Human pharmacology trials pharmacokinetic studies

Clinical trials and clinical trial authorizations in the European Union are controlled under the Clinical Trial Directive, 2001/20/EC [9], and all member states are bound by its requirements. Under the provisions of the Directive, a clinical trial is an investigation in human subjects that is intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of one or more medicinal products, identify any adverse reactions or study the absorption, distribution, metabolism, and excretion, with the object of ascertaining the safety and/or efficacy of those products. This definition includes pharmacokinetic studies. 

Nonclinical Studies In vitro (laboratory) or in vivo (animal) pharmacology, toxicology and pharmacokinetic studies that support the testing of a product in humans. Usually at least two species are evaluated prior to Phase I clinical trials. Nonclinical studies continue throughout all phases of research to evaluate long-term safety issues. 

As described in Chapter 31, Phase I includes first-in-human (FIH) trials to provide information about the safety (tolerability) and pharmacokinetics of a new drug. These trials are usually conducted in healthy volunteers unless the trials involve certain cytotoxic drugs such those used in cancer and HIV treatments. It should be noted that Phase I-type clinical pharmacology trials, such as those to study pharmacokinetics in special populations, can and do occur throughout the clinical drug development process (see Chapter 1, Figure 1.1). 

Fewer cephalosporins have been of clinical interest for oral administration. Studies of cefatrizine (BLS-640 SKF 60771) (7) have continued to determine in vitro characteristics,65-67 human pharmacokinetics,66 68,69 and clinical effectiveness.69-71 Extensive clinical trial data documented the effectiveness of cefadroxil (BLS-578 -OH cephalexin).72 Cefaclor (Lilly 99638) ( ) has been shown in in vitro studies to have better activity than cephalexin against gram-negative bacteria, especially H. influenzae. 56 60 73 7 The excellent oral absorption in mice, rats, and dogs paralleled that of cephalexin.75 Metabolism was observed in dogs76 but not in rodents. Human pharmacology studies indicated that cefaclor gave acceptable blood and urine levels.77... 

In view of the regulatory delay that was caused by the need to apply for a CTC, a Statutory Order (SI 1974/498) was made during 1974, to provide an exemption from the need to hold a CTC in such cases, subject to certain conditions. This order applied to trials conducted by doctors and dentists on their own responsibility (DDX). The basis of the clinical trial exemption (CTX) scheme, introduced in 1981, to include studies initiated by the pharmaceutical industry, was that together with a detailed clinical trial protocol and summaries of chemical, pharmaceutical, pharmacological, pharmacokinetic, toxicological and human volunteer studies, a clinical trial in patients may proceed without the need for the additional details normally required for a CTC or Product Licence application. This exemption scheme was based on the requirements that ... 

For FTIH trials, all applications should include a summary of projected free plasma concentrations of the new active substance (NAS) in humans and a brief description of any pharmacokinetic modelling programs used to generate the estimates. A comparison with the concentrations obtained in the nonclinical toxicity studies and projected safety margins should be given. In the same section, an estimate of the extent of the intended pharmacological or pharmacodynamic response at the expected plasma concentrations should be included, with a list of the assumptions used in deriving that estimate. 

Drug metabolism and pharmacokinetic (DMPK) studies are used to show how the concentrations of the drug and its metabolites vary with the administered dose of the drug and the time from administration. They are normally carried out using suitable animal species and in humans in Phase I trials. The information obtained from animal studies is used to determine safe dose levels for use in the Phase I clinical trials in humans. However, the accuracy of the data obtained from animal tests is limited, since it is obtained by extrapolation. In addition, it is necessary to determine the dose that just saturates the absorption and elimination processes so that the toxicological and pharmacological events may be correctly interpreted. 

Nonclinical pharmacokinetic investigation is helpful when interpreting the data from safety (pharmacological) studies, and it also provides support for toxicology studies. While nonhuman pharmacokinetic parameters are not perfectly predictive of human pharmacokinetics, they do constitute meaningful quantitative data that improve the chances of selecting the correct range of safe doses to test in humans. This dose selection is critically important to the success of clinical trials. 

The basis of the CTX scheme is that, following an evaluation of a detailed clinical trial protocol and summaries of chemical, pharmaceutical, pharmacological, pharmacokinetic, toxicological and, when appropriate, human volunteer studies, a clinical trial may be permitted. This obviates the provision of the additional details normally required for a Clinical Trial Certificate or Product Licence application. 

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