Pharmacodynamics of PLX5622 in preclinical studies
PLX5622 (1200 ppm; chow; for 3 weeks or 3 days; adult C57/Bl6 wild type mice) leads to around 80% of microglia lost after 3 days of treatment and a 99% microglia loss after 3 weeks of treatment. PLX5622 (adult C57/Bl6 wild type mice aged 3 months; diet for 3 weeks) decreases microglia in cortex, striatum, cerebellum and hippocampus[4].
PLX5622 (50 mg/kg; intraperitoneal injection; once (neonatal rat) or twice (adult rat) a day; for a total of 14 days) depletes microglia by 80-90% within 3 days of treatment, which increases to > 90% by 7 days. After 14 days of PLX5622 treatment, microglia is depleted by > 96% in both neonates and adults while preserving baseline astrocyte quantity. (A single daily injection of 0.65% PLX5622 suspended in 5% dimethyl sulfoxide and 20% Kolliphor RH40 in 0.01 M PBS is sufficient for neonatal microglia depletion, adult depletion requires injections twice daily)[5].
PLX5622 (formulated in AIN-76A standard chow at 1200 mg/kg; for 28 days) leads to reduction in microglia throughout the CNS in 14-month-old 5xfAD mice[6].
Pharmacokinetics of PLX5622 in preclinical species[1]
| Species | IV | PO (gavage) |
Dose
(mg/kg) | AUC0-∞
(ng hr/mL) | CL
(mL/min/kg) | Vss
(L/kg) | t1/2
(hr) | Dose
(mg/kg) | AUC0-∞
(ng hr/mL) | Cmax
(ng/mL) | F |
| Mouse | 1.92 | 15,500 | 2.1 | 0.34 | 2.6 | 45 | 215,000 | 26,300 | 59% |
| Rat (male) | 1.13 | 2,630 | 7.7 | 1.2 | 2.3 | 45 | 99,600 | 12,000 | 95% |
| Rat (female) | 1.13 | 5,110 | 3.7 | 1.0 | 3.9 | 45 | 181,000 | 15,600 | 89% |
| Dog | 1.00 | 6,230 | 3.0 | 2.3 | 15 | 45 | 96,500 | 3,630 | 34% |
| Monkey | 1.35 | 2,100 | 11 | 1.6 | 2.2 | ND | ND | ND | ND |
Preparation of gavage dosing suspensions for PLX5622[1]
PLX5622 is dissolved in DMSO at a concentration that is 20x the final dosing solution. The compound stock is protected from light. A fresh stock is made each week.
The components of the diluent generally are prepared a day or more in advance because they take time to dissolve completely: a) 2% hydroxypropyl methyl cellulose (HPMC): 2.0 g powder was brought to 100 mL deionized water; b) 25% Polysorbate 80 (PS80): 25 g was brought to 100 mL deionized water. To make 100 mL diluent, add 25 mL of 2% HPMC stock (0.5% final) and 4 mL of 25% PS80 stock (1% final) to 71 mL deionized water to have final 100 mL. Final composition after mixing with compound: 0.5% HPMC, 1% PS80, 5% DMSO.
On each dosing day, the compound stock is diluted 20-fold as follows: 19 volumes of diluent are measured into the tube, and 1 volume of the 20x compound/DMSO stock is added. The cap is closed and the content of the tube is mixed by inversion and placed in a sonicating water bath to make a uniform suspension.
