Table 1.
Summary of troglitazone (TGZ)-mediated hepatotoxicity in human SimPops and clinical trials.
| Simulationsa | Clinical Trials2,3 | ||||
|---|---|---|---|---|---|
|
| |||||
| TGZ 200 mg (n=331) |
TGZ 400 mg (n=331) |
TGZ 600 mg (n=331) |
TGZ 200 – 600 mg (n=2510) |
Placebo (n=475) |
|
| ALT > 3× ULN (%)b | 0.3 | 3.0 | 5.1 | 1.9 | 0.6 |
| ALT > 5× ULN (%)b | 0.3 | 1.8 | 4.2 | 1.7 | N/A |
| ALT > 8× ULN (%)b | 0.3 | 1.8 | 3.6 | 0.9 | 0 |
| ALT > 30× ULN (%)b | 0 | 0.6 | 0.9 | 0.2 | 0 |
| Time to peak ALT (Days)c | 180d | 118 ± 61 | 111 ± 61 | 147 ± 86 | N/A |
| Total Bilirubin > 2× (%)e | 0.3 | 1.8 | 3.6 | N/A | N/A |
| Hy’s Law cases (%) | 0.3 | 1.8 | 3.6 | N/A | N/A |
| Jaundice (%) | N/A | N/A | N/A | 0.08 | 0 |
a
Each dose level was simulated for 6 months.
b
Upper limit of normal (ULN) was 34 U/L in the clinical trials. In the human SimPops, ULN was 30 U/L because all the individuals had the same baseline ALT (30 U/L) before troglitazone administration.
c
Mean ± S.D.
d
S.D. was not calculated because only one individual showed ALT elevation > 3× ULN
e
Baseline serum total bilirubin in human SimPops was 0.55 mg/dL.
N/A, not available.