TABLE 3.
Pharmacokinetics: Plasma DTG in LM/Bc MICE on HIGH Mg2+ SOY DIET. Published pharmacokinetic (PK) parameters (Cmax, AUC, t½, and Tmax) for single or multiple doses of DTG in non-pregnant and pregnant humans are compared to the PK parameters in LM/Bc mice receiving a single oral dose (non-pregnant) or multiple doses (pregnant) of DTG. The maximum human recommended dose (MHRD) for DTG is 50 mg twice a day (100 mg/d). Female LM/Bc mice were maintained on high Mg2+ soy diet. Non-pregnant females were administered a single oral dose of DTG (750 mg/kg/d) and pregnant females were administered the same oral dose (DTG750) daily (from GD 0.5 to GD9.5). For developmental toxicology studies, the goal is to provide a systemic exposure >25x the MHRD (Cmax or AUC) [ICH S5 (R3)]. In pregnant LM/Bc mice the Cmax approximates 35x the Cmax in pregnant women (second trimester) taking oral DTG (50 mg/d); however, in the same comparison, the AUC in pregnant mice approximates only 18x the AUC in pregnant women because the DTG t½ is much shorter in mice.
| Mouse (DTG750 mg/kg, oral gavage) | Human | Mouse (multiplication factor) | ||
|---|---|---|---|---|
| PARAMETER | UNIT | VALUE | ||
| Cmax | ||||
| Non-pregnant (single dose DTG750) | µg/mL | 132.98 | 4.6 (50 mg single dose) 1 | 28.9 x |
| 6.7 (100 mg × 7d) 2 | 19.8 x | |||
| 8.1 (100 mg single dose) 1 | 16.4 x | |||
| Pregnant (10 daily doses DTG750) GD 0.5—GD 9.5 | µg/mL | 127.89 | 3.62 (2.57–4.63) | 35.3 x |
| (2nd trimester, 50 mg/d) 3 | ||||
| AUC 0-24 | ||||
| Non-pregnant (single dose DTG750) | µg*h/mL | 1299.36 | 70.8 (50 mg single dose) 1 | 18.4 x |
| 92.3 (100 mg × 7d) 2 | 14.1 x | |||
| 131 (100 mg single dose) 1 | 9.9 x | |||
| Pregnant (10 daily doses DTG750) GD 0.5—GD 9.5 | µg*h/mL | 846.55 | 47.6 (33.4–63.7) (2nd trimester, 50 mg/d) 3 | 17.8 x |
| t½ | ||||
| Non-pregnant (single dose DTG750) | h | 6.30 h | 13–14 h (50 mg single dose) 1 | |
| Pregnant (10 daily doses DTG750) | h | 4.40 h | 11 h (2nd trimester, 50 mg/d) 3 | |
| Tmax | ||||
| Non-pregnant (single dose DTG750) | h | 2.00 h | 1.25 h (50 mg single dose) 1 | |
| Pregnant (10 daily doses DTG750) | h | 2.00 h | 2 h (2nd trimester, 50 mg/d) 3 | |