221 The clinical use of mycophenolate mofetil is limited by its gastrointestinal toxicity caused by the enterohepatic circulation of its active metabolite, MPA. Based on the 3D crystal structure of inosine monophosphate dehydrogenase (IMPDH), VX-497 was designed specifically to inhibit IMPDH but not to undergo enterohepatic circulation. We wanted to investigate the ability of VX-497 to suppress rejection of organ allografts. Methods: The body weights and graft function by palpation (graded on a scale from 0-4) of 28 Lew recipients of BN hearts were monitored daily. Hct and WBC were monitored preop (day -3) and weekly after Tx. Drug plasma concentrations (HPLC) were measured on day 14 (1h and 6h) and day 28 (0h, 0.5h, 1h, 2h, 6h, 10h) or on the day of sacrifice. Grafts were removed on day 28 or after cessation of a palpable heartbeat for histologic grading. Groups were: vehicle allograft groups (n=8), 25 mg/kg BID (n=6), 50 mg/kg BID (n=6) and 75 mg/kg BID (n=8). Results: Hct and WBC were not significantly (p >0.05) affected in any of the VX-497 treatment groups. All treated rats gained weight. Graft survival was significantly prolonged in all drug treatment groups compared to untreated controls (p<0.01, log rank). The median histology scores (0-4 scale) were 4 (25 mg/kg group) and 3.25 (50 and 75mg/kg group). The median palpation score (graph) was 1 on day 28 for both the 50 and 75 mg/kg BID group. The peak average (day 14 and day of sacrifice) plasma concentration (C1h) 1h after dosing ± SEM (mg/L) did not differ (p= 0.12) between the 50 mg/kg (2.6±0.3) and 75 mg/kg (4.8±0.7) groups. C1h for the 25 mg/kg group was significantly (p= 0.02) lower at 0.6±0.2, consistent with a shorter median survival time of 16 days for this group compared to more than 28 days for the higher dose groups (ANOVA, Dunnet T3). Conclusions: This is the first study to evaluate an immunosuppressant discovered using structure-based drug design in a solid organ transplant model. VX-497 prolongs graft survival in the rat. Histologic rejection was present, but since the drug exposures were non-toxic, higher and more effective doses may be tolerated and need to be studied. (Figure)FigureThis research was funded by Vertex Pharmaceuticals, Cambridge, Ma.
No takes yet. Share an insight, caveat, or question.
Gummert et al. (1999) studied this question.