Purpose: The purpose of this study was to determine the objective response rate (ORR) following treatment of canine mast cell tumors (MCT) with toceranib phosphate (Palladia, SU11654), a kinase inhibitor with both antitumor and antiangiogenic activity through inhibition of KIT, vascular endothelial growth factor receptor 2, and PDGFRβ. Secondary objectives were to determine biological response rate, time to tumor progression, duration of objective response, health-related quality of life, and safety of Palladia. Experimental Design: Dogs were randomized to receive oral Palladia 3.25 mg/kg or placebo every other day for 6 weeks in the blinded phase. Thereafter, eligible dogs received open-label Palladia. Results: The blinded phase ORR in Palladia-treated dogs (n = 86) was 37.2% (7 complete response, 25 partial response) versus 7.9% (5 partial response) in placebo-treated dogs (n = 63; P = 0.0004). Of 58 dogs that received Palladia following placebo-escape, 41.4% (8 complete response, 16 partial response) experienced objective response. The ORR for all 145 dogs receiving Palladia was 42.8% (21 complete response, 41 partial response); among the 62 responders, the median duration of objective response and time to tumor progression was 12.0 weeks and 18.1 weeks, respectively. Palladia-treated responders scored higher on health-related quality of life versus Palladia-treated nonresponders (P = 0.030). There was no significant difference in the number of dogs with grade 3/4 (of 4) adverse events; adverse events were generally manageable with dose modification and/or supportive care. Conclusions: Palladia has biological activity against canine MCTs and can be administered on a continuous schedule without need for routine planned treatment breaks. This clinical trial further shows that spontaneous tumors in dogs are good models to evaluate therapeutic index of targeted therapeutics in a clinical setting.

ABSTRACT:Little information regarding the metabolic pathways of pharmaceutical agents administered to dogs, or the inhibition of those metabolic pathways, is available. Without this information, it is difficult to assess how combinations of drugs, whether new or old or approved or nonapproved, may increase the risk for metabolic drug-drug interactions in dogs. Because mammalian xenobiotic metabolism pathways often involve the hepatic cytochrome P450 (P450) monooxgenases, canine liver microsome P450 inhibition screens were tested to evaluate the potential metabolic drug interaction risk of commonly used veterinary medicines. A probe substrate cocktail was developed for four of the five major hepatic canine P450s and used to evaluate their inhibition by 45 canine therapeutic agents in a single-point IC 50 screen. Moderate inhibitors (>25%) were further characterized with an automated ninepoint IC 50 assay that identified ketoconazole, clomipramine, and loperamide as submicromolar CYP2D15 inhibitors. Additional inhibitors belonged to the antiemetic, antimitotic, and anxiolytic therapeutic classes. According to the marker activities, the relative frequency of P450 inhibition by isoform followed the sequence CYP2D15 > CYP2B11 > CYP2C21/41 > CYP3A12/26 > CYP1A1/2. The findings presented suggest there is some overlap in canine and human P450 inhibition specificity. However, occasional differences may give human drugs used off-label in dogs unexpected P450 inhibition profiles and, therefore, cause an unexpected drugdrug interaction risk.The number of reports describing the basic enzymology of drugmetabolizing enzymes in nonhuman species has increased the last decade. Notable examples include the characterization of several homologs of the major human xenobiotic-metabolizing cytochromes P450 that were cloned from canine hepatocytes (Roussel et al., 1998;Shou et al., 2003). Single nucleotide polymorphisms within canine P450s that alter activity have also been identified, as have P450 isoforms that appear to only be expressed in a fraction of the beagle population (Sakamoto et al., 1995;Blaisdell et al., 1998). More recently, three hepatic feline P450s cDNAs were characterized, two of which were expressed and characterized (Tanaka et al., 2005(Tanaka et al., , 2006. Whereas some of these reports bring a better understanding of when metabolism in preclinical species may or may not reflect the human situation (Martignoni et al., 2006;Turpeinen et al., 2007), there have been few reports on how specific P450s are inhibited by or metabolize pharmaceuticals used in the animal health field.For instance, in the development of new therapies for dogs, prediction of whether concomitant medications in the patient population may inhibit metabolic clearance pathways would be helpful in the assessment of the metabolic drug-drug interaction (DDI) potential. However, there is a lack of canine P450 inhibition data and understanding of basic canine enzymology that has caused in vitro canine drug interaction assessment to lag behind that of h...

