DETERMINATION OF THE POPULATION PHARMACOKINETIC PARAMETERS OF SUSTAINED-RELEASE AND ENTERIC-COATED ORAL FORMULATIONS, AND THE SUPPOSITORY FORMULATION OF DICLOFENAC SODIUM BY SIMULTANEOUS DATA FITTING USING NONMEM

Data from sustained-release and enteric-coated oral formulations, and the suppository formulation of diclofenac sodium are fitted simultaneo usly using NONMEM(R) and the general linear model, ADVAN 5. Absorption and disposition parameters, serum levels, and absorption profiles wer e determined. The in viva absorption profiles were determined using th e program TOPFT(R). The in vivo absorption for the sustained-release f ormulation is slow first order and follows a flip-flop model since dis position rate constants are greater than absorption rate constants. Ab sorption from the enteric-coated form is essentially complete (greater than or equal to 95%) at about 7.5 h, while it is 95% complete at 24 h from the sustained-release formulation. This suggests likely absorpt ion from the colon in the case of the sustained-release formulation si nce absorption is only 75% complete during the first 10 h. The sustain ed-release relative bioavailability is 90-99%. Absorption from the sup pository is essentially complete at about 4.5 h. However, the relative bioavailability of the suppository formulation is low (55%), since de fecation may remove the drug from the absorption site before complete absorption. (C) 1998 John Wiley & Sons, Ltd.