I am trying to calculate PDE for cephradine based on the results of reproduction and chronic toxicity studies as in the attachment. According to EMA guideline, the equation used to calculate PDE is:
PDE = (NOAEL x Weight Adjustment) / (F1 x F2 x F3 x F4 x F5)
F3 = A variable factor to account for toxicity studies of short-term exposure
F3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for cats, dogs and monkeys). F3 =1 for reproductive studies in which the whole period of organogenesis is covered.
F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents.
F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents.
F3 = 10 for studies of a shorter duration.i.e less thank 4 weeks
For dogs and monkeys for 26, and 13 weeks study ,what will be the F3?
and F4
1 = for fetal toxicity associated with maternal toxicity
5 = for fetal toxicity without maternal toxicity
5 = for a teratogenic effect with maternal toxicity
10 = for a teratogenic effect without maternal toxicity
As, In reproduction studies in mice and rats given either
daily oral doses (100 or 300 mg/lkg) or daily intraperitoneal doses (rats only; 80 or 320 mg/kg) of cephradine, no drug-related teratogenic changes in the offspring were observed.
what will be F4?
And F5: A variable factor, up to 10, applied to results in which a NOAEL has not been established, the PDE being derived from a LOAEL.
As i don't have NOAEL Value ,i am using highest dose used in chronic study ( what will be the F5 Value?
also I have attached full article and the abstract with NOAEL value determination.Is it right or wrong ?
Thanks in advance.
Since cephradine is a semi-synthetic cephalosporin; therefore, a beta-lactam antibiotic, be careful when trying to apply the EMA PDE equation. Cephalosporins, like all other beta-lactams, would required dedicated facilities (see EU Guidelines for GMP, v4, part 1, chapter 3, 3.6 ii). However, even with a facility that is dedicated for beta-lactam antibiotics you would need PDEs to prevent cross-product contamination between different beta-lactam antibiotics. Since beta-lactams are consider sensitizers, the use of an animal NOAEL is of little value. As indicated in the EMA HBEL Guideline, "The use of other approaches to determine health based exposure limits could be considered acceptable if adequately and scientifically justified." This is a case where an alternative approach to the use of a NOAEL is required.
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