PII-109 - A LITERATURE REVIEW OF DRUG-DRUG-DISEASE INTERACTION IN PATIENTS WITH HEPATIC OR RENAL IMPAIRMENT.

Y. Chiang Yu¹, D. Zhou², P. Sharma³, D. Boulton⁴, J. Dong⁴; ¹University of Maryland, Baltimore, MD, USA, ²AstraZeneca, Boston, MA, USA, ³AstraZeneca, Cambridge, UK, ⁴AstraZeneca, Gaithersburg, MD, USA.

Background: Poly-pharmacy associated with increased risk of drug-drug interactions (DDI) is common in patients with hepatic (HI) or renal impairment (RI). The DDI risk in patients are commonly informed by studies in healthy subjects (HS) to alleviate ethical concerns whereas the impact of hepatic or renal disease on the magnitude of DDI is complex and unclear. The objective of the present literature review was to summarize the clinical trials of DDI in patients with HI or RI to compare the magnitude of DDI in these patients with that in HS.

Methods: The review focused on the clinical DDI studies with substrates, inhibitors, or inducers of CYP enzymes and transporters listed in the US FDA website (219 drugs/substances) in patients with HI or RI. Clinical DDI data were obtained from the Drug Interaction Database (DIDB®), PubMed, and Drugs@FDA.
When the clinical DDI study in patients did not include a control cohort with HS, DDI studies with the same or similar design (matched route of administration and dosing regimen) in HS was evaluated and compared.

Results: 11 clinical studies were found in patients with HI, with 7 and 5 DDIs via enzyme inhibition and induction, respectively. Additionally, 5 clinical DDI studies were found in patients with RI and studied 9 DDI interactions all through enzyme/transporter inhibition.
The majority of observed DDIs in patients were similar or reduced in magnitude compared to those in HS as shown in Figure 1. The two exceptions were the induction on the metabolism of istradefylline by smoking (patient vs HS AUC ratio, 0.17 vs 0.58, respectively) and the inhibition of midazolam metabolism by grapefruit juice (patient vs HS AUC ratio, 2.3 vs 1.5, respectively) in patients with HI. As the contribution by pulmonary CYP1A1 metabolism of istradefylline and intestinal CYP3A metabolism of midazolam to their overall metabolism could be increased in patients with reduced hepatic metabolism, the exceptions may be explained by the increased fraction of metabolism via the interaction relevant pathways in patients.

Conclusion: Overall, the available clinical DDI studies in patients with HI or RI indicated similar or reduced magnitude of DDI in patients compared with those in HS in the majority of the cases whereas the increase of fraction of metabolism/transport by the interaction relevant pathways may cause stronger DDI in patients.