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of the potential toxicity (or subtherapeutic effect) when the drugs are coprescribed. Warning patients of all potential drug interactions may lead to information paralysis on the part of both the patient and clinician. The addition of dynamic testing goes a large step further in assessing the clinical relevance of drug interactions. |
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Problem 5: How can preclinical information be used to target drug interactions studied during clinical drug development? |
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There has been a historical tendency to perform drug interaction studies of new drugs with many drugs having a potential to be concurrently administered. This can lead to a number of drug interactions being presented within the NDA that do not confer a safety concern. Providing drug interaction information early in the development program allows patients taking potentially interacting drugs to be entered into clinical trials earlier. An alternative strategy to studying all potential interactions is to perform clinical drug interaction studies only with drugs where it is reasonable to assume a dynamic interaction of clinical significance or a kinetic interaction that is predicted from preclinical models. |
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By mapping out the elimination mechanism in animals and human tissues or cells, it is increasingly possible to predict which elimination clearance interactions are likely to occur clinically. Mapping out the metabolic pathway including the predominant cytochrome P450 isozymes allows the scientist to plan a drug interaction program more logically and to conserve resources. When the drug is primarily eliminated by renal clearance mechanisms, the isolated perfused rat kidney preparation provides a system for predicting human drug interactions. |
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Lamivudine (3TC) is a new nucleoside analogue being used to treat patients with HIV infection. Early in the preclinical program is was known that the primary clearance mechanism for lamivudine is renal secretion and that the drug would be routinely coadministered with a variety of other antivirals and antibiotics that are also primarily eliminated by the kidney. It was decided to select drugs for clinical interaction studies by using an isolated perfused rat kidney screen and to support the clinical efficacy program with population pharmacokinetics to detect other large interactions not specifically studied. This preclinical model found that trimethoprim produced a large decrease in lamivudine renal clearance, whereas AZT, ddI, and ddC did not [13]. A clinical study then found coadministration of trimethoprim/sulfamethoxazole to HIV infected patients taking lamivudine produced a 45% increase in the lamivudine serum concentration and a 35% decrease in renal clearance (Figure 6) [14]. Lamivudine did not significantly alter the pharmacokinetics of either trimethoprim or sulfamethoxazole. Since lamivudine has a wide safety margin, no change in the dosing strategy was recommended as a result of this drug interaction. |
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