1241/030 39 weeks IV 1 1.44 0.319 54 44 – – 10 12.6 3.10 474 431 – – 0.3 0.067–0.1 6# 4# 0.7 – – 1241/012 4 weeks 3 0.67–1 56# 43# 7 – – 30 6.7–10 7.51 1.53 565 425 67 topical 0.3 0.075–0.1 6# 4# 0.7 – – ocular Monkey (single 1241/020 13 weeks 3 0.75–1 0.74 56 39# 7 – eye; twice 30 7.5–10 5.81 1.39 437 386 67 daily) 0.3 0.075–0.1 4# 3.4# 0.7 – – 1241/034 52 weeks 3 0.75–1 0.54 41 34# 7 – 30 7.5–10 4.38 1.23 329 342 67 topical Human 0.45 0.018 0.0266 0.0072 – – – [MRHD, 900 ng] ocular * = of tafluprost acid (active metabolite); a = calculated as animal:human Cmax multiplied by dosing frequency; b = calculated as animal:human AUC0–t multiplied by dosing frequency; c = calculated as animal:human ocular dose/day; = not detected/not calculated/not applicable; – # = estimate based on linear extrapolation; once daily administration for SC and IV routes; Note that exposure ratios in the monkey studies refer to a 24 h period, ratios after each dose are half the given value; MRHD = maximum recommended human dose (based on once daily bilateral use with 30 μL drop volume); Human body weight of 50 kg assumed. Table 2. Relative exposure in reproductive toxicity studies Relative exposurea Dose Cmax* AUC0–t* Study Species Type Route (μg/kg/day) (ng/mL) (ng∙h/mL) Cmax AUC 10 26.8¶ 1.70¶ 1008 236 Rat 1241/32 fertility IV 30 108.8¶ 6.30¶ 4090 875 (SD) 100 379.4¶ 26.4¶ 14263 3667
1241/030 39 weeks IV – 1 1.44 0.319 54 44 – – 10 12.6 3.10 474 431 – 1241/012 Monkey 4 weeks topical ocular (single eye; twice daily) 0.3 0.067–0.1 – – 6# 4# 0.7 3 0.67–1 – – 56# 43# 7 30 6.7–10 7.51 1.53 565 425 67 1241/020 13 weeks 0.3 0.075–0.1 – – 6# 4# 0.7 3 0.75–1 0.74 – 56 39# 7 30 7.5–10 5.81 1.39 437 386 67 1241/034 52 weeks 0.3 0.075–0.1 – – 4# 3.4# 0.7 3 0.75–1 0.54 – 41 34# 7 30 7.5–10 4.38 1.23 329 342 67 Human [MRHD, 900 ng] topical ocular 0.45 0.018 0.0266 0.0072 – – – * = of tafluprost acid (active metabolite); a = calculated as animal:human Cmax multiplied by dosing frequency; b = calculated as animal:human AUC0–t multiplied by dosing frequency; c = calculated as animal:human ocular dose/day; – = not detected/not calculated/not applicable; # = estimate based on linear extrapolation; once daily administration for SC and IV routes; Note that exposure ratios in the monkey studies refer to a 24 h period, ratios after each dose are half the given value; MRHD = maximum recommended human dose (based on once daily bilateral use with 30 μL drop volume); Human body weight of 50 kg assumed. Table 2. Relative exposure in reproductive toxicity studies Study Species Type Route Dose (μg/kg/day) Cmax* (ng/mL) AUC0–t* (ng∙h/mL) Relative exposurea Cmax AUC 1241/32 Rat (SD) fertility IV 10 26.8¶ 1.70¶ 1008 236 30 108.8¶ 6.30¶ 4090 875 100 379.4¶ 26.4¶ 14263 3667
auspar-tafluprost-120503.docx