Evaluation of utility of pharmacokinetic studies in phase I trials of two oncology drugs
A partir d'une revue de la littérature publiée entre 2007 et 2011 sur des essais de phase I d'évaluation de combinaisons de traitements (152 essais identifiés), cette étude évalue l'intérêt de mener systématiquement, en l'absence d'une hypothèse sur les mécanismes à l'œuvre, une analyse pharmacocinétique des interactions entre les deux médicaments évalués
Purpose: There are many phase I trials of oncology drug combinations, very few of which report clinically significant pharmacokinetic interactions. We hypothesized that the utility of such pharmacokinetic drug-drug interaction (DDI) studies is low in the absence of a mechanistic hypothesis.
Experimental Design: We retrospectively reviewed 152 phase I (2 drug) combination studies published in 2007-2011.
Results:Only 28 (18%) studies had an implicit or explicit rationale, either inhibition/induction of a drug metabolizing enzyme or transporter, co-substrates for the same enzyme or transporter, potential for end-organ toxicity, or protein binding. Only 12 (8%) studies demonstrated a statistically significant DDI, based on change in clearance (or area under the curve) of parent drug and/or active metabolite. There was a strong association between a rationale and a demonstrable drug interaction, as only 2% of studies without a rationale demonstrated a DDI, compared to 32% of studies with a rationale (Fisher's exact test, p<10-6).
Conclusions: DDI studies should not be routinely performed as part of phase I trials of oncology combinations.
Clinical Cancer Research , résumé, 2013