Modelling is seldom used to describe pharmacokinetics in phase I clinical trials
Emmanuelle Comets (1), Sarah Zohar (2,3)
(1) Inserm, U738, Paris, France; Université Paris 7, Faculté de Médecine, Paris, France; (2) Inserm CIC 9504, Centre d'Investigations Cliniques, Hôpital Saint-Louis, Paris, France; (3)Inserm U717, Département de Biostatistique et Informatique Médicale, Hôpital Saint-Louis, Paris, France
Objectives: During the drug development process, phase I trials are the first occasion to study the pharmacokinetics (PK) of a drug. They are performed in healthy volunteers, or 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 PK is 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 PK study. We read a third of these papers, randomly selected, using a spreadsheet to record general information concerning the study, and specific information regarding the PK.
Results: Nearly all the papers in our review concerned cancer studies, although this was not a requirement in the search. Consistent with the selection process, 8 out of 10 papers explicitely stated PK as an objective of the study. The methods section usually included a description of the PK (83%), but 12% of the papers provided no information concerning the methods used for the PK, and in 6% the description was only partial. The analysis method was usually basic, and modelling was used only in about 15% of the studies. Observed concentrations and area under the curves were the PK variables most often reported.
The results of the PK study were frequently reported in a separate paragraph of the results section, and only around 15% of the studies related the PK findings to other results from the study, such as toxicity or efficacy. In addition, important information such as the number of patients included in the PK study was often not reported explicitely.
Conclusions:Concerns about the decreasing cost-effectiveness in the drug development process prompted the regulatory authorities to recently recommend a better integration of all available information, including in particular PK. In our review we found that this information was often either missing or incomplete, which hinders that objective. We suggest several improvements to the design and the reporting of methods and results for these studies, to ensure all relevant information has been included. PK findings should also be integrated in the broader perspective of drug development, including for instance the modelling of their relationship with toxicity and/or efficacy, even in early phase I stages.
