Key result
In a virtual dog population, ABCB1 deficiency increased doxorubicin exposure in serum by 24% and in the gut by 174%, suggesting gastrointestinal toxicosis would be dose-limiting.
Why the study?
Does ABCB1 deficiency alter doxorubicin pharmacokinetics and tissue exposure in dogs?
Does ABCB1 deficiency alter doxorubicin pharmacokinetics and tissue exposure in dogs?
In silico modeling suggests that ABCB1-deficient dogs have significantly increased doxorubicin tissue exposure, particularly in the gut, indicating that dose reductions to prevent GI toxicity may result in subtherapeutic systemic concentrations.
Answers are grounded in this paper and cite their sources.
May warrant ABCB1-guided dose reductions in dogs to limit GI toxicity; leaves open translation to clinical veterinary practice.
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.
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Gustafson et al. (2010) studied ABCB1 (MDR1) deficiency in dogs. ABCB1(null) polymorphism vs. ABCB1(wt) dogs was evaluated on Doxorubicin exposure in tissues including serum and gut (24% increase in serum, 174% increase in gut). In a virtual dog population, ABCB1 deficiency increased doxorubicin exposure in serum by 24% and in the gut by 174%, suggesting gastrointestinal toxicosis would be dose-limiting.
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