DOXORUBICIN Clinical Pharmacology

(doxorubicin hydrochloride)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The cytotoxic effect of doxorubicin hydrochloride on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin hydrochloride cytocidal activity.

12.3 Pharmacokinetics

Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 mg/m2 to 70 mg/m2.

Distribution

The distribution half-life is approximately 5 minutes. Steady-state distribution volume ranges from 809 L/m2 to 1214 L/m2. Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is 75% and is independent of plasma concentration of doxorubicin up to 1.1 µg/mL.

Doxorubicin does not cross the blood brain barrier.

Elimination

Plasma clearance is ranges from 324 mL/min/m2 to 809 mL/min/m2. The terminal half-life is 20 hours to 48 hours.

Metabolism

Doxorubicin is a substrate of CYP3A4, CYP2D6, and P-gp.

Enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of doxorubicin hydrochloride.

Disposition of doxorubicinol in patients is formation rate limited, with the terminal half-life of doxorubicinol being similar to doxorubicin. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of doxorubicin is approximately 0.5.

Excretion

Plasma clearance is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5% to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as doxorubicinol over 7 days.

Specific Populations

Weight

Systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.

Pediatric Patients

Following administration of doses ranging from 10 mg/m2 to 75 mg/m2 of doxorubicin hydrochloride to 60 patients ranging from 2 months to 20 years, doxorubicin clearance averaged 1443 ± 114 mL/min/m2. Further analysis demonstrated that clearance in 52 patients ranging from 2 to 20 years (1540 mL/min/m2) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m2) was decreased compared with older patients (ranging from 2 to 20 years) and approached the range of clearance values determined in adults [see Use in Specific Populations (8.4)].

Sex

A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in men compared to women (1088 mL/min/m2 versus 433 mL/min/m2). However, the terminal half-life of doxorubicin was longer in men compared to women (54 versus 35 hours).

Patients with Hepatic Impairment

The clearance of doxorubicin and doxorubicinol was reduced in patients with elevated serum total bilirubin concentrations [see Dosage and Administration (2.4), Warnings and Precautions (5.5)].

Find DOXORUBICIN medical information:

Find DOXORUBICIN medical information:

Our scientific content is evidence-based, scientifically balanced and non-promotional. It undergoes rigorous internal medical review and is updated regularly to reflect new information.

DOXORUBICIN Quick Finder

Prescribing Information
Download Prescribing Information

Health Professional Information

Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The cytotoxic effect of doxorubicin hydrochloride on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin hydrochloride cytocidal activity.

12.3 Pharmacokinetics

Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 mg/m2 to 70 mg/m2.

Distribution

The distribution half-life is approximately 5 minutes. Steady-state distribution volume ranges from 809 L/m2 to 1214 L/m2. Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is 75% and is independent of plasma concentration of doxorubicin up to 1.1 µg/mL.

Doxorubicin does not cross the blood brain barrier.

Elimination

Plasma clearance is ranges from 324 mL/min/m2 to 809 mL/min/m2. The terminal half-life is 20 hours to 48 hours.

Metabolism

Doxorubicin is a substrate of CYP3A4, CYP2D6, and P-gp.

Enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of doxorubicin hydrochloride.

Disposition of doxorubicinol in patients is formation rate limited, with the terminal half-life of doxorubicinol being similar to doxorubicin. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of doxorubicin is approximately 0.5.

Excretion

Plasma clearance is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5% to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as doxorubicinol over 7 days.

Specific Populations

Weight

Systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.

Pediatric Patients

Following administration of doses ranging from 10 mg/m2 to 75 mg/m2 of doxorubicin hydrochloride to 60 patients ranging from 2 months to 20 years, doxorubicin clearance averaged 1443 ± 114 mL/min/m2. Further analysis demonstrated that clearance in 52 patients ranging from 2 to 20 years (1540 mL/min/m2) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m2) was decreased compared with older patients (ranging from 2 to 20 years) and approached the range of clearance values determined in adults [see Use in Specific Populations (8.4)].

Sex

A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in men compared to women (1088 mL/min/m2 versus 433 mL/min/m2). However, the terminal half-life of doxorubicin was longer in men compared to women (54 versus 35 hours).

Patients with Hepatic Impairment

The clearance of doxorubicin and doxorubicinol was reduced in patients with elevated serum total bilirubin concentrations [see Dosage and Administration (2.4), Warnings and Precautions (5.5)].

Medication Guide

Health Professional Information

{{section_name_patient}}

{{section_body_html_patient}}

Resources

Didn’t find what you were looking for? Contact us.

MI Digital Assistant

Chat online with Pfizer Medical Information regarding your inquiry on a Pfizer medicine.

Call 800-438-1985*

*Speak with a Pfizer Medical Information Professional regarding your medical inquiry. Available 9AM-5PM ET Monday to Friday; excluding holidays.

Medical Inquiry

Submit a medical question for Pfizer prescription products.

Report Adverse Event

Pfizer Safety

To report an adverse event related to the Pfizer-BioNTech COVID-19 Vaccine, and you are not part of a clinical trial* for this product, click the link below to submit your information:

Pfizer Safety Reporting Site

*If you are involved in a clinical trial for this product, adverse events should be reported to your coordinating study site.

If you cannot use the above website, or would like to report an adverse event related to a different Pfizer product, please call Pfizer Safety at (800) 438-1985.

FDA Medwatch

You may also contact the U.S. Food and Drug Administration (FDA) directly to report adverse events or product quality concerns either online at www.fda.gov/medwatch or call (800) 822-7967.