R Value-Based Criteria Outperform Alkaline Phosphatase Less than Twice Normal in Identifying Hy's Law Cases in...

Area of Science:

• Hepatology
• Clinical Pharmacology
• Drug Safety

Background:

• Identifying hepatocellular drug-induced liver injury (HC DILI) consistent with Hy's Law is crucial in clinical trials.
• The diagnostic utility of the nR value (ALT or AST/ULN ÷ AP/ULN) ≥ 5 versus alkaline phosphatase (AP) < 2x ULN for HC DILI remains unclear.

Purpose of the Study:

• To compare the efficacy of nR value ≥ 5 and AP < 2x ULN in identifying HC DILI cases meeting specific criteria in clinical trials.
• To assess these markers' performance in detecting severe outcomes like DILI-related fatality and acute liver failure (ALF).

Main Methods:

• Retrospective analysis of clinical trial DILI cases (July 2020-April 2024) with ALT or AST ≥ 3x ULN and total bilirubin (TB) > 2x ULN.
• Categorization of cases based on nR value ≥ 5 and AP < 2x ULN.
• Determination of positive predictive values (PPVs) and sensitivities for HC DILI-related fatality and ALF.

Main Results:

• Of 52 eligible DILI cases, 16 (31%) met nR ≥ 5, 5 (10%) met AP < 2x ULN, and 21 (40%) met both criteria.
• For HC DILI fatalities (excluding cholestatic), nR ≥ 5 showed 100% sensitivity and 8% PPV; AP < 2x ULN had 33% sensitivity and 4% PPV.
• Including an ALF case, nR ≥ 5 demonstrated 100% sensitivity and 11% PPV for severe outcomes, outperforming AP < 2x ULN (25% sensitivity, 4% PPV).

Conclusions:

• The nR value ≥ 5 better approximates Hy's Law criteria for identifying severe HC DILI in clinical trials.
• The nR value ≥ 5 demonstrated superior sensitivity compared to AP < 2x ULN in detecting DILI-related fatalities and ALF.
• Despite small numbers, findings suggest nR ≥ 5 is a more effective marker for severe HC DILI outcomes.