5hr interval. Again, it is hypothesized that with such a short interval, drug “overlapped”
from dose to dose which caused the nonabsorbable portion to increase thereby reducing the exposure (similar to a s.i.d. dose). Better efficiency was achieved when the dose interval increased to 2.5hrs. Better drug delivery efficiency was achieved when the dose interval increased to 1.5 and 2.5hrs. This is not surprising, since for a low solubility drug, the nonabsorbable portion increases when the dose Inhibitors,research,lifescience,medical increases due to solubility limited absorption. It is also understood that the dose interval should be Tmax (from single dose) dependent. The overlap from the shorter dosing interval becomes more significant and the nonabsorbable portion increases as dose increases; thus, the dosing interval and the dose are interdependent, and both must be considered Inhibitors,research,lifescience,medical in order to minimize the “drug overlap” in the GI track. The Cmax and AUC (Tables (Tables44 and and5)5) obtained from
the 1.5hrs dosing scheme are comparable to the values obtained from the s.i.d. dose (Table 2. 1000mg/kg). Cmax and AUC from the 2.5hrs dosing scheme well exceed the values obtained from the s.i.d. dose of 1000mg/kg. The obtained Cmax of 200mg/kg tandem dose (with 2.5hr interval) was 26.3 ± 4.0μM, and AUC/Dose Inhibitors,research,lifescience,medical (for 2.5hr interval) was calculated to be 0.87 ± 0.08μM*hr/mg/kg.This suggests that for this dose (100mg/Kg X3) 1.5hrs may be sufficient to separate two doses; however, Inhibitors,research,lifescience,medical the 2.5hr interval delivers the best results. Similarly, the data obtained from the 1.5hr interval exhibits higher variability when compared to the 2.5hr interval. This again suggests that 1.5hrs may not be the ideal
interval for higher doses as the risk of drug overlap in the GI is higher and may contribute to higher variability in exposures. The variability could also be subject dependent. The simulated exposure (2.5hrs interval) versus obtained exposure for 200mg/kg X3 tandem dose Inhibitors,research,lifescience,medical is presented in Figure 8. A Wagner-Nelson plot (see Section 2) was used to calculate drug absorbed and to assess the absorption as a function of time for the 200mg/kg X3 dose is presented Rolziracetam as Figure 9. Similarly, a noticeable increase in beta phase half-life was observed for the tandem doses versus the predicted curve using our linear PK model. It is possible that via accumulation drug exposure has reached the nonlinear range (saturated the CL), and therefore a linear PK model underpredicts the beta phase half-life. It is also possible that this phenomena was due to the selleck chemicals larger amount of drug dosed which altered some physiological factor (i.e., transit time) in the animal or saturated the absorption. Thus, the parameters generated by simple PK studies at a lower dose may not be sufficient to predict every aspect of a higher dose study. However, since both AUC and Cmax were actually well within our target, we believed this model work well.
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