A novel physiologically-based pharmacokinetic model to estimate reduced CYP3A4 activity in cancer patients utilizing the neutrophil-to-lymphocyte ratio as an inflammatory marker.

PURPOSE: In advanced cancer patients the CYP3A4-mediated clearance of drugs is dependent on the severity of inflammation. In a study in patients with advanced cancer (n = 44) with solid tumors, prior to cancer treatment, high inter-patient variability was observed in the plasma pharmacokinetic (PK) parameters of the CYP3A4 substrate midazolam. The neutrophil-to-lymphocyte ratio (NLR) was used to categorize the degree of inflammation of each patient and in turn to correlate increases in NLR to decreases in CYP3A4 expression.

METHODS

Patients with NLR ≥ 5 were categorized as having high inflammation, and patients with NLR < 5 as having low-to-moderate inflammation. A physiologically-based PK (PBPK) model of midazolam PK and a top-down approach was used to determine the reductions in CYP3A4 abundance in the liver and gut wall needed to match the PK parameters of midazolam in the NLR ≥ 5 and NLR < 5 groups of patients.

RESULTS

The midazolam mean CL/F was 33 L/h in the NLR < 5 group, and midazolam CL/F was 20 L/h in the NLR ≥ 5 group. To match the PK of midazolam in the NLR < 5 group, the CYP3A4 expression was reduced 40% in both the liver and the gut. In the NLR ≥ 5 group, CYP3A4 expression was reduced approximately 40% in the liver and at least 90% in the gut to produce the best fit.

CONCLUSION

Overall, these results support that NLR may be used as an inflammatory marker that broadly correlates to inflammation-driven changes in CYP3A4 activity.