Population Pharmacokinetic Model for Topotecan Derived From Phase I Clinical Trials

Gallo, James M.; Laub, Paul B.; Rowinsky, Eric K.; Grochow, Louise B.; Baker, Sharyn D.

doi:10.1200/jco.2000.18.12.2459

Cited by 53 publications

(32 citation statements)

References 20 publications

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“…Population pharmacokinetic parameters of topotecan were similar to previously reported parameter estimates obtained using a population approach (Gallo et al, 2000) and a standard two-stage analysis (Wall et al, 1992;van Warmerdam et al, 1995) after singleagent administration of 0.5 -2.0 mg m À2 topotecan in the daily times five schedule. Gallo et al reported a CL of 32 l h À1 and volume of distribution at steady state (V ss ) of 120 l, whereas the current analysis found 29 l h À1 and 80 l, respectively.…”

Section: Discussionsupporting

confidence: 62%

Phase I and pharmacokinetic study of the combination of topotecan and ifosfamide administered intravenously every 3 weeks

et al. 2004

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To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetics of topotecan administered as a 30-min intravenous (i.v.) infusion over 5 days in combination with a 1-h i.v. infusion of ifosfamide (IF) for 3 consecutive days every 3 weeks. Patients with advanced malignancies refractory to standard therapy were entered into the study. The starting dose of topotecan was 0.4 mg m À2 day À1 Â 5 days. Ifosfamide was administered at a fixed dose of 1.2 g m À2 day À1 Â 3 days. In all, 36 patients received 144 treatment courses. Owing to toxicities, the schedule of topotecan administration was reduced from 5 to 3 days. The MTD was reached at topotecan 1.2 mg m À2 day À1 Â 3 days with IF 1.2 g m À2 day À1 Â 3 days. Haematological toxicities were dose limiting. Neutropenia was the major toxicity. Thrombocytopenia and anaemia were rare. Nonhaematological toxicities were relatively mild. Partial responses were documented in three patients with ovarian cancer dosed below the MTD. Topotecan and IF did not appear to interact pharmacokinetically. The relationships between the exposure to topotecan lactone and total topotecan, and the decrease in absolute neutrophil count and the decrease in thrombocytes, were described with sigmoidal -E max models. The combination of 1.0 mg m À2 day À1 topotecan administered as a 30-min i.v. infusion daily times three with 1.2 g m À2 day À1 IF administered as a 1-h i.v. infusion daily times three every 3 weeks was feasible. However, the combination schedule of topotecan and IF did result in considerable haematological toxicity and in conjunction with previously reported pronounced nonhaematological toxicities and treatment related deaths, it may be concluded that this is not a favourable combination.

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Section: Discussionsupporting

confidence: 62%

Phase I and pharmacokinetic study of the combination of topotecan and ifosfamide administered intravenously every 3 weeks

et al. 2004

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“…body weight, serum creatinine, and sex), the accuracy of prediction of topotecan clearance (CL) can be improved only partly (Gallo et al, 2000;Montazeri et al, 2000;Mould et al, 2002). Moreover, clinical protocols are based on repeated daily administrations (usually, 5 consecutive days) giving the opportunity to perform a dose adjustment according to the observed exposure on Day 1.…”

mentioning

confidence: 99%

Factors affecting pharmacokinetic variability of oral topotecan: a population analysis

et al. 2004

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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 with lag-time (oral data), and a two-compartment model with linear elimination from the central compartment. The Cockcroft -Gault creatinine clearance (CrCl) and WHO performance status (PS) were the only significant covariates: CL ¼ (12.8 þ 2.1 Â CrCl) Â (1À0.12 Â PS). For the volume of distribution, a correlation was found between body weight and the central volume (V1) ¼ 0.58 Â body weight. Based on the structural models, a limited-sampling strategy was developed with minor bias and good precision that can be applied a posteriori using timed samples obtained at 1.5, and 6 h after the administration of topotecan. In conclusion, a population pharmacokinetic model for topotecan has been developed that incorporates measures of renal function and PS to predict CL. In combination with drug monitoring, the limited sampling strategy allows individualised treatment for patients receiving oral topotecan.

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“…Numerous patients present severe neutropenia as a consequence of a large area under the curve of plasma topotecan concentrations (14). These observations are not surprising regarding the poor correlation between topotecan clearance and BSA (12). In the summary of product characteristics, guidelines for adaptation of topotecan dosage recommend reducing the administered dose by 50% for patients with creatinine clearance ranging between 20 and 40 mL/minute, and to exclude patients with lower values (15).…”

Section: Discussionmentioning

confidence: 99%

“…A proportional error model was used for residual and interpatient variabilities. This model has been previously selected as the best structural pharmacokinetic model for three-population pharmacokinetic analyses (8,12,13).…”

Section: Methodsmentioning

confidence: 99%

Serum Cystatin C is a Better Marker of Topotecan Clearance than Serum Creatinine

Hoppe¹,

Séronie-Vivien²,

Thomas³

et al. 2005

Clinical Cancer Research

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Purpose: To evaluate plasma cystatin level as a covariate to predict topotecan pharmacokinetics.Cystatin C, a member of the cystatin superfamily of cysteine proteinase inhibitors, has been recently proposed as an alternative endogenous marker of glomerular filtration. Renal function is known as a key factor of topotecan clearance. Experimental Design: Data were obtained from 59 patients who underwent drug monitoring for individual dosing of topotecan. Topotecan plasma concentrations versus time were analyzed using a nonlinear mixed effect model according to a two-compartment pharmacokinetic model and a first-order conditional estimation method. A proportional error model was used for residual and interpatient variabilities. Data-splitting was done randomly to create a model-building data set (44 patients) and a model validation data set (15 patients).Results: Using the building data set, four covariates significantly decreased the objective function value and interindividual variability on topotecan clearance (CL) when tested individually: ideal body weight (IBW), serum creatinine, age, and cystatin C level. The best model was: CL (L/hour) = 20.2 [cystatin C (mg/L) / 1.06] À0.60 [IBW (kg) / 57] 0.95 . Prospective evaluation using the validation data set confirmed that the model based on cystatin C had a better predictive value than the models based on serum creatinine or body surface area. Conclusion: Cystatin C is a marker of drug elimination which is superior to serum creatinine for topotecan. It deserves to be further explored as a promising covariate for drug dosing as well as selection criteria for clinical studies of drugs eliminated mainly or partially by the kidney.

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Population Pharmacokinetic Model for Topotecan Derived From Phase I Clinical Trials

Cited by 53 publications

References 20 publications

Phase I and pharmacokinetic study of the combination of topotecan and ifosfamide administered intravenously every 3 weeks

Phase I and pharmacokinetic study of the combination of topotecan and ifosfamide administered intravenously every 3 weeks

Factors affecting pharmacokinetic variability of oral topotecan: a population analysis

Serum Cystatin C is a Better Marker of Topotecan Clearance than Serum Creatinine

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