Table 3.
Studies assessing the influence of anti-inflammatory biological agents administered during acute or chronic inflammatory conditions on the pharmacokinetics of drugs that behave as substrates of CYP
| Study and year of publication | Study population and design (N of included patients) | Drug and dosage | Inflammatory conditions and biomarker levels | Mechanism | Pharmacokinetic effect | Pharmacodynamic effect | Clinical relevance |
|---|---|---|---|---|---|---|---|
| Schmitt et al., 2011 [30] | Multicenter, open-label, randomized, single-sequence disease–drug interaction study: patients with rheumatoid arthritis (12) | Simvastatin 40 mg administered as a single dose on days 1, 15, and 43 (probe for 3A4), and a single infusion of tocilizumab 10 mg/kg on day 8 |
Rheumatoid arthritis and assessment of IL-6 and CRP Mean IL-6 serum levels (baseline vs day 15): 50 pg/mL vs 256 pg/mL Mean CRP serum levels (baseline vs day 15): 5 mg/dL vs 0.3 mg/dL |
Reversal of CYP downregulation after tocilizumab administration due to IL-6 inhibition |
Mean effect ratio (day 15/day 1): Simvastatin AUC0–∞: 43% (90% CI 34–55) Simvastatin Cmax: 43% (90% CI 33–55) Mean effect ratio (day 43/day 1): Simvastatin AUC0–∞: 61% (90% CI 47–78) Simvastatin Cmax: 60% (90% CI 46–76) |
Not assessed |
Tocilizumab approximately halves the simvastatin AUC by almost doubling simvastatin clearance (a CYP3A4-dependent process) as compared with baseline values in patients with rheumatoid arthritis. This finding could be clinically remarkable also for other drugs metabolized by CYP3A4 |
| Zhuang et al., 2015 [31] | Open-label, multicenter, phase I study: patients with rheumatoid arthritis (12) | Midazolam 0.03 mg/kg (probe for 3A4), warfarin 10 mg (2C9), omeprazole 20 mg (2C19), caffeine 100 mg (1A2) 1 week before, and 1,3, and 6 week after a single dose of 300 mg sirukumab |
Rheumatoid arthritis treated with sirukumab Assessment of serum CRP levels (baseline vs day 14/28/49, after sirukumab administration at day 8): 25.3 mg/L vs 1.8/0.5/0.7 mg/L |
Reversal of CYP downregulation after sirukumab administration due to IL-6 inhibition |
Geometric mean Cmax ratio (1/3/6 weeks after sirukumab administration vs baseline): Midazolam 0.77 (0.56–1.05); 0.69 (0.50–0.94); 0.66 (0.48–0.90) Omeprazole 0.61 (0.42–0.89); 0.62 (0.43–0.91); 0.70 (0.48–1.02) Warfarin 1.00 (0.89–1.15); 1.00 (0.87–1.15); 0.99 (0.86–1.14) Caffeine 1.04 (0.75–1.43); 1.10 (0.80–1.52); 1.05 (0.76–1.45) Geometric mean AUC ratio (1/3/6 weeks after sirukumab administration vs baseline): Midazolam 0.70 (0.51–0.96); 0.65 (0.47–0.89); 0.67 (0.49–0.92) Omeprazole 0.55 (0.32–0.96); 0.59 (0.34–1.02); 0.63 (0.36–1.09) Warfarin 0.82 (0.73–0.92); 0.82 (0.73–0.92); 0.81 (0.72–0.91) Caffeine 1.20 (0.75–1.91); 1.34 (0.84–2.15); 1.28 (0.80–2.04) |
Not assessed |
Sirukumab may reverse IL-6-mediated suppression of CYP3A, CYP2C9, and CYP2C19 activities in patients with active inflammation associated with rheumatoid arthritis |
| Tran et al., 2016 [32] | Two-sequences phase I study: patients with multiple sclerosis (20) | Caffeine 200 mg (probe for 1A2), warfarin 10 mg (2C9), omeprazole 40 mg (2C19), dextromethorphan 30 mg (2D6), midazolam 5 mg (3A4) before and after administration of daclizumab 150 mg every 4 weeks | Multiple sclerosis | Potential reversal downregulation of CYP mediated by IL-2 blockade |
