The Biopharmaceutics Classification System (BCS) was developed to allow prediction of in vivo pharmacokinetic performance of drug products from measurements of permeability (determined as the extent of oral absorption) and solubility. Here, we suggest that a modified version of such a classification system may be useful in predicting overall drug disposition, including routes of drug elimination and the effects of efflux and absorptive transporters on oral drug absorption; when transporter-enzyme interplay will yield clinically significant effects (e.g., low bioavailability and drug-drug interactions); the direction, mechanism, and importance of food effects; and transporter effects on postabsorption systemic drug concentrations following oral and intravenous dosing. These predictions are supported by a series of studies from our laboratory during the past few years investigating the effect of transporter inhibition and induction on drug metabolism. We conclude by suggesting that a Biopharmaceutics Drug Disposition Classification System (BDDCS) using elimination criteria may expand the number of Class 1 drugs eligible for a waiver of in vivo bioequivalence studies and provide predictability of drug disposition profiles for Classes 2, 3, and 4 compounds.
The ability to predict drug disposition involves concurrent consideration of many chemical and physiological variables and the effect of food on the rate and extent of availability adds further complexity due to postprandial changes in the gastrointestinal (GI) tract. A system that allows for the assessment of the multivariate interplay occurring following administration of an oral dose, in the presence or absence of meal, would greatly benefit the early stages of drug development. This is particularly true in an era when the majority of new molecular entities are highly permeable, poorly soluble, extensively metabolized compounds (BDDCS Class 2), which present the most complicated relationship in defining the impact of transporters due to the marked effects of transporter-enzyme interplay. This review evaluates the GI luminal environment by taking into account the absorption/transport/elimination interplay and evaluates the physiochemical property issues by taking into account the importance of solubility, permeability and metabolism. We concentrate on the BDDCS and its utility in predicting drug disposition. Furthermore, we focus on the effect of food on the extent of drug availability (F), which appears to follow closely what might be expected if a significant effect of high fat meals is inhibition of transporters. That is, high fat meals and lipidic excipients would be expected to have little effect on F for Class 1 drugs; they would increase F of Class 2 drugs, while decreasing F for Class 3 drugs.
PURPOSE Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab. METHODS A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review. RESULTS A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively. CONCLUSION Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.
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