Abstract A35: Comparative drug exposures in mouse, dog, and human CHOP protocols for lymphoma therapy

Background: Combination chemotherapy protocols are a mainstay of cancer therapy and their development played an important role in curative therapy for a number of disseminated neoplastic diseases including both adult and childhood lymphoma. A standard poly-chemotherapeutic protocol for human diffuse large B-cell lymphoma is the CHOP protocol that includes cyclophosphamide (C), hydroxydaunorubicin (H, doxorubicin), Oncovin® (O, vincristine) and prednisone (P). A virtually identical CHOP protocol is used in veterinary oncology for pet dogs that develop spontaneous lymphomas with differences only existing in the dosing regimen. An experimental mouse CHOP protocol has also been described for testing drug responsiveness of experimentally introduced lymphomas. An important issue in the testing of drug therapies across species is drug exposure in that interspecies dose scaling lacks precision and can lead to disparate pharmacokinetics (PK) due to species-specific differences in drug disposition. Recent studies have shown that prediction of the human clinical response of both targeted and cytotoxic agents in murine subcutaneous tumor models only correlate when significant responses were observed in the mice at clinically relevant drug exposures based on human PK of the specific agents (Clin Cancer Res 18:3846, 2012). Thus, the purpose of the study presented here is to simulate and compare drug pharmacokinetics and exposures of cyclophosphamide (C), doxorubicin (H) and vincristine (O) when administered at prescribed doses in mice, dogs and humans. Methods: PK data for C, H and O in mice, dogs and humans was compiled from the literature and reviewed for consistency and the use of appropriate analytical methodology. Prediction of drug levels at the CHOP prescribed doses was done using nonparametric superposition based on concentration data at single or multiple doses for each species. Predicted PK parameters were then estimated using non-compartmental analysis. Results: Drug exposures for H and O were appreciably higher in mice with the prescribed CHOP protocols with AUC values for O in mice at 206.4 ng•hr/ml whereas human and dog values are predicted at 73.1 ng•hr/ml and 34.6 ng•hr/ml, respectively. Exposure to H in the mouse was predicted to be 1122 ng•hr/ml and in humans and dogs 759 ng•hr/ml and 837 ng•hr/ml, respectively. Analysis of C data was complicated by the wide disparity in analytical methods used and the lack of comprehensive PK data for C and its9 active metabolite 4-OH cyclophosphamide (4OHC) in species other than the dog. Exposure to C was predicted to be 100.21 µg•hr/ml, 7.15 µg•hr/ml and 15.02 µg•hr/ml with 4OHC exposure estimated at 0.44 µg•hr/ml, 1.63 µg•hr/ml and 0.89 µg•hr/ml in human, dog and mouse, respectively. Conclusions: Drug exposures to the cytotoxic components of standard CHOP protocols in humans, dogs and mice can be estimated with the resulting predictions showing that mouse doses result in drug exposures for H and O at 2.8 and 1.5-fold higher than those observed in humans and 4OHC exposures approximately 2-fold higher. Drug exposure to dogs undergoing CHOP therapy is approximately 50% of that of humans with regard to O and H exposures are nearly equivalent. Dog exposure to 4OHC is predicted to be appreciably higher (4-fold) than that of humans, although confidence in the accuracy of prediction of C and 4OHC PK values based on available data for human and mouse is low. Citation Format: Daniel L. Gustafson, Luke A. Wittenburg. Comparative drug exposures in mouse, dog, and human CHOP protocols for lymphoma therapy. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A35.