Unreasonable VSS estimate

From: Eyas Abu-Raddad <RADDADE@mail.rx.uga.edu> Subject: Unreasonable VSS estimate Date: Mon, 07 May 2001 15:44:17 GMT Dear NONMEM users, I am trying to fit a 2-compartment model with first order absorption (ADVAN4 TRANS3) to IV and PO data (4-10 points from each of 10 rats in a cross over study). The IV data clearly show biphasic decline of the compound, but the first phase is usually very short, with only 1 to 3 points. PO data show flip flop kinetics (terminal half life after PO is longer than after IV).If I do not specify an upper bound, the estimate for Vss that I got is unreasonably high (about 30 times what I obtained from SHAM (noncompartmental) analysis). If I specify a reasonable upper bound, the estimate is always equal to the upper bound, no matter what the initial estimate is. The same problem persisted when only intravenous data were used for fitting. Any suggestions are appreciated. Eyas AbuRaddad University of Georgia