Myopathy related to administration of a cationic amphiphilic drug and the use of multidose drug distribution analysis to predict its occurrence.
Many cationic amphiphilic (phospholipidosis-inducing) drugs (CADs) accumulate in tissues following repeated dosing in preclinical models, and this is sometimes associated with dose-limiting toxicities. Plasma drug levels cannot be used to estimate tissue accumulation of CADs since it occurs in tissues despite stabilization of plasma levels. Severe myopathy was found in skeletal muscles of rats during the initial safety evaluation of a dopamine D3 receptor antagonist, PNU-177864, and was associated with phospholipidosis in numerous tissues. The myopathy was observed only when plasma levels of PNU-177864 remained essentially constant throughout the 24-hour dosing period. A repeat dose drug distribution study using whole body autoradiography demonstrated that drug-related material did not accumulate in skeletal muscle or other tissues following repeated doses at levels considered within the therapeutic range and showing toxicokinetic profiles acceptable for further development. These observations provided support for the continued development of and longer-term toxicity studies with this candidate compound.
Vonderfecht
Steven L
SL
Worldwide Safety Sciences, Pfizer Global Research and Development, Pfizer Inc., Kalamazoo, Michigan 49007, USA. vonderfechts@lilly.com
Stone
Marjorie L
ML
Eversole
Robert R
RR
Yancey
Mark F
MF
Schuette
Margaret R
MR
Duncan
Barbara A
BA
Ware
Joseph A
JA
D000818:Animals; D001345:Autoradiography; D018492:Dopamine Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D008064:Lipidoses / Q000139:chemically induced; D008297:Male; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D009135:Muscular Diseases / Q000139:chemically induced*; D010743:Phospholipids / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D018492:Dopamine Antagonists; D010743:Phospholipids