycle of topotecan was given at a median (range) of 25 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) days after the start of the first cycle. The dosage given on day 1 of the second cycle was that determined to attain the target AUC during the first course of therapy.…”
Section: Methodsmentioning
confidence: 99%
“…Th e individual concentration-timecourse of topotecan and etoposide were derived from observed plasma concentrations and PK models developed by Legér et al [20] and Toff oli et al [21], respectively. For etoposide two plasma concentration samples per patient and treatment course were sampled [14] and for topotecan 185 plasma concentration measurements of total topotecan were obtained in the fi rst treatment course [15,16].…”
Section: Pharmacokineticsmentioning
confidence: 99%