This presented a major hurdle as learn more Compound 1 advanced to safety studies where high exposures (both Cmax and AUC) were needed. In the first single dose range finding safety study, Compound 1 was dosed in rats as suspension formulations. Compound 1 was dosed once a day (s.i.d.) at 300, 600, and 1000mg/kg in rats. Nondose proportional AUC and Cmax increases were observed (see Table 2).The exposure increase between 300mg/Kg and 600mg/Kg doses was small. A two-fold dose increase only resulted in a 0.2 times increase in AUC and a
0.39 times increase in Cmax. Even smaller increments were found when comparing exposures between the 600mg/Kg dose and 1000mg/Kg dose. Exposure (especially the Cmax) was not Inhibitors,research,lifescience,medical high enough to establish appropriate margins Inhibitors,research,lifescience,medical to assess the safety liabilities. The exposures for Compound I reached a plateau at high doses. As compound 1 possesses low aqueous solubility, it was hypothesized that for Compound 1, absorption was limited by solubility at high dose. Formulation options were evaluated for Compound
1 in order to improve the exposure. In vitro data (not included) led us to believe that improving exposure sufficiently via formulation would be time consuming, expensive, and therefore not an option. Regular multidoses Inhibitors,research,lifescience,medical b.i.d. (every 12hrs) or t.i.d. (every 8hrs) were considered and found less favorable since increased staffing and overtime pay (for late night dosing) would be required.
Upon close examination of the data, Compound 1 exhibits nondose dependent exposure increases at higher doses. Inhibitors,research,lifescience,medical However, it is entirely possible that oral absorption may be linear at doses below the lowest dose (300mg/Kg). Based on this assumption, we hypothesized that if each dose is less than 300mg/Kg and administered in a tandem dose scheme, the high Inhibitors,research,lifescience,medical FA (for each dose) and short dose frequency (every 2.5hrs) would allow drug exposure to build up very quickly (both AUC and Cmax). The 2.5hrs dose interval was chosen to test at first [12]. The 2.5hrs interval was picked based on the literature reviews [12–22] and in house data (not included). This dose interval has successfully demonstrated to be sufficient to separate two doses (represented oxyclozanide by the geometric mean of the unabsorbed drug at the moment) from each compartment [12]. In general, rats were dosed at 7 o’clock in the morning (first dose), nine thirty (second dose), and twelve o’clock (third dose). The exposure results obtained from the tandem dose were very encouraging. In general, much higher Cmax and AUC were obtained by the tandem dose compared with the s.i.d. dose. The 100mg/Kg tandem dose (300mg/kg total) gave an AUC and Cmax similar to the 1000mg/Kg s.i.d. dose. The 200mg/Kg tandem dose (600mg/kg total) resulted in double the exposure of the 1000mg/Kg s.i.d. dose. Most importantly, the Cmax increase was observed as predicted.
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