Healthy volunteer studies subsequent

In summary, studies in healthy volunteers are an integral part of the development of most drugs because they are capable of rapidly providing a large amount of data that are not confounded by other variables and that can thereby expedite the subsequent evaluation of the drug in patients. 

The NME can now be administered to humans. The first step in clinical evaluation is one or more phase I studies designed to assess the drug s safety and pharmacokinetic profile. Phase I studies usually involve a small number of healthy volunteers who are closely monitored after receiving escalating doses of the drug candidate. Phase I studies of drugs for cancer or HIV infection must be carried out in patients, not in healthy subjects. Ordinarily, until more information is available, the minimum dose to induce side effects is stipulated as the upper dose limit for subsequent administration to human subjects. 

The occurrence of cardiac toxicity was closely correlated with terfenadine use, and subsequent in vitro studies confirmed that terfenadine (but not fexofenadine) efficiently blocks cardiac potassium channels (14). A study in healthy volunteers treated concomitantly with terfenadine and ketoconazole found a linear relationship between trough terfenadine concentrations and QTC intervals. The QTC interval lengthened up to 110 millisecond at the highest plasma concentrations of 45 ng/mL (9). Thus, the direct inhibitory effect of terfenadine on cardiac potassium channels results in prolongation of cardiac repolarization, which is a well-known cause of ventricular arrhythmias. In one death in which terfenadine was implicated, plasma level of the drug was 55 ng/mL several hours after the last ingestion of the drug (when it normally should be undetectable). 

In addition to the first in man studies there are subsequent studies in healthy volunteers, which are performed in parallel to the phase II/III clinical development. These studies address issues like drug-drug interactions, special sub-populations (e.g. patients with liver and renal impairment), or bioavailability/bioequivalence issues. These studies are also conducted under the same well controlled conditions and therefore contribute rich data. 

The study was performed employing GC-MS, using bis-trimethylsilyl-trifluor-oacetamide (BSTFA) as derivatization agent during sample preparation. The aim of the study was to compare the metabolic profiles of urine samples from patients with liver cancer (n = 20) and healthy volunteers (n = 20) and, subsequently, to develop a diagnostic model that would include selected metabolites of potential diagnostic significance in HCC [21]. 

A sponsor conducts a drug interaction study in healthy volunteers of their NME, a CYP3A substrate, co-administered with ketoconazole as an enzyme inhibitor. Subsequent to the study, the subjects are geno-typed for their CYP3A5 alleles to determine the relative contribution of this polymorphism to inter-individual variabihty in AUC. 

The chnical phase of development may start once nonchnical testing has demonstrated that the product may be administered to human test subjects without unjustified risk. From the results of the nonchnical studies one tries to calculate an initial safe dose and subsequent dose-escalation schemes in humans. Any studies conducted in human beings must follow the guidehnes set forth by the Declaration of Helsinki (designed to protect healthy volunteers). The international Good Chnical Practice (GCP) guidehnes are based on this document and are compulsory for all chnical studies performed. 

The changes in GST observed post-halothane anesthesia are small and it is possible that they may reflect circadian changes in the enzyme levels. To study this we measured plasma B, concentrations in 30 healthy volunteers after an overnight fast and subsequently at 3, 6, and 24 hr, i.e., the sampling intervals used for the study on the effects of halothane on GST. We could detect no signiflcant increase in B, subunits over this time period. 

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