The currently accepted algorithm for calculating a starting dose in clinical trials with oncology drugs is to use one-tenth of the dose that causes severe toxicity (or death) in 10% of the rodents (STD10) on amg/m2 basis, provided that this starting dose (i.e., 1/10 the STD10) does not cause serious, irreversible toxicity in a nonrodent species (in this case, the dog) (DeGeorge et al., 1998). If irreversible toxicities are induced at the proposed starting dose in nonrodents or if the nonrodent (i.e., the dog) is known to be the more appropriate animal model, the starting dose would generally be one-sixth of the highest dose tested in the nonrodent (the dog) that does not cause severe, irreversible toxicity.
Calculation of the initial phase I starting dose of PD0325901 was based on the pivotal one-month toxicology studies in rats and dogs. Doses tested in the one-month rat study were 0.1, 0.3, and 1 mg/kg (0.6, 1.8, and 6mg/m2, respectively), and doses in the one-month dog study were 0.05, 0.1, and 0.3 mg/kg (1, 2, and 6 mg/m2 - respectively). Both studies included animals assigned to a one-month reversal phase, in the absence of dosing, to assess reversibility of any observed toxicities. In addition to standard toxicology and toxicokinetic parameters, these studies included frequent evaluation of serum chemistries, and measurement of vitamin D, osteocalcin, PTH, and inhibition of tissue pMAPK levels.
In the one-month rat study, no drug-related deaths occurred and systemic mineralization occurred in multiple tissues in both sexes at 1 mg/kg. Hypocellularity of the metaphyseal region of distal femur and/or proximal tibia occurred in males at 1 mg/kg. Toxicologic findings at lower doses included skin sores (at >0.1 mg/kg) and mineralization of gastric mucosa in one male at 0.3 mg/kg. The findings at <0.3 mg/kg were not considered to represent serious toxicity. In previous two - week dose - range - finding studies in rats, death occurred at 3 mg/kg (18mg/m2), indicating this to be the minimal lethal dose in rats. Based on these results, the STD1 0 in rats was determined to be 1 mg/kg (6 mg/m2)
In the one - month dog study, doses up to 0.3 mg/kg (6 mg/m2) were well tolerated with minimal clinical toxicity. Primary drug-related toxicity was limited to skin sores in two animals at 0.3 mg/kg. One-tenth the STD10 in rats is 0.6 mg/m2, which is well below a minimally toxic dose (6 mg/m2) in dogs. These data indicate an acceptable phase I starting dose to be 0.6 mg/m2, which is equivalent to 1 mg in a 60-kg person. The relationships between the primary toxicities in rats and dogs with dose and exposure are presented in Figure 4 .
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