Oral pharmacokinetics sparse (no absorption phase)

From: "atul" Subject:[NMusers] Oral pharmacokinetics sparse (no absorption phase) Date: Tue, 7 May 2002 23:23:21 -0700 Hello nmusers I am sure this issue might have been discussed before but I was not able to find it. Could you share your views on it? I am analysing a real sparse data (only 4 points at 2, 4, 8 and 12h) after oral administration at steady state. So no points in the absorption phase at all. Upon examination of the data I saw that a one compartment model is good enough. So I went ahead and did analysis in ADVAN2. I have previous values from a paper reporting a ka of 2.8 for my drug. If I fix initial estimate of Ka as 2.8 and try to give eta on ka then NONMEM gives me error message 1. If I give the initial estimate of ka as 2.8 (without eta) and do not fix it then still I get the error message 1. Now when I change the initial estimate of ka to 1.3 surprisingly the run converges (everything is same as before with inital estimate as 2.8). I get final estimates of CL, V and ka as 233, 1240 and 1.13. I then changed the initial estimate of ka to 0.3. I then get the final estimates of CL, V and ka as 251, 211 and 0.174. The estimate of V (211) is similar to what has been reported earlier. However, The PRED vs DV plots are much better with higher ka. I get totally different meaningless values if I choose ka as 0.8. I think the ratio (ka/V) is really which is affecting the run. From what I observe is that the whole analysis is critically dependent on the initial value of ka which I choose. In case of ka=0.3 I end up with a flip-flop situation. How can I be sure of the final estimates which I get from these results? How would one decide in these situations? Is there any reference which discusses this. LIST OF ERROR MESSAGES: 1. ERROR IN NCONTR WITH INDIVIDUAL 13 ID= .19000000E+02 NUMERICAL HESSIAN OF OBJ. FUNC. FOR COMPUTING CONDITIONAL ESTIMATE IS NON POSITIVE DEFINITE MESSAGE ISSUED FROM ESTIMATION STEP AT 0TH ITERATION, UPON EVALUATION OF GRADIENT WITH RESPECT TO OMEGA 0TRY SUBSTANTIALLY INCREASING "INITIAL ESTIMATE OF SIGMA" 2. Elimination from some compartment is negligible. Steady state not achievable. 3. MATH overflow error. Thanks in advance for your time Venaktesh Atul Bhattaram Post-doctoral Fellow University of Florida Gainesville-32610