A Survey of the Way Pharmacokinetics are Reported in Published Phase I Clinical Trials, with an Emphasis on Oncology

Abstract

Background and objective

During the drug development process, phase I trials are the first occasion to study the pharmacokinetics of a drug. They are performed in healthy subjects, or in patients in oncology, and are designed to determine a safe and acceptable dose for the later phases of clinical trials. We performed a bibliographic survey to investigate the way pharmacokinetics are described and reported in phase I clinical trials.

Methods

We performed a MEDLINE search to retrieve the list of papers published between 2005 and 2006 and reporting phase I clinical trials with a pharmacokinetic study. We used a spreadsheet to record general information concerning the study and specific information regarding the pharmacokinetics, such as the sampling times, number of subjects and method of analysis.

Results

The search yielded 349 papers, of which 37 were excluded for various reasons. Nearly all of the papers in our review concerned cancer studies, although this was not a requirement in the search. Consistent with the selection process, 84% papers explicitly stated pharmacokinetics as an objective of the study. The methods section usually included a description of the pharmacokinetics (88%), but 10% of the papers provided no information concerning the methods used for the pharmacokinetics and in 2% the description was only partial. The analytical method was usually basic, with non-compartmental or purely descriptive methods. Observed concentrations and areas under the concentration-time curves were the pharmacokinetic variables most often reported. The results of the pharmacokinetic study were frequently reported in a separate paragraph of the results section, and only 22% of the studies related the pharmacokinetic findings to other results from the study, such as toxicity or efficacy. In addition, important information such as the number of subjects included in the pharmacokinetic study or the pharmacokinetic sampling scheme was sometimes not reported explicitly.

Conclusion

Concerns about the decreasing cost-effectiveness of the drug development process prompted the regulatory authorities to recently recommend better integration of all available information — including, in particular, pharmacokinetics — in this process. In our review, we found that this information was often either missing or incomplete, which hinders that objective. We suggest several improvements in the design and the reporting of the methods and results of these studies, to ensure that all relevant information has been included. Pharmacokinetic findings should also be integrated into the broader perspective of drug development, through the study of their relationship with toxicity and/or efficacy, even in the early phase I stages.