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 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.

Population Pharmacokinetic-Pharmacodynamic Model for Neutropenia with Patient Subgroup Identification: Comparison across Anticancer Drugs

“…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.…”

Using Pharmacokinetic and Pharmacodynamic Modeling and Simulation to Evaluate Importance of Schedule in Topotecan Therapy for Pediatric Neuroblastoma

“…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).…”

“…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.…”

Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression

“…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].…”