Pharmacokinetics, pharmacodynamics and adherence to oral topotecan in myelodysplastic syndromes: A cancer and leukemia group B study

Cheri E. Klein, Helen Kastrissios, Antonius A. Miller, Donna Hollis, Daohai Yu, Gary L. Rosner, David L. Grinblatt, Richard A. Larson, Mark J. Ratain

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: To evaluate medication adherence, pharmacokinetics and exposure versus response relationships in patients with myelodysplastic syndromes (MDS). Methods: Ninety adult patients with MDS received oral topotecan (1.2 mg/m 2) either once a day for 10 days or twice a day for 5 days every 21 days for up to six cycles. Dosing histories were collected using electronic monitoring devices fitted to medication vials. Topotecan plasma concentrations were measured, and exposure was determined by a sparse sampling approach and Bayesian estimation methods. Relationships between exposure and clinical response and toxicity were evaluated using logistic regression. Results: Overall adherence was excellent with 90% of patients taking the prescribed number of doses in cycle 1. Adherence did not differ between the two regimens. Topotecan pharmacokinetics were described using a one compartment open model with first order absorption and elimination. Pharmacokinetic parameter estimates did not differ between the once a day and twice a day dosing groups. While topotecan exposure was greater in the twice a day arm compared to the once a day arm due to drug accumulation, exposure did not correlate with clinical response. However, the probability of needing a platelet transfusion in the twice a day arm was significantly increased (by 35%) as a result of greater steady-state plasma topotecan concentrations. Conclusions: Adherence is high in patients with MDS receiving oral topotecan, whether the drug is prescribed once or twice daily. The optimal schedule cannot be determined from this study, as there was no evident relationship between any pharmacokinetic parameter and clinical response.

Original languageEnglish (US)
Pages (from-to)199-206
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume57
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

Keywords

  • Adherence
  • Exposure-response
  • Myelodysplastic syndromes
  • Pharmacokinetics
  • Topotecan

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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