., Stegemann, M. R. The pharmacokinetics of oclacitinib maleate, a Janus kinase inhibitor, in the dog. J. vet. Pharmacol. Therap. 37, 279-285.The pharmacokinetics of oclacitinib maleate was evaluated in four separate studies. The absolute bioavailability study used a crossover design with 10 dogs. The effect of food on bioavailability was investigated in a crossover study with 18 dogs. The breed effect on pharmacokinetics was assessed in a crossover study in beagles and mongrels dogs. Dose proportionality and multiple dose pharmacokinetics were evaluated in a parallel design study with eight dogs per group. In all four studies, serial blood samples for plasma were collected. Oclacitinib maleate was rapidly and well absorbed following oral administration, with a time to peak plasma concentration of <1 h and an absolute bioavailability of 89%. The prandial state of dogs did not significantly affect the rate or extent of absorption of oclacitinib maleate when dosed orally, as demonstrated by the lack of significant differences in pharmacokinetic parameters between the oral fasted and oral fed treatment groups. The pharmacokinetics of oclacitinib in laboratory populations of beagles and mixed breed dogs also appeared similar. Following oral administration, the exposure of oclacitinib maleate increased dose proportionally from 0.6 to 3.0 mg/kg. Additionally, across the pharmacokinetic studies, there were no apparent differences in oclacitinib pharmacokinetics attributable to sex.(Paper

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Tamoxifen has proven to be beneficial in the chemoprevention of breast cancer in women at increased risk for the disease. Other compounds that mediate the estrogen pathway remain to be tested for clinical efficacy. The mechanism of action, efficacy, and dose response of the estrogen modulators is determined by the hormonal milieu of the host which should be considered in the early clinical trials for dose range finding studies and surrogate endpoint biomarker (SEB) evaluation. This review presents the hormonal effects to consider in the clinical testing of an agent in premenopausal vs. postmenopausal cohorts. Recommended SEBs that may be evaluated in Phase I/II clinical trials of estrogen modulators for breast cancer chemoprevention are presented. J. Cell. Biochem. Suppl. 34:103-114, 2000. 2000 Wiley-Liss, Inc.Key words: selective estrogen receptor modulators; SERMs; aromatase inhibitors; isoflavones; ovarian-pituitary axis; bone turnover; lipid metabolism; endometrium Hormonal approaches to breast cancer have been successful in both the treatment and prevention of the disease. Studies in breast cancer epidemiology and laboratory in vitro and in vivo investigations have suggested a role for estrogen in the initiation, promotion and spread of breast cancer. In the treatment setting, estrogen modification with oophorectomy or tamoxifen has had a significant impact on the survival of women diagnosed with breast cancer [Early Breast Cancer Trialists Group, 1992]. The chemopreventive properties of tamoxifen were first demonstrated by the reduction of second primaries in a meta-analysis of breast cancer survivors who had taken the drug for five years [Fisher et al., 1989;Rutqvist et al., 1991]. Based on this analysis, tamoxifen became the lead compounds in breast cancer chemoprevention studies. A large breast cancer prevention trial recently completed in the United States showed a 49% risk reduction for invasive breast cancer among subjects who took tamoxifen; the benefit was seen in both pre-and postmenopausal age groups [Fisher et al., 1998]. These results are encouraging, and other compounds that affect estrogen are currently under evaluation to determine whether they might have clinical advantages over tamoxifen. Clinical testing of estrogen modulators has shown that the hormonal milieu is a critical determinant of their mechanism of action, efficacy, and dose response. This review will present some of the estrogen-mediated effects to be considered in testing estrogen modulators for cancer prevention in premenopausal and postmenopausal women.The clinical effects of estrogen have been extensively studied in postmenopausal women. In this population, decreased estrogen is associated with risk for osteoporosis, cardiovascular disease, and vasomotor symptoms. Emerging evidence suggests that neuropsychiatric function may also be impacted [Grady et al., 1992;Henderson et al., 1994]. In contrast, the effect of estrogen modulation in premenopausal women is largely unknown, although the impact in this younger coh...