Geometric mean AUC ratio (probe substrate with daclizumab/probe substrate alone): Caffeine 1.03 (90% CI 0.93–1.14) Midazolam 1.01 (90% CI 0.89–1.15) Warfarin 1.00 (90% CI 0.95–1.06) Omeprazole 1.00 (90% CI 0.88–1.13) Dextromethorphan 1.01 (90% CI 0.76–1.34) |
Not assessed | In patients with multiple sclerosis, daclizumab has no effect on CYP activity |
| Jiang et al., 2016 [33] | Physiologically based pharmacokinetic model: patients with rheumatoid arthritis (12) | Midazolam 0.03 mg/kg (probe for 3A4), warfarin 10 mg (2C9), caffeine 100 mg (1A2), and omeprazole 20 mg (2C19) administered one week before (day 1) and three weeks after (day 29) sirukumab 300 mg single dose | Rheumatoid arthritis and assessment of IL-6 | Reversal of CYP downregulation after sirukumab administration due to IL-6 inhibition |
Geometric mean AUC ratio (day 29/day 1): Midazolam 0.65 (90% CI 0.47–0.89) Omeprazole 0.59 (90% CI 0.34–1.02) Warfarin 0.82 (90% CI 0.73–0.92) Caffeine 1.34 (90% CI 0.84–2.15) |
Not assessed | Sirukumab may reverse CYP downregulation affecting CYP3A4, CYP2C9, and CYP2C19, resulting in a decrease of substrate exposure (range 20–40%) compared with inflammatory conditions |
| Lee et al., 2017 [34] | Open-label, single-sequence, nonrandomized, phase I study: patients with rheumatoid arthritis (19) | Simvastatin 40 mg (probe for 3A4) administered one day before and seven days after sarilumab 200 mg |
Rheumatoid arthritis and assessment of IL-6 and CRP Mean IL-6 serum levels (baseline vs day 8): 47.5 pg/mL vs 219.9 pg/mL Mean CRP serum levels (baseline vs day 8): 22.1 mg/L vs 1.9 mg/L |
Reversal of CYP3A4 downregulation after sarilumab administration due to IL-6 inhibition |
Mean effect ratio (day 8/baseline): Simvastatin AUC0–∞: 54.7% (90% CI 47.2–63.3) Simvastatin Cmax: 54.1% (90% CI 42.2–69.4) |
Not assessed |
Sarilumab treatment resulted in a reduction in exposure of simvastatin, consistent with reversal of IL-6- mediated CYP3A4 suppression in patients with active rheumatoid arthritis |
| Davis et al., 2018 [35] | Open-label, multicenter study, single-sequence phase I PK study: patients with moderate-to-severe atopic dermatitis (14) | Midazolam 2 mg (probe for 3A4), omeprazole 20 mg (2C19), warfarin 10 mg (2C9), caffeine 100 mg (1A2), and metoprolol 100 mg (2D6) administered before (day 1) and after dupilumab 300 mg/week (day 36) |
Moderate-to-severe atopic dermatitis and assessment of CCL-17 and LDH Mean CCL-17 serum levels (baseline vs day 35): 8060 ± 17,200 pg/mL vs 667 ± 402 pg/mL |
Potential downregulation of CYP isoenzymes due to increased IL-4/IL-13 levels and reversal of activity after dupilumab administration |
Geometric mean AUC ratio (day 36/day 1): Midazolam 0.98 (90% CI 0.87–1.09) Omeprazole 1.00 (90% CI 0.88–1.12) Warfarin 0.90 (90% CI 0.83–0.98) Caffeine 1.12 (90% CI 0.87–1.45) Metoprolol 1.29 (90% CI 1.10–1.51) |
Not assessed |
No drug–disease interaction was identified in patients with type 2 inflammation. Blockade of IL-4/IL-13 signaling in patients with type 2 inflammation does not appear to significantly affect CYP enzyme activities; the use of dupilumab in patients with atopic dermatitis is unlikely to influence the pharmacokinetics of CYP substrates |
| Khalilieh et al., 2018 [36] | Open-label, fixed-sequence, two-period trial: patients with moderate-to-severe psoriasis (20) | Midazolam 2 mg (probe for 3A4), warfarin 10 mg (2C9), caffeine 200 mg (1A2), omeprazole 40 mg (2C19), and dextromethorphan 30 mg (2D6) administered at day 1 (period 1). In period 2, probe cocktail was administered on day 57 after tildrakizumab 200 mg on day 1 and 29 | Moderate-to-severe psoriasis and assessment of CRP and IL-6 | Potential reversal of CYP downregulation after tildrakizumab administration due to IL-23 inhibition |
