Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans.

Gianni, Luca; Kearns, Cristin; Giani, Antonio; Capri, Giuseppe; Viganò, Lucia; Lacatelli, A; Bonadonna, Gianni; Egorin, Merrill J.

doi:10.1200/jco.1995.13.1.180

Cited by 479 publications

(300 citation statements)

References 17 publications

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“…The pharmacokinetics of full-dose paclitaxel at much higher concentrations of 135 mg/m 2 , 175 mg/m 2 and 225 mg/m 2 was previously investigated by Gianni et al (16). These investigators reported important pharmacokinetic characteristics and the impact on bone marrow suppression by the differences of drug concentrations and infusion time.…”

Section: Discussionmentioning

confidence: 98%

“…A previously described 3-compartment non-linear model was fit to the plasma paclitaxel concentration versus time profile of each patient (16). In this analysis, the model was fit to the data using Bayesian estimation with previously described population means and variances as prior information for each pharmacokinetic parameter estimated by the model as described (16).…”

Section: Pharmacokinetic Measurementsmentioning

confidence: 99%

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Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule–Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non–Small-Cell Lung Cancer

Chen

Pandya

Feins

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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Purpose-We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a phase I study for inoperable non-small cell lung cancer (NSCLC).Methods and Materials-Paclitaxel at escalating doses of 15 mg/m 2 , 20 mg/m 2 , and 25 mg/m 2 were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation (RT) was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by High Performance Liquid Chromatography (HPLC).Results-Dose-limiting toxicities included 3/18 patients with grade 3 pneumonitis and 3/18 patients with grade 3 esophagitis. There was no grade 4 or 5 pneumonitis or esophagitis. There was no grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For dose levels I (15 mg/m 2 ), II (20 mg/m 2 ), and III (25 mg/m 2 ), the mean peak plasma level was 0.23 ±0.06 μM, 0.32±0.05 μM, and 0.52±0.14 μM, respectively; AUC was 0.44± 0.09 μM, 0.61± 0.1 μM, and 0.96± 0.23 μM, respectively; and duration of drug concentration above 0.05 μM (t >0.05 μM) was 1.6± 0.3 hr, 1.9± 0.2 hr, and 3.0± 0.9 hr, respectively. Conclusion-Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration above 0.05 μM for a minimum of 1.6 hours was sufficient for effective radiosensitization.

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Section: Discussionmentioning

confidence: 98%

Section: Pharmacokinetic Measurementsmentioning

confidence: 99%

Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule–Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non–Small-Cell Lung Cancer

Chen

Pandya

Feins

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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“…Interestingly, the BID dose regimen provided a higher overall response rate than the QD dose regimen under the same total daily dose of 750 mg or 1000 mg. The threshold analysis has been previously conducted to explore whether there was a drug concentration level above which exposure correlated with a clinical event (clinical responses or toxicity) 21, 24. The current threshold analysis identified a relatively high threshold concentration of approximately 300 ng/mL (Figure 4), exposure above which is well correlated with the clinical response and is consistent with the findings from the population pharmacokinetic analysis, which showed that CC‐292 has a relatively poor distribution property; ie, the CC‐292 clearance rate is much faster than its distribution rate.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Exposure Response Assessment of CC‐292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia

Li¹,

Ramírez‐Valle²,

Xue³

et al. 2017

The Journal of Clinical Pharma

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CC‐292, a potent Bruton tyrosine kinase inhibitor, is under development for the treatment of B‐cell malignancies. An analysis was performed to develop a population pharmacokinetic model of CC‐292 and assess the influence of demographics and disease‐related covariates on CC‐292 exposure and to assess the exposure‐response (overall response rate) relationship in patients with chronic lymphocytic leukemia. Population pharmacokinetic analysis was based on a 2‐compartment base model conducted in NONMEM. Categorical exposure‐response analysis was performed using logistic regression in SAS. The population pharmacokinetic analysis results indicated that CC‐292 pharmacokinetic disposition is similar between healthy subjects and patients. CC‐292 showed a larger central compartment volume of distribution than the peripheral compartment volume of distribution (158 L and 72 L, respectively) and a faster clearance than intercompartmental clearance (134 L/h and 18.7 L/h, respectively), indicating that for CC‐292, clearance from blood occurs faster than distribution into deep tissues and organs. CC‐292 clearance is not affected by demographics or baseline clinical lab factors, except for sex. Although sex significantly reduced variation of apparent clearance, the sex effect on apparent clearance is unlikely to be clinically relevant. The exposure‐response analysis suggested that higher drug exposure is linearly correlated with higher overall response rate. A twice‐daily dose regimen showed higher overall response rate as compared to once‐daily dosing, consistent with a threshold concentration of approximately 300 ng/mL, above which the probability of overall response rate significantly increases.

