Pharmacokinetics of Paclitaxel in Correlation With Adverse Events in Cancer Patients With and Without Liver Impairment

Study Overview
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Brief Summary
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The study aims to assess the pharmacokinetics of paclitaxel and its two major metabolites in patients with normal and impaired liver functions.

Detailed Description
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population pharmacokinetic study in patients with normal or impaired liver functions, receiving paclitaxel for cancer treatment. 40 Patients with histologically confirmed solid tumors will be enrolled in the study: 20 patients have normal liver functions as defined by transaminase < 2.6 x ULN and bilirubin values < 1.26 x ULN. 20 patients with liver impairment as defined by transaminase 2.6 - 10 x ULN and bilirubin values 1.26 - 5 x ULN.

Official Title
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Effect of CYP3A4 and CYP2C8 Activity on Pharmacokinetics of Paclitaxel, Correlation With Adverse Events in Cancer Patients With and Without Liver Impairment

Conditions
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Liver Diseases

Intervention / Treatment
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* Other: Blood samples


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically proven non haematopoietic malignancy (ovarian, breast and lung cancer). Age between 18 and 70 years At least a 4-week interval between the last dose of previous chemotherapy protocol and registration (6 weeks in case of treatment with carboplatin). Glomerular filtration rate > 60 ml/min An Eastern Cooperative Oncology Group performance status 0-2, a life expectancy of > 12 weeks, adequate bone marrow function [absolute neutrophil count (ANC) ≥ 1 X 109 and platelets ≥ 100 X 109] Patient accessible for treatment and follow-up and written informed consent. Exclusion Criteria: Prior treatment with paclitaxel or other taxanes. Pre-existing motor or sensory neurotoxicity > grade 2 according to World Health Organization (WHO) criteria. Active infection or other serious underlying medical condition (including prior allergic reactions to Paclitaxel or the drug's constituents), dementia or significantly altered mental status, symptomatic brain or liver metastases, history of atrial or ventricular arrhythmias or congestive heart failure even if medically controlled, history of clinical and electrocardiographically documented myocardial infarction. Simultaneous use of any medication, dietary supplements, or other compounds known to inhibit affect the pharmacokinetics of paclitaxel. Patients with difficult blood sampling.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: Blood samples|Plasma concentrations of paclitaxel and its metabolites will be obtained during the first treatment cycle. The samples for paclitaxel analysis will be collected in ethylenediamine tetraacetic acid tubes at 7-time points: just before infusion, in the middle of the infusion, at the end of infusion, at 1, 2, 4 and 6 hours post-infusion.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| plasma concentrations of paclitaxel | determination of plasma concentration and pharmacokinetic analysis of paclitaxel | predose till 6 hours post infusion of paclitaxel | 
| plasma concentrations of 6-α-hydroxypaclitaxel | determination of plasma concentration and pharmacokinetic analysis of 6-α-hydroxypaclitaxel | predose till 6 hours post infusion of paclitaxel | 
| plasma concentrations of 3'-p-hydroxypaclitaxel | determination of plasma concentration and pharmacokinetic analysis of 3'-p-hydroxypaclitaxel | predose till 6 hours post infusion of paclitaxel | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probing CYP 3A4 activity | metabolite ratio of 6-α-hydroxypaclitaxel/paclitaxel | predose till 6 hours post infusion of paclitaxel | 
| Probing CYP 2C8 activity | metabolite ratio of 3'-p-hydroxypaclitaxel/paclitaxel | predose till 6 hours post infusion of paclitaxel | 
| Incidence of adverse effects | Complete blood count, liver functions and neuropathy evaluation (according to Common Terminology Criteria for Adverse Events (CTCAE), version 5) will be assessed | baseline ( before first dose) till 100 days after the first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paclitaxel, Pharmacokinetics, Egypt