PMID- 7799018
OWN - NLM
STAT- MEDLINE
DCOM- 19950123
LR  - 20220410
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 13
IP  - 1
DP  - 1995 Jan
TI  - Nonlinear pharmacokinetics and metabolism of paclitaxel and its 
      pharmacokinetic/pharmacodynamic relationships in humans.
PG  - 180-90
AB  - PURPOSE: To characterize and model the disposition of paclitaxel in humans and 
      define a pharmacodynamic relationships between paclitaxel disposition and its 
      toxicity and efficacy. PATIENTS AND METHODS: Paclitaxel pharmacokinetics were 
      studied in 55 courses of therapy in 30 patients. Paclitaxel was administered at 
      135 mg/m2 or 175 mg/m2 by either a 3- or a 24-hour infusion schedule to patients 
      with advanced ovarian cancer (n = 15), or at 225 mg/m2 by 3-hour infusion to 
      patients with advanced breast cancer (n = 15). Paclitaxel and 6 
      alpha-hydroxylpaclitaxel were quantified by high-performance liquid 
      chromatography (HPLC). Pharmacokinetics were assessed by noncompartmental and 
      model-dependent methods. Pharmacodynamic correlations were evaluated 
      statistically and by regression models. RESULTS: Paclitaxel disposition is 
      nonlinear in humans and, on the 3-hour schedule, 6 alpha-hydroxylpaclitaxel was 
      identified in the plasma of all patients treated. The plasma disposition of 
      paclitaxel and 6 alpha-hydroxylpaclitaxel was well described by a model that 
      featured multiple nonlinear processes. Neutropenia was not related to the areas 
      under the curves (AUCs) of paclitaxel or 6 alpha-hydroxylpaclitaxel, or to 
      palitaxel peak concentrations (Cmax). Neutropenia was related to the duration 
      that plasma concentrations were > or = 0.05 mumol/L, a relationship that is well 
      described by a sigmoid maximum response (Emax) model. CONCLUSION: The disposition 
      of paclitaxel in humans is nonlinear. Paclitaxel metabolism to 6 
      alpha-hydroxylpaclitaxel is likely an important detoxification pathway. 
      Myelosuppression is related to the duration that plasma paclitaxel concentrations 
      are > or = 0.05 mumol/L. Trials of new doses and schedules of paclitaxel should 
      take into account its nonlinear disposition to rule out adverse clinical 
      consequences, especially if the drug is administered by short infusion. Our 
      pharmacokinetic model should prove to be a powerful tool in predicting paclitaxel 
      disposition, regardless of dose and schedule, and should facilitate further 
      pharmacodynamic investigations.
FAU - Gianni, L
AU  - Gianni L
AD  - Division of Medical Oncology, Instituto Nazinale per lo Studio e la Cura dei 
      Tumori, Milano, Italy.
FAU - Kearns, C M
AU  - Kearns CM
FAU - Giani, A
AU  - Giani A
FAU - Capri, G
AU  - Capri G
FAU - Vigano, L
AU  - Vigano L
FAU - Lacatelli, A
AU  - Lacatelli A
FAU - Bonadonna, G
AU  - Bonadonna G
FAU - Egorin, M J
AU  - Egorin MJ
LA  - eng
GR  - U10.CA44691/CA/NCI NIH HHS/United States
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
MH  - Aged
MH  - Breast Neoplasms/*metabolism
MH  - Chromatography, High Pressure Liquid
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Middle Aged
MH  - Neutropenia/*chemically induced
MH  - Ovarian Neoplasms/*metabolism
MH  - Paclitaxel/administration & dosage/*adverse effects/blood/*pharmacokinetics
MH  - Time Factors
EDAT- 1995/01/01 00:00
MHDA- 1995/01/01 00:01
CRDT- 1995/01/01 00:00
PHST- 1995/01/01 00:00 [pubmed]
PHST- 1995/01/01 00:01 [medline]
PHST- 1995/01/01 00:00 [entrez]
AID - 10.1200/JCO.1995.13.1.180 [doi]
PST - ppublish
SO  - J Clin Oncol. 1995 Jan;13(1):180-90. doi: 10.1200/JCO.1995.13.1.180.