Application of blood level data to dinical trials

In the evaluation of drugs, especially in the early phases, interpatient variation in response to a fixed dose may give misleading results concerning both efficacy and toxicity. Unless blood level determinations are made during the clinical trial, an effective drug could unnecessarily be lost or discarded. A lack of correlation between the administered dose of drug or its metabolites in plasma may be due to a multiplicity of factors: (1) individual difJerences in rate of metabolism (e.g., slow biotransformation); (2) disease states (e.g., gastrointestinal problems leading to malabsorption),'low renal clearance, hepatic disease, congestive heart failure; (3) natural history of the disease (e.g., if characterized by spontaneous remissions, efficacy is difficult to establish); (4) drug interactions (e.g., phenobarbital accelerating cyclophosphamide metabolism); (5) noncompliance (may be interpreted as either poor bioavailability or rapid elimination); (6) nature of formulation used during investigation (e.g" crushed drug in an opaque capsule‐for double‐blind purposes‐may alter bioavailability compared with the formulation finally marke ted); (7) electrolytes, anoxia, aCidosis in certain chronic diseases may modify response of drug at receptor; (8) abnormal protein binding of the drug; (9) environmental factors, such as the difference in response to niridazole in bilharziasis, i.e., well tolerated in Africa, and toxic to central nervous system in South American patients; (10) unknown genetic factors. Accordingly, measurement of plasma concentratiom of drugs during clinical investigations, while not an infallible aid, can be useful when applied under proper circumstances.