Evaluation of utility of pharmacokinetic studies in phase I combination trials.

2611 Background: There are many phase I clinical combination trials including drug-drug interaction (DDI) studies, but very few of them report positive results. We hypothesized that the utility of DDI studies is low in the absence of a mechanistic hypothesis. Methods: We retrospectively reviewed 119 phase I (2 drug) combination studies published in 2007-2011. Results: Only 23 (19%) studies had a positive 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 9 (8%) studies demonstrated a statistically significant effect DDI, based on AUC of parent drug or active metabolite. There was a strong association between lack of rationale and a lack of interaction, as only 2% of studies without a rationale demonstrated a DDI, compared to 30% of studies with a rationale (Fisher’s exact test, p=0.0004) (Table). Conclusions: DDI studies should not be routinely performed as part o...