Is there a place for drug combination strategies using clinical pharmacology attributes?--review of current trends in research.
Drug discovery is the main flag ship of the pharmaceutical industry in order to ensure that innovations constantly occur in the identification and development of novel therapeutic options for the management of diseases. Recently, research trends that take advantage of the safety and efficacy of marketed products by combining such products with other agents to influence certain clinical pharmacology attribute(s) have emerged. The focus of the review is to evaluate ongoing research trends that have considered leveraging on certain clinical pharmacology attributes in the areas of viral infection (HIV and influenza) and oncology. Case studies discussed in this review include: a) the use of probenecid to block the organic anion renal transport of oseltamivir carboxylate (a key active metabolite of oseltamivir phosphate) to reduce the oral dose of oseltamivir phosphate; b) the use of rifampicin to induce the CYP2C19 enzyme and thereby, promote the formation of a potent active metabolite M8 (nelfinavir hydroxyl-t-butylamide) and achieve sustained blood levels to combat HIV infection along with ritonavir; c) the use of CYP3A4 inhibitors such as ketoconazole, cyclosporin A, ritonavir etc to overcome the extensive presystemic metabolism of docetaxel and enhance the oral bioavailability of docetaxel. Along with the case studies, several hurdles for drug development such as dose selection, frequency of dosing, and duration of the clinical studies, picking the right surrogate(s) for efficacy, evaluation of drug-drug interaction potential with other co-substrates have been discussed in line with the current day requirements for a sound clinical and regulatory strategy. In summary, based on the collated information, a pragmatic approach would render feasibility for a balanced therapy management using combined clinical pharmacology attributes of drugs.
Srinivas
Nuggehally R
NR
Integrated Drug Development, Suramus Biopharm, 77, 10th Cross, 29th Main, J.P. Nagar I Phase, Bangalore 560078, India. Srini.suramus@yahoo.com
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000493:pharmacokinetics; D035843:Biomedical Research / Q000639:trends*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D000077143:Docetaxel; D004338:Drug Combinations; D055808:Drug Discovery / Q000639:trends*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D049990:Membrane Transport Modulators / Q000494:pharmacology; D019888:Nelfinavir / Q000493:pharmacokinetics; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053139:Oseltamivir / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D010601:Pharmacology, Clinical / Q000639:trends*; D043823:Taxoids / Q000493:pharmacokinetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D049990:Membrane Transport Modulators; D027362:Organic Anion Transport Protein 1; D043823:Taxoids; D000077143:Docetaxel; D053139:Oseltamivir; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019888:Nelfinavir; C535162:oseltamivir carboxylate