Biowaiver monographs for immediate release solid oral dosage forms: piroxicam.

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing piroxicam in the free acid form are reviewed. Piroxicam solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA), and corresponding dissolution data are taken into consideration. The available data suggest that according to the current biopharmaceutics classification system (BCS) and all current guidances, piroxicam would be assigned to BCS Class II. The extent of piroxicam absorption seems not to depend on manufacturing conditions or excipients, so the risk of bioinequivalence in terms of area under the curve (AUC) is very low, but the rate of absorption (i.e., BE in terms of Cmax ) can be affected by the formulation. Current in vitro dissolution methods may not always reflect differences in terms of Cmax for BCS Class II weak acids; however, minor differences in absorption rate of piroxicam would not subject the patient to unacceptable risks: as piroxicam products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR piroxicam solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients, which are also present in IR solid oral drug products containing piroxicam, which have been approved in ICH or associated countries, for instance, those presented in Table 3 of this paper; (b) both the test and comparator drug products dissolve 85% in 30 min or less at pH 1.2, 4.5, and 6.8; and (c) the test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When not all of these conditions can be fulfilled, BE of the products should be established in vivo.

Biowaiver monographs for immediate-release solid oral dosage forms: ketoprofen.

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing ketoprofen are reviewed. Ketoprofen's solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA)/dissolution data were taken into consideration. The available data suggest that according to the current Biopharmaceutics Classification System (BCS) and all current guidances, ketoprofen is a weak acid that would be assigned to BCS Class II. The extent of ketoprofen absorption seems not to depend on formulation or excipients, so the risk of bioinequivalence in terms of area under the curve is very low, but the rate of absorption (i.e., BE in terms of peak plasma concentration, C(max) ) can be altered by formulation. Current in vitro dissolution methods may not always reflect differences in terms of C(max) for BCS Class II weak acids; however, such differences in absorption rate are acceptable for ketoprofen with respect to patient risks. As ketoprofen products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR ketoprofen solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients present also in IR solid oral drug products containing ketoprofen, which are approved in International Conference on Harmonisation or associated countries, for instance, as presented in this paper; (b) both the test drug product and the comparator dissolve 85% in 30 min or less in pH 6.8 buffer; and (c) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When one or more of these conditions are not fulfilled, BE should be established in vivo.