RE: DRUG AND METABOLITE

From: "Perez Ruixo, Juan Jose [JanBe]" <JPEREZRU@janbe.jnj.com> Subject: RE: DRUG AND METABOLITE Date: Tue, 29 May 2001 14:19:20 +0200 Hello all, When we fit simultaneously parent drug and metabolite concentrations it is not possible to estimate the distribution volume of the metabolite (for this reason, S3=1) and fraction of parent drug dose that is converted to metabolite (you assume F3 = 0). If K10 is the total elimination rate constant of parent drug, and we assume that all parent drug is converted into the metabolite, and then K10 is the formation rate constant of the metabolite (this is K10 = K13). You say 'In the $DES I used only K10 (which is a sum of elimination of the parent drug and formation rate of its metabolite)'. It is OK, but your initial estimates of K10 and K13 are not properly constrained to avoid K13 > K10. Possible solutions: 1. Using the constraint K10 >= K13 the estimation step could work better. 2. Modifying actual control file as follows: CL1=THETA(.) CL2=THETA(.) V1=THETA(.) KEL=CL1/V1 K13=CL2/V1 K10=KEL+K13 $DES DADT(1)=-K10*A(1)+K21*A(2)-K12*A(1) DADT(2)=K12*A(1)-K21*A(2) DADT(3)=K13*A(1)-K30*A(3)-K34*A(3)+K43*A(4) DADT(4)=K34*A(3)-K43*A(4) Now the elimination rate constant of parent drug (KEL+K13) is always greater than K13 (if lower boundaries are 0). Moreover, usually the actual half life of the metabolite is shorter than that of the parent drug and, consequently, the apparent metabolite elimination is controlled by the parent drug elimination. It could be useful thus to restrict K30 =< K13. This is something like a flip-flop model. In your case, however, I think it is not needed because initial estimate of K30 is 0.18 (lower than 2.96). Best regards. Juan Jose Perez Ruixo. Janssen Research Foundation.