{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T17:42:55Z","timestamp":1760204575815,"version":"3.38.0"},"reference-count":31,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2011,10,17]],"date-time":"2011-10-17T00:00:00Z","timestamp":1318809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research Pt B"],"published-print":{"date-parts":[[2012,2]]},"abstract":"<jats:p>PPD10558 is an orally active, lipid\u2010lowering 3\u2013hydroxy\u20103\u2010methylglutaryl coenzyme A (HMG\u2010CoA) reductase inhibitor (statin) being developed as a treatment for hypercholesterolemia in patients who have not been able to tolerate statins because of statin\u2010associated myalgia. We have studied the potential developmental toxicity effects of PPD10558 in pregnant rats and rabbits given daily oral doses during the period of organogenesis. Rats were dosed with 0, 20, 80, or 320\u2009mg\/kg\/day from Gestation Day (GD) 6 to 17 and rabbits received dose levels of 0, 12.5, 25, or 50\u2009mg\/kg\/day from GD 6 to 18. Additional groups in both studies served as toxicokinetic animals and received the PPD10558 in the same manner as the main study groups at the same dose levels. Blood samples were collected from toxicokinetic animals at designated time points on GD 6 and 17 in rats and GD 6 and 18 in rabbits. Fetal exposure in rats was assessed on GD 20. Maternal and developmental parameters were evaluated in rats and rabbits on GD 20 and GD 29, respectively. No maternal and developmental toxicity was observed at any of the dose levels used in the rat study. Evidence of fetal exposure was determined in fetal plasma with mean fetal concentrations of PPD10558 and the metabolite (PPD11901) found to be between 1 and 6% of the mean maternal concentrations. In rabbits, marked maternal toxicity including mortality (eight deaths; 1 dose at 25 and 7 at 50\u2009mg\/kg\/day), abortions (2 at 25\u2009mg\/kg\/day and 6 at 50\u2009mg\/kg\/day) and reduction in gestation body weight, gestation body weight changes and decreased food consumption were observed. In addition, fetal body weights of the combined sexes were significantly reduced at 50\u2009mg\/kg\/day in comparison with the controls. Mean peak exposure (<jats:italic>C<\/jats:italic>max) and total exposure (AUC(0\u201324)) of PPD11901 in both rats and rabbits were higher than that of PPD10558 on GD 6 and GD 17 at each of the three dose levels.. Based on the results of these studies, the no observed adverse effect level (NOAEL) for maternal and developmental toxicity in rats was considered to be \u2265320\u2009mg\/kg\/day, the highest dose level used in the study. The NOAEL for maternal and developmental toxicity in rabbits was 12.5\u2009mg\/kg\/day and 25\u2009mg\/kg\/day, respectively.<\/jats:p>","DOI":"10.1002\/bdrb.20337","type":"journal-article","created":{"date-parts":[[2011,10,17]],"date-time":"2011-10-17T20:38:30Z","timestamp":1318883910000},"page":"23-37","source":"Crossref","is-referenced-by-count":7,"title":["Developmental Toxicity of the HMG\u2010CoA Reductase Inhibitor (PPD10558) in Rats and Rabbits"],"prefix":"10.1002","volume":"95","author":[{"given":"Ali S.","family":"Faqi","sequence":"first","affiliation":[{"name":"MPI Research, Inc. Mattawan Michigan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Prohaska","sequence":"additional","affiliation":[{"name":"Furiex Pharmaceuticals Morrisville North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rocio","family":"Lopez","sequence":"additional","affiliation":[{"name":"Furiex Pharmaceuticals Morrisville North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail","family":"McIntyre","sequence":"additional","affiliation":[{"name":"Furiex Pharmaceuticals Morrisville North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,10,17]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.3513311"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.20058"},{"key":"e_1_2_5_4_1","first-page":"163","volume-title":"Comprehensive toxicology","author":"Carney 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