3 9.13 343 227# – embryofetal 1241/29 IV 10 62.4 5.45 2346 757 development 30 136.9 5.59 5147 776 0.3 34# 23# – – 1 114# 76# – – pre-/postnatal MP04098 IV development 3 9.13† 343 227# – 10 62.4† 5.45† 2346 757 0.03 3# – – – 1241/28 IV 0.1 0.26 10 – – 0.3 1.18 44 – – Rabbit embryofetal (NZW) development 0.001 1241/35 IV <0.02 <0.75 0.003 – – 0.01 topical 77551 [MRHD, 900 ng] 0.018 0.0266 0.0072 – – ocular * = of tafluprost acid (active metabolite); = not detected/not calculated/not applicable; – a = calculated as animal:human Cmax or AUC0–t; ¶ = based on data in the 4-week IV rat study (1241/018); = based on data from the embryofetal development study (1241/29); # = estimate based on linear † extrapolation; Reported pharmacokinetic parameters are for GD17 (rat) or GD19 (rabbit); MRHD = maximum recommended human dose (based on once daily bilateral use; 30 drop). μL Acute toxicity In single-dose toxicity studies, neither oral (PO) administration of tafluprost at dose levels up to 100 mg/kg nor IV administration at up to 3 mg/kg produced significant signs of toxicity in rats. In dogs, single IV administration at produced salivation, vomiting, ≥3 μg/kg moderate miosis, irregular respiration and increased heart rate. At 30 µg/kg, the miosis was severe and blood pressure was also increased. No adverse effects were noted at 0.3 µg/kg IV, associated with a Cmax for tafluprost acid estimated to be ~24 times the level in humans at the maximum recommended clinical dose.
1241/29 embryofetal development IV 3 9.13 – 343 227# 10 62.4 5.45 2346 757 30 136.9 5.59 5147 776 MP04098 pre-/postnatal development IV 0.3 – – 34# 23# 1 – – 114# 76# 3 9.13† – 343 227# 10 62.4† 5.45† 2346 757 1241/28 Rabbit (NZW) embryofetal development IV 0.03 – – 3# – 0.1 0.26 – 10 – 0.3 1.18 – 44 – 1241/35 IV 0.001 <0.02 – <0.75 – 0.003 0.01 77551 [MRHD, 900 ng] topical ocular 0.018 0.0266 0.0072 – – * = of tafluprost acid (active metabolite); – = not detected/not calculated/not applicable; a = calculated as animal:human Cmax or AUC0–t; ¶ = based on data in the 4-week IV rat study (1241/018); † = based on data from the embryofetal development study (1241/29); # = estimate based on linear extrapolation; Reported pharmacokinetic parameters are for GD17 (rat) or GD19 (rabbit); MRHD = maximum recommended human dose (based on once daily bilateral use; 30 μL drop). Acute toxicity In single-dose toxicity studies, neither oral (PO) administration of tafluprost at dose levels up to 100 mg/kg nor IV administration at up to 3 mg/kg produced significant signs of toxicity in rats. In dogs, single IV administration at ≥3 μg/kg produced salivation, vomiting, moderate miosis, irregular respiration and increased heart rate. At 30 µg/kg, the miosis was severe and blood pressure was also increased. No adverse effects were noted at 0.3 µg/kg IV, associated with a Cmax for tafluprost acid estimated to be ~24 times the level in humans at the maximum recommended clinical dose.
auspar-tafluprost-120503.docx