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“…Among the major toxicities of paclitaxel, neutropenia has been shown to be schedule dependent (Tamura et al, 1994;Gianni et al, 1995;Ohtsu et al, 1995;Tamura et al, 1995). As for neuromuscular toxicity, although neuropathy and myalgia/arthralgia appeared to be more severe in a phase I trial in which a shorter infusion was used (Schiller et al, 1994), the results of a randomized trial with moderate dosages of paclitaxel have not supported its schedule dependency (Eisenhauer et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Neuromuscular toxicities of paclitaxel 210 mg m-2 by 3-hour infusion

Kunitoh

Saijo²,

Furuse³

et al. 1998

Br J Cancer

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Summary We retrospectively analysed neuromuscular toxicity associated with paclitaxel 210 mg m-2 given by 3-h infusion in 247 patients. The severity correlated significantly with total cumulative dose, but could not be predicted by the pretreatment clinical variables or by pharmacokinetic parameters. The toxicity tended to occur in early treatment cycles.Keywords: paclitaxel; peripheral neuropathy; myalgia; arthralgia; pharmacokinetics; risk factor Peripheral neuropathy and myalgia/arthralgia are among the significant toxicities of paclitaxel. It has been reported that neuropathy associated with paclitaxel by a 24-h injection is dependent upon total cumulative dosage, and no known risk factors have been identified (Wiemik et al, 1987;Chaudhry et al, 1994). Little information is available on the pharmacokinetics and this toxicity. There are also few reports of neuromuscular toxicity of the drug given by shorter infusion, the currently preferred method of administration (Gianni, 1995).The aim of this retrospective analysis was to evaluate the risk factors for neuromuscular toxicity associated with paclitaxel by a 3-h infusion. Pharmacodynamics were also analysed in patients in whom pharmacokinetic data were available. PATIENTS AND METHODSA retrospective analysis was performed on four phase II trials of paclitaxel at a dose of 210 mg m-2 given as a 3-h infusion. Two trials included patients with non-small-cell lung cancer, one trial patients with breast cancer and the other trial patients with ovarian cancer. A summary of the patient characteristics is given in Table 1.Paclitaxel was supplied by Bristol-Myers Squibb (Tokyo, Japan) as a solution containing 30 mg of the drug in 5 ml of 50% polyoxyethylated castor oil (Cremophor EL) and 50% dehydrated alcohol. Each patient received 210 mg m-2 paclitaxel diluted in 500 ml of 5% glucose in a 3-h i.v. infusion, every 3 weeks.Adverse reactions to paclitaxel were graded according to the toxicity criteria of the Japan Society for Cancer Therapy (Japan Society for Cancer Therapy, 1993).Pharmacokinetic analysis was performed during the first course of the treatment in 50 patients. Heparinized blood samples for the measurement of plasma paclitaxel concentration were collected before the infusion and at 5, 15 and 30 min, and 1, 2, 3, 4, 6, 12, 24 Spearman's correlation coefficient was used to determine the correlation between two variables. The difference in the grade of toxicity between the two groups was evaluated using the Mann-Whitney U-test. RESULTSThe median number of paclitaxel chemotherapy cycles was three (range 1-15), and the median cumulative dose of the drug was 630 mg m-2 (range 35-3150 mg m-2).Peripheral neuropathy was grade 0 in 51 (21%), grade I in 120 (49%), grade 2 in 64 (26%) and grade 3 in 12 (5%) patients; no patient suffered grade 4 neuropathy. The neuropathy was predominantly sensory, and only five patients (four with grade 2 and one with grade 3) experienced motor neuropathy. The severity of myalgia/arthralgia was grade 0 in 88 (36%), grade 1 in 74 (30%)...

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Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans.

Cited by 479 publications

References 17 publications

Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule–Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non–Small-Cell Lung Cancer

Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule–Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non–Small-Cell Lung Cancer

Population Pharmacokinetics and Exposure Response Assessment of CC‐292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia

Neuromuscular toxicities of paclitaxel 210 mg m-2 by 3-hour infusion

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