Pharmacokinetic modeling of doxorubicin pharmacokinetics in dogs deficient in ABCB1 drug transporters.

BACKGROUND

The identification of dogs defective in ATP-binding cassette transporter B1 (ABCB1, MDR1) activity has prompted questions regarding pharmacokinetics (PK), efficacy and toxicity of ABCB1 substrates in these dogs.

HYPOTHESIS/OBJECTIVES: Dogs defective in ABCB1 activity (ABCB1(null)) have doxorubicin (DOX) PK different from that of normal dogs (ABCB1(wt)). Utilization of a physiologically based pharmacokinetic (PBPK) model allows computer simulation to study this polymorphism's impact on DOX PK.

ANIMALS

None.

METHODS

A virtual ABCB1(wt) dog population was generated and DOX distribution, elimination, and metabolism simulated by PBPK modeling. An in silico population of virtual dogs was generated by Monte Carlo simulation, with variability in physiologic and biochemical parameters consistent with the dog population. This population was used in the PBPK model. The ABCB1 components of the model were inactivated to generate an ABCB1(null) population and simulations repeated at multiple doses. Resulting DOX levels were used to generate PK parameters.

RESULTS

DOX exposures in the ABCB1(null) population were increased in all simulated tissues including serum (24%) and gut (174%). Estimated dosages in the ABCB1(null) population to approximate exposure in the ABCB1(wt) population at a dose of 30 mg/m(2) were 24.8 +/- 3.5 mg/m(2) for serum and 10.7 +/- 5.9 mg/m(2) for gut.

CONCLUSIONS AND CLINICAL IMPORTANCE

These results suggest that serum DOX concentrations are not indicative of tissue exposure, especially those with appreciable ABCB1 activity, and that gastrointestinal (GI) toxicosis would be dose limiting in ABCB1(null) populations. Dosage reductions necessary to prevent GI toxicosis likely result in subtherapeutic concentrations, thereby reducing DOXs efficacy in ABCB1(null) dogs.