Pharmacokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs.
The anthracycline glycoside antibiotics represent a group of potent anticancer agents with a wide spectrum of activity against solid tumours and haematological malignancies, and are the mainstay of a large number of clinical protocols for the treatment of adult and childhood neoplastic diseases. Their clinical activity is limited, however, by acute and chronic adverse effects. Myelosuppression, predominantly neutropenia and leucopenia, is the dose-limiting toxicity; in addition to this, mucositis, nausea, vomiting and alopecia are frequent, whereas hepatopathy, characterised by elevated bilirubin concentrations, occurs less frequently. Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and can be acute or chronic; in the acute setting, electrocardiographic abnormalities may be seen, including ST-T elevations and arrhythmias, but chronic cardiotoxicity represents a serious adverse effect that may be lethal due to the development of irreversible, cumulative dose-dependent, congestive cardiomyopathy. The occurrence of toxicity displays a marked interindividual variation, and for this reason the pharmacokinetics and pharmacodynamics of anthracyclines have been extensively investigated in order to identify integrated models that can be used in the clinical setting to prevent the development of serious toxicity, mainly leucopenia, and maximise tumour exposure. Pharmacokinetics has been recognised to influence both the toxicity and the activity of anthracyclines; in particular, there is increasing evidence that the mode of administration plays an important role for cumulative cardiotoxicity and data indicate that bolus administration, rather than continuous infusion, appears to be an important risk factor for anthracycline-induced cardiomyopathy, thus implying that this type of toxicity is maximum concentration-dependent. On the contrary, exposure to the drug, as measured by area under the curve, seems best related to the occurrence of leucopenia. Finally, the development of pharmacokinetic-pharmacodynamic models allows the simulation of drug effects and ultimately dose optimisation in order to anticipate important toxicities and prevent their occurrence by the administration of prophylactic treatments.
Danesi
Romano
R
Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy. r.danesi@med.unipi.it
Fogli
Stefano
S
Gennari
Alessandra
A
Conte
Pierfranco
P
Del Tacca
Mario
M
D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D004317:Doxorubicin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D015251:Epirubicin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D015255:Idarubicin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D011355:Prodrugs; D015251:Epirubicin; D004317:Doxorubicin; D015255:Idarubicin