TY - JOUR
T1 - The pharmacokinetics and pharmacodynamics of high-dose paclitaxel monotherapy (825 mg/m2 continuous infusion over 24 h) with hematopoietic support in women with metastatic breast cancer
AU - Papadopoulos, Kyriakos P.
AU - Egorin, Merrill J.
AU - Huang, May
AU - Troxel, Andrea B.
AU - Kaufman, Elizabeth
AU - Balmaceda, Casilda M.
AU - Vahdat, Linda T.
AU - Hesdorffer, Charles S.
PY - 2001
Y1 - 2001
N2 - Purpose: We evaluated the pharmacokinetics and pharmacodynamics of high-dose paclitaxel (HDP) monotherapy (825 mg/m2 continuous infusion over 24 h) with peripheral blood progenitor cell (PBPC) and G-CSF support in 17 women with metastatic breast cancer. Methods: Pharmacokinetic and pharmacodynamic data were collected in 17 women entered in a phase II trial of sequential HDP, and high-dose melphalan and cyclo-phosphamide/thiotepa/carboplatin. Results: The maximal plasma concentration (Cmax), area under the plasma concentration time curve (AUC), apparent clearance (Clapp), duration of plasma concentration above 0.05 μM (t > 0.05 μM) for paclitaxel were (means±SD): 9.11 ± 7.45 μM, 145 ± 88 μM·h, 8.06 ± 2.90 1/h per m2 and 82.4 ± 31.2 h, respectively. There was a significant correlation between the plasma paclitaxel concentration at 1 h (r2 = 0.87), 12 h (r2 = 0.85) and 23 h (r2 = 0.92) and the AUC (P < 0.0001). Duration of neutropenia was brief (median 3 days, range 0-5 days) and neutrophil recovery occurred earlier (median 6 days, range 0-7 days) than could be attributed to infused PBPC. Median nadir count for platelets was 66 × 109/l (range 13-160 × 109/l). Pharmacodynamic analysis showed no correlation between pharmacokinetic parameters (Cmax, AUC, t > 0.05 μM) and time to neutropenic nadir, duration of neutropenia, platelet count nadir and grades of neuropathy or mucositis. In ten patients in whom detailed neurologic and nerve conduction studies were performed, linear regression analysis showed a significant correlation between pre- and post-HDP treatment total neuropathy scores (r2 = 0.46, P = 0.03). Conclusions: HDP (825 mg/m2 continuous infusion over 24 h) did not appear to be myeloablative. The degree of neurotoxicity subsequent to HDP was associated with the degree of baseline neuropathy but was not predictable from pharmacokinetic parameters.
AB - Purpose: We evaluated the pharmacokinetics and pharmacodynamics of high-dose paclitaxel (HDP) monotherapy (825 mg/m2 continuous infusion over 24 h) with peripheral blood progenitor cell (PBPC) and G-CSF support in 17 women with metastatic breast cancer. Methods: Pharmacokinetic and pharmacodynamic data were collected in 17 women entered in a phase II trial of sequential HDP, and high-dose melphalan and cyclo-phosphamide/thiotepa/carboplatin. Results: The maximal plasma concentration (Cmax), area under the plasma concentration time curve (AUC), apparent clearance (Clapp), duration of plasma concentration above 0.05 μM (t > 0.05 μM) for paclitaxel were (means±SD): 9.11 ± 7.45 μM, 145 ± 88 μM·h, 8.06 ± 2.90 1/h per m2 and 82.4 ± 31.2 h, respectively. There was a significant correlation between the plasma paclitaxel concentration at 1 h (r2 = 0.87), 12 h (r2 = 0.85) and 23 h (r2 = 0.92) and the AUC (P < 0.0001). Duration of neutropenia was brief (median 3 days, range 0-5 days) and neutrophil recovery occurred earlier (median 6 days, range 0-7 days) than could be attributed to infused PBPC. Median nadir count for platelets was 66 × 109/l (range 13-160 × 109/l). Pharmacodynamic analysis showed no correlation between pharmacokinetic parameters (Cmax, AUC, t > 0.05 μM) and time to neutropenic nadir, duration of neutropenia, platelet count nadir and grades of neuropathy or mucositis. In ten patients in whom detailed neurologic and nerve conduction studies were performed, linear regression analysis showed a significant correlation between pre- and post-HDP treatment total neuropathy scores (r2 = 0.46, P = 0.03). Conclusions: HDP (825 mg/m2 continuous infusion over 24 h) did not appear to be myeloablative. The degree of neurotoxicity subsequent to HDP was associated with the degree of baseline neuropathy but was not predictable from pharmacokinetic parameters.
KW - Neurotoxicity
KW - Paclitaxel
KW - Three-compartment nonlinear model
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U2 - 10.1007/s002800000193
DO - 10.1007/s002800000193
M3 - Article
C2 - 11221961
AN - SCOPUS:0034919865
SN - 0344-5704
VL - 47
SP - 45
EP - 50
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 1
ER -