Abstract

Introduction: Deferasirox (Exjade®, ICL670) is an oral iron chelator approved for the treatment of iron overload due to chronic transfusions in more than 80 countries. Deferasirox is mainly eliminated via biliary excretion following glucuronidation. Oxidative metabolism, presumably by CYP1A and CYP2D6 enzymes, accounts for approximately 6% and 2%, respectively. Deferasirox has been shown to be a weak inhibitor of CYP3A4/5 in vitro. It is possible that deferasirox could potentially alter the metabolism of other drugs eliminated via this pathway. Midazolam, a rapid-onset benzodiazepine, is almost exclusively metabolized via CYP3A4/5 making it an ideal probe to investigate the effect of an inhibitor/inducer of CYP3A4/5 in vivo. This drug-drug interaction study was undertaken to investigate the effect of deferasirox on midazolam pharmacokinetics (PK).

Methods: This was a single-center, open-label, one-sequence, cross-over study conducted in healthy volunteers. There were two treatment periods. During Period 1, volunteers received a midazolam 5 mg oral solution and midazolam PK were performed at 0–12 hours. During Period 2, volunteers received doses of deferasirox 30 mg/kg daily for 5 days and on Day 4, a midazolam 5 mg oral solution was given. Midazolam PK were performed at 0–48 hours.

Results: Twenty-two healthy volunteers were enrolled, and 21 completed the study. Mean age was 32 years, 59% of volunteers were male and all were Caucasian. Descriptive statistics for mean plasma concentration of midazolam and its metabolite, 1-hydroxymidazolam, are summarized below:

AUCinf (h.ng/mL)AUClast (h.ng/mL)Cmax (ng/mL)Tmax (h)T½ (h)
Midazolam PK 
Midazolam alone, n=22 
Mean (SD) 68.3 (28.4) 63.8 (26.4) 34.4 (17.4) 0.44 (0.17) 3.7 (0.9) 
Deferasirox + midazolam, n=22 
Mean (SD) 61.7 (37.4) 60.3 (37.2) 27.1 (13.6) 0.47 (0.26) 4.4 (1.4) 
1-hydroxymidazolam PK 
Midazolam alone, n=22 
Mean (SD) 22.3 (8.8) 20.8 (7.9) 12.8 (6.7) 0.48 (0.15) 3.3 (1.5) 
Deferasirox + midazolam, n=22 
Mean (SD) 25.6 (10.9) 23.8 (10.0) 11.7 (5.3) 0.5 (0.24) 6.1 (3.5) 
AUCinf (h.ng/mL)AUClast (h.ng/mL)Cmax (ng/mL)Tmax (h)T½ (h)
Midazolam PK 
Midazolam alone, n=22 
Mean (SD) 68.3 (28.4) 63.8 (26.4) 34.4 (17.4) 0.44 (0.17) 3.7 (0.9) 
Deferasirox + midazolam, n=22 
Mean (SD) 61.7 (37.4) 60.3 (37.2) 27.1 (13.6) 0.47 (0.26) 4.4 (1.4) 
1-hydroxymidazolam PK 
Midazolam alone, n=22 
Mean (SD) 22.3 (8.8) 20.8 (7.9) 12.8 (6.7) 0.48 (0.15) 3.3 (1.5) 
Deferasirox + midazolam, n=22 
Mean (SD) 25.6 (10.9) 23.8 (10.0) 11.7 (5.3) 0.5 (0.24) 6.1 (3.5) 

There was a statistically, but not clinically, significant reduction (17%) in midazolam exposure (AUC) in the presence of deferasirox in comparison with midazolam administered alone. Similarly, Cmax was decreased on average by 23%.

Conclusion: An increase in midazolam exposure, which would have been expected for an inhibitory effect of deferasirox on the CYP3A4-mediated metabolic pathway, was not observed. A decrease in midazolam exposure is suggestive of an induction effect, albeit weak in nature. Drugs that are substrates for CYP3A4 can be co-administered with deferasirox if necessary.

Author notes

Disclosure:Employment: C Arrowsmith-Bensasson, L Rojkjaer, V Sethuraman and A Skerjanec are employees of Novartis.