Abstract
Purpose
Controversy exists over the optimal dose rate for administration of gemcitabine. There is a strong pharmacologic rationale for increased intracellular accumulation with prolonged infusions, but this failed to translate into a significant benefit in a large randomized study. The purpose of this study was to compare the intracellular pharmacokinetics of gemcitabine given for 30 minutes or for 100 minutes in a crossover design.
Patients and Methods
We randomly assigned 33 patients to a standard dose of 1,000 mg/m2 over either 30 minutes or 100 minutes. At the second week, they were transferred to the alternate schedule. Blood samples were collected at various times after the gemcitabine infusion. Gemcitabine and difluorodeoxyuridine were measured in plasma by high-performance liquid chromatography (HPLC), and gemcitabine-triphosphate was measured by HPLC in leukocytes.
Results
Intracellular accumulation was greater during the 100-minute infusion, which was consistent with previous data. This effect was confounded by an increase in gemcitabine-triphosphate accumulation between weeks 1 and 2, which was consistent with self-induction of gemcitabine accumulation. There was significant heterogeneity: 27% of patients had greater WBC accumulation during the 30-minute infusion (regardless of treatment order). Patients with relatively greater levels of gemcitabine-triphosphate in WBCs tended to have less under-dosing and a greater reduction in midcycle neutrophils. However, this observation did not correlate with plasma gemcitabine levels.
Conclusion
This work identifies significant variations in intracellular gemcitabine-triphosphate accumulation between and within individuals, and it provides evidence that this variation has potential clinical significance. The observed self-induction of gemcitabine metabolism has broad implications for the dosing of nucleoside analogs.
Controversy exists over the optimal dose rate for administration of gemcitabine. There is a strong pharmacologic rationale for increased intracellular accumulation with prolonged infusions, but this failed to translate into a significant benefit in a large randomized study. The purpose of this study was to compare the intracellular pharmacokinetics of gemcitabine given for 30 minutes or for 100 minutes in a crossover design.
Patients and Methods
We randomly assigned 33 patients to a standard dose of 1,000 mg/m2 over either 30 minutes or 100 minutes. At the second week, they were transferred to the alternate schedule. Blood samples were collected at various times after the gemcitabine infusion. Gemcitabine and difluorodeoxyuridine were measured in plasma by high-performance liquid chromatography (HPLC), and gemcitabine-triphosphate was measured by HPLC in leukocytes.
Results
Intracellular accumulation was greater during the 100-minute infusion, which was consistent with previous data. This effect was confounded by an increase in gemcitabine-triphosphate accumulation between weeks 1 and 2, which was consistent with self-induction of gemcitabine accumulation. There was significant heterogeneity: 27% of patients had greater WBC accumulation during the 30-minute infusion (regardless of treatment order). Patients with relatively greater levels of gemcitabine-triphosphate in WBCs tended to have less under-dosing and a greater reduction in midcycle neutrophils. However, this observation did not correlate with plasma gemcitabine levels.
Conclusion
This work identifies significant variations in intracellular gemcitabine-triphosphate accumulation between and within individuals, and it provides evidence that this variation has potential clinical significance. The observed self-induction of gemcitabine metabolism has broad implications for the dosing of nucleoside analogs.
| Original language | English |
|---|---|
| Pages (from-to) | 5704-5709 |
| Number of pages | 6 |
| Journal | Journal of Clinical Oncology |
| Volume | 25 |
| Issue number | 36 |
| DOIs | |
| Publication status | Published - 20 Dec 2007 |
| Externally published | Yes |