title: Formulation approaches in mitigating toxicity of orally administrated drugs.
abstract: This paper provides an overview of current formulation approaches to mitigate toxicity of orally administrated drugs. The formulation approaches are characterized by their intended impact on a drug's pharmacokinetic parameters, pharmacological properties or metabolic pathways. Regulatory opportunities and constraints with focus on U.S. regulations in optimizing a drug's safety or efficacy profile are reviewed. The following formulation approaches are described: (i) pharmacokinetic-modulating and (ii) pharmacodynamic-modulating. In the pharmacokinetic-modulating approach, the pharmacokinetic profile of drug release is modified by, for example, a reduction in peak drug plasma concentration while preserving or improving AUC, thereby potentially reducing toxic effects that may be related to C(max). In the pharmacodynamic-modulating approach, the drug is co-dosed with pharmacologically active or nonpharmacologically active agent or agents intended for mitigation of the drug's toxicity. The pharmacodynamic-modulating approach requires information on the specificity of drug interactions with other compounds and also on metabolic pathways. Examples demonstrating successful formulation work in reducing drug toxicity are provided. The in-depth knowledge of the drug's PK and PD properties combined with a greater understanding of the biology of diseases are necessary for successful drug product formulation leading to optimized in vivo exposure and minimized toxicity.
authors: Formulation Department, Vertex Pharmaceuticals, Cambridge, MA 02139-04242, USA. irina_kadiyala@vrtx.com
authors: Irina
authors: I
authors: Kadiyala
authors: Elijah
authors: E
authors: Tan
mesh_terms: D000284:Administration, Oral; D002626:Chemistry, Pharmaceutical / Q000592:standards*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry / Q000592:standards
chemical_list: D004364:Pharmaceutical Preparations