Geometric mean AUC ratio (probe + tildrakizumab vs probe alone) Midazolam 1.11 (90% CI 0.94–1.32) Omeprazole 0.96 (90% CI 0.77–1.19) Warfarin 1.07 (90% CI 0.98–1.17) Dextromethorphan 1.20 (90% CI 1.00–1.45) Caffeine 1.14 (90% CI 1.01–1.28) Geometric mean Cmax ratio (probe + tildrakizumab vs probe alone) Midazolam 1.06 (90% CI 0.86–1.29) Omeprazole 0.99 (90% CI 0.85–1.15) Warfarin 0.99 (90% CI 0.95–1.03) Dextromethorphan 1.17 (90% CI 0.96–1.43) Caffeine 0.96 (90% CI 0.88–1.05) |
Not assessed |
Tildrakizumab had no clinically relevant effect on the pharmacokinetics of any of the probe substrates tested, possibly related to the lower degree of inflammation in psoriasis compared with other pro-inflammatory diseases. There were no clinically relevant changes in IL-6 or CRP before and after tildrakizumab administration |
| Bruin et al., 2019 [37] | Open-label, multicenter study, single-sequence phase I PK study: patients with moderate-to-severe plaque psoriasis (24) | Midazolam 5 mg (3A4) administered before (day 0) and after secukinumab 300 mg/week (day 8 and 36) | Moderate-to-severe psoriasis and assessment of CRP, TNF-α, IL-6, and BD-2 | Potential reversal of CYP3A4 downregulation after secukinumab administration due to IL-17A inhibition |
Midazolam AUC0–∞ day8/baseline 0.99 (90% CI 0.88–1.12) Midazolam AUC0–∞ day36/baseline 0.97 (90% CI 0.85–1.09) |
Not assessed |
Secukinumab can be used in the treatment of psoriasis without significant PK interactions with drugs metabolized by CYP3A4. Because of only slightly increased cytokine levels, such as IL-17A and IL-6, in patients with psoriasis, a reduction in cytokine levels to levels observed in healthy subjects will have no impact on any of the CYP activities |
| Zhu et al., 2020 [38] | Open-label, multicenter, phase I study: patients with moderate-to-severe psoriasis (14) | Midazolam (probe for 3A4), warfarin (2C9), omeprazole (2C19), dextromethorphan (2D6), and caffeine (1A2) before (day 1) and after (day 15 and 36) guselkumab 200 mg administration | Moderate-to-severe psoriasis | Potential reversal of CYP downregulation after guselkumab administration due to IL-23 inhibition |
Geometric mean Cmax ratio (15/36 day vs day 1): Midazolam 1.11 (0.75–1.65); 1.14 (0.77–1.69) Warfarin 1.07 (0.90–1.27); 0.90 (0.74–1.11) Omeprazole 0.96 (0.72–1.28); 0.96 (0.67–1.36) Dextromethorphan 1.06 (0.46–2.43); 1.33 (0.55–3.18) Caffeine 1.07 (0.94–1.22); 1.06 (0.89–1.26) Geometric mean AUC ratio (15/36 day vs day 1): Midazolam 1.01 (0.70–1.45); 1.04 (0.75–1.44) Warfarin 1.12 (0.90–1.40); 1.05 (0.82–1.36) Omeprazole 0.96 (0.61–1.52); 1.19 (0.75–1.90) Dextromethorphan 1.13 (0.56–2.26); 1.24 (0.46– 3.31) Caffeine 1.00 (0.77–1.31); 1.02 (0.77–1.35) |
Not assessed |
No significant drug interactions between guselkumab and substrates of various CYP enzymes are reported. Dose adjustment for concomitant CYP substrates in patients treated with guselkumab does not seem to be necessary |
Ae amount excretion, AUC area under the concentration–time curve, C concentration, CCL-17 chemokine 17, CI confidence interval, Cmax peak concentrations, CRP C-reactive protein, CYP cytochrome P450, IL interleukin, LDH lactate dehydrogenase, PK pharmacokinetic, T2D type 2 diabetes, TNF-α tumor necrosis factor-α