Chapter 24: Pharmacokinetic Considerations in Oncology

DOXORUBICIN

The anthracycline age began over half century ago, when a soil sample harvested near the Castel del Monte in Italy revealed Streptomyces peucetius, a new bacterial strain producing a bright red pigment that was found to have good activity against murine tumors. A mutated strain of S. peucetius was found to produce a different red compound that was named Adriamycin, after the Adriatic Sea. Today, also known as doxorubicin (DOXO), this prototype compound remains one of the most prescribed antineoplastic agents. Currently, more than 2,000 known DOXO analogues provide invaluable clinical and research applicability.

DOXO has an exceptional chemical reactivity and is able to react with several molecules within the cell, leading to a variety of toxic effects, all of which contribute to its unique antineoplastic efficacy. Beginning with polymerase inhibition and DNA intercalation and ending with perturbation of calcium homeostasis, DOXO finds itself a place in most antineoplastic combo regimens.^{1, 2, 3, 4, and 5}

In order to relate DOXO dosing to its therapeutic effect or occurrence of toxicity, a number of physiologically based pharmacokinetic (PBPK) models have been tested to allow for simulation and prediction of therapeutic drug or metabolite levels.⁶ Roughly a decade ago, Gustafson and colleagues developed a DOXO PBPK model capable to predict PK alterations in special human populations; however, despite its invaluable utility, this model is largely underutilized for clinical benefit.⁶ The model described here is available as a complete model code from Gustafson and others. We provide this information with the hope of promoting its utilization in direct patient care.

1. Tissue compartment mass balance:

   

2. Blood compartment mass balance:

   

3. DOXO metabolism by aldo-keto reductases:

   

4. DOXO metabolism by aglycone:

   

5. Amount of DOXO eliminated in urine (U):

   

6. Amount of DOXO eliminated in feces (F):

   

NOMENCLATURE⁸

• Q: Blood flow (L/h)

• A: Amount of drug (mols)

• V: Tissue volume (L)

• C_A:_: Arterial blood concentration of free DOXO (M)

• C_V: Venous blood concentration of total DOXO leaving tissues (M)

• C_BL: Arterial blood concentration of total DOXO (M)

• F_B: Fraction of DOXO bound to plasma proteins

• T_DNA: Tissue-specific DNA binding capacity for DOXO (M)

• T_CAL: Tissue-specific cardiolipin binding capacity for DOXO (M)

• K_DNA: Binding affinity of DOXO for DNA (M)

• K_CAL: Binding affinity of DOXO for cardiolipin (M)

• AM: Amount metabolized (mols)

• AE: Amount excreted (mols)

• V_MAX: Maximum rate of activity (mols/hr/L tissue)

• K_M: Michaelis's constant (M)

• K_MET: First-order metabolic rate constant (h^–1 kg tissue^–1)

• F_FILT: Fraction renal blood flow filtered at the glomerulus

Subscripts:

• T: Generic tissue compartment

• C: Total cardiac output

• L: Liver

• K: Kidney

• G: Gut

• B: Blood

• AKR: Aldo-keto reductase

• AG: Aglycone

• PGP: P-glycoprotein

Given DOXO's liver metabolism and bile ...