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P390 Open-label study to evaluate the pharmacokinetics of fidaxomicin in inflammatory bowel disease patients with Clostridium difficile infection (the PROFILE study): pharmacokinetics analysis

Högenauer C.1, Mahida Y.2, Stallmach A.3, Marteau P.4, Rydzewska G.5, Ivashkin V.6, Gargalianos-Kakolyris P.7, Michon I.8, Adomakoh N.9, Reinisch W.*10

1Medical University of Graz, Graz, Austria 2University of Nottingham, Nottingham, United Kingdom 3Jena University Hospital, Jena, Germany 4Hôpital Saint Antoine, Paris, France 5Central Clinical Hospital of the Ministry of the Interior, Warsaw and Jan Kochanowski University, Kielce, Poland 6'First Moscow State Medical University named after I.M. Sechenov' of the Ministry of Health of Russian Federation, Moscow, Russian Federation 7General Hospital of Athens “G. Gennimatas”, Athens, Greece 8Astellas Pharma Europe, Leiden, Netherlands 9Astellas Pharma, Chertsey, United Kingdom 10Medical University of Vienna, Vienna, Austria

Background

Clostridium difficile infection (CDI) causes a substantial healthcare burden in hospitalised and community-based inflammatory bowel disease (IBD) patients. Fidaxomicin (FDX), a non-absorbable antibiotic, is approved for CDI treatment in adults, but FDX data in IBD patients are lacking. Whether FDX absorption differs in these patients owing to IBD-associated intestinal inflammation is unknown.

Methods

The PROFILE study aimed to investigate plasma pharmacokinetics (PK) of FDX and primary metabolite OP-1118 in patients with IBD and CDI in the EU. This open-label, multicentre, single-arm study enrolled patients ≥18 years diagnosed with active IBD and a positive local standard CDI test ≤48 h prior to enrolment (with subsequent central laboratory testing). Patients received 10 days' FDX treatment (200 mg, twice daily). Blood samples to assess PK were taken on days 1, 5 and 10 (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5 and 12 h post-dose).

Results

PK data were obtained from 24 patients (54% male; mean [standard deviation, SD] age 38.9 [16.9] years); 14 with Crohn's disease (CD) and 10 with ulcerative colitis (UC). Median (range) baseline Harvey Bradshaw Index score was 8 (5–20) and partial Mayo score was 5 (3–8). E3 UC (pancolitis) was present in 8 patients. Baseline CDI severity (ESCMID criteria) was severe for 5 patients and non-severe for 19 patients. PK findings are shown in Table 1. No difference was observed in FDX or OP-1118 levels between CD and UC patients and there was no apparent correlation between FDX exposure and the extent of intestinal inflammation. Tmax values were similar to those in healthy volunteers for both FDX and OP-1118 (range 0.5–11.5 h). Cmax values for FDX (1.2–154 ng/mL) and OP-1118 (4.7–555 ng/mL) were within the measured range of concentration values found in CDI patients without IBD 3–5 h post-dose on days 1 and 10 of FDX Phase III studies (FDX, 0.4–197 ng/mL; OP-1118, 0.3–871 ng/mL; n=97–309) [1]. The Cmax values were well below the human equivalent no-observed-adverse-effect levels in 3-month dog toxicology studies (3000 ng/mL). Treatment-emergent adverse events were reported in 15 (60.0%) patients. These were possibly or probably drug related in 10 (40.0%) and serious in 2 (8.0%) patients (hypoxia and skin ulcer). There were no deaths.

Table 1. FDX PK parameters

DayAUC* (ng/h/mL)Cmax (ng/mL)Ctrough (ng/mL)Tmax (h)
177.7 (79.8); 22.7, 339; n=1414.6 (16.1); 2.5, 75.3; n=232.8 (3.0); 0.5, 11.5**; n=23
5155.6 (150.9); 38.0, 513; n=1120.3 (31.8); 1.2, 154; n=236.2 (6.5); 0.7, 28.8; n=231.3 (0.7); 0.5, 3.0; n=13
10129.1 (115.0); 19.2, 364; n=1116.3 (15.1); 4.6, 71.3; n=244.4 (3.2); 1.0, 11.6; n=222.2 (1.7); 0, 5.4; n=14

Values are mean (SD); min, max. PK parameters were not measured in all patients at each time point; *AUC12 day 1; AUCtau day 5–10; **Outlier (patient had 1.0 h and 1.5 h as Tmax on Day 5 and Day 10, respectively). 8.9 h was second largest Tmax.

Conclusion

FDX plasma PK parameters fell within historical PK ranges observed in patients without IBD, suggesting no increase in FDX absorption in this patient population with IBD.

References:

[1] European Medicines Agency, (2011), European public assessment report, Dificlir, www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002087/WC500119707.pdf, 2016–08–31