Evaluation of utility of pharmacokinetic studies in phase I trials of two oncology drugs.
OBJECTIVE
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.


METHODS
We retrospectively reviewed 152 phase I (two drug) combination studies published between 2007 and 2011.


RESULTS
Only 28 (18%) studies had an implicit or explicit rationale, either inhibition/induction of a drug-metabolizing enzyme or transporter, cosubstrates for the same enzyme or transporter, potential for end-organ toxicity, or protein binding. Only 12 (8%) studies demonstrated a statistically significant DDI, on the basis of 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 with 32% of studies with a rationale (Fisher exact test; P < 10(-6)).


CONCLUSIONS
DDI studies should not be routinely performed as part of phase I trials of oncology combinations.
Authors' Affiliations: Departments of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
Kehua
K
Wu
Larry
L
House
Jacqueline
J
Ramírez
Michael J
MJ
Seminerio
Mark J
MJ
Ratain
D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D004347:Drug Interactions; D006801:Humans
D000970:Antineoplastic Agents