S. Hardiman, K. Miller, M. Murphy
Nov 1, 1993
Citations
0
Influential Citations
4
Citations
Quality indicators
Journal
Acta Neurologica Scandinavica
Abstract
Safety observations during the clinical development of Mentane® (velnacrine maleate) have included the occurrence of generally asymptomatic liver enzyme elevations confined to patients with Alzheimer's disease (AD). The clinical presentation of this reversible hepatocellular injury is analogous to that reported for tetrahydroaminoacridine (THA). Direct liver injury, possibly associated with the production of a toxic metabolite, would be consistent with reports of aberrant xenobiotic metabolism in Alzheimer's disease patients. Since a patient related aberration in drug metabolism was suspected, a biostatistical strategy was developed with the objective of predicting hepatotoxicity in individual patients prior to exposure to velnacrine maleate. The method used logistic regression techniques with variable selection restricted to those items which could be routinely and inexpensively accessed at screen evaluation for potential candidates for treatment. The model was to be predictive (a marker for eventual hepatotoxicity) rather than a causative model, and techniques employed “goodness of fit”, percentage correct, and positive and negative predictive values. On the basis of demographic and baseline laboratory data from 942 patients, the PROPP statistic was developed (the Physician Reference Of Predicted Probabilities). Main effect variables included age, gender, and nine hematological and serum chemistry variables. The sensitivity of the current model is approximately 49%, specificity approximately 88%. Using prior probability estimates, however, in which the patient's likelihood of liver toxicity is presumed to be at least 30%, the positive predictive value ranged between 64–77%. Although the clinical utility of this statistic will require refinements and additional prospective confirmation, its potential existence speaks to the possibility of markers for idiosyncratic drug metabolism in patients with Alzheimer's disease.