Lack of Effect of 12-Week Treatment with Risankizumab on the Pharmacokinetics of Cytochrome P450 Probe Substrates in Patients with Moderate to Severe Chronic Plaque Psoriasis

Abstract

Objective The objective of this study was to characterize the effects of risankizumab on the in vivo activity of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in psoriasis patients using a cocktail approach. Methods Patients with moderate to severe chronic plaque psoriasis (n = 21) received single oral doses of sensitive probe substrates for CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) on day 1, followed by 12 weeks of subcutaneous risankizumab treatment of 150 mg once every 4 weeks from day 8 to day 92, and again the same cocktail of substrates on day 98. Serial blood samples were collected for determination of the CYP probe drugs and metabolites with and without risankizumab. Trough samples were collected for risankizumab. Results The 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC ∞ ) ratios for the CYP probe substrates administered with risankizumab versus without risankizumab were within the default 0.8-1.25 equivalence bounds. Similar results were observed for maximum plasma concentration (C max ), except for omeprazole, for which the lower bound of the 90% CI for C max (0.73) extended slightly below the default equivalence limit. No differences were observed in metabolite-to-parent drug C max or AUC ratios with risankizumab versus without risankizumab. Risankizumab trough plasma concentrations significantly exceeded those of the phase III regimen of risankizumab in psoriasis (150 mg subcutaneously at weeks 0 and 4 and every 12 weeks thereafter). Conclusions Risankizumab did not affect the in vivo activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A enzymes in patients with moderate or severe plaque psoriasis and therefore has no potential for drug interactions through these enzymes. Clinical trial registration ClinicalTrials.gov Identifier: NCT02772601. Key Points12 weeks of treatment with risankizumab 150 mg administered subcutaneously every 4 weeks had no relevant effects on cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A in vivo.No dose adjustment is needed for concomitant medications that are substrates of these CYP enzymes during coadministration with risankizumab.

<p>Clinical Evaluation of Risankizumab-rzaa in the Treatment of Plaque Psoriasis</p>

“…Following 12 weeks of dosing with risankizumab 150 mg Q4W, no clinically relevant variations in vivo activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A enzymes were observed. 18 These findings were consistent with those found in other IL-23p19 inhibitors guselkumab and tildrakizumab. 19,20…”

Secukinumab Treatment Does Not Alter the Pharmacokinetics of the Cytochrome P450 3A4 Substrate Midazolam in Patients With Moderate to Severe Psoriasis

“…Based on results in our study, in the above‐mentioned studies, and in other recently published cocktail DDDI studies in patients with moderate‐to‐severe psoriasis in cases of minimal systemic inflammation with only moderate increases in hsCRP, IL‐6, and TNF‐α, there will be insufficient change in CYP activity to result in any clinically significant change in plasma exposure of comedications metabolized by CYP enzymes. Therefore, dedicated DDDI studies in this patient population may not be needed anymore.…”

“…However, in patients with psoriasis and atopic dermatitis, the situation seems to be different. DDDI studies, such as with the anti‐IL‐4/IL‐13 antibody dupilumab in patients with moderate‐to‐severe atopic dermatitis and with the anti‐IL‐23p19 monoclonal antibodies risankizumab and tildrakizumab in patients with moderate‐to‐severe psoriasis, showed no significant effect on the PK of CYP3A4, CYP2C19, CYP2C9, CYP1A2, or CYP2D6 substrates …”

Clinical Pharmacokinetics and Pharmacodynamics of Risankizumab in Psoriasis Patients

“…A dedicated drug interaction study (Study 8) was conducted for risankizumab in patients with moderate-to-severe plaque psoriasis to assess the effect of repeated administration of risankizumab on the pharmacokinetics of CYP-sensitive probe substrates. Repeated administration of risankizumab 150 mg subcutaneously at weeks 0, 4, 8, and 12 (more frequent administration resulting in higher risankizumab exposure than the clinical regimen) had no effect on the exposures of probe substrates of CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) in patients with moderate-tosevere plaque psoriasis (n = 21) [25]. The 90% confidence intervals for the ratios of the probe substrates C max and AUC when administered 6 days following the fourth dose of risankizumab 150 mg subcutaneously every 4 weeks versus when these substrates were administered prior to initiating risankizumab treatment were within the default no-effect boundaries of 0.8-1.25 (with the exception of the lower 90% confidence bound for omeprazole C max ratio, which extended slightly below 0.8).…”

“…The 90% confidence intervals for the ratios of the probe substrates C max and AUC when administered 6 days following the fourth dose of risankizumab 150 mg subcutaneously every 4 weeks versus when these substrates were administered prior to initiating risankizumab treatment were within the default no-effect boundaries of 0.8-1.25 (with the exception of the lower 90% confidence bound for omeprazole C max ratio, which extended slightly below 0.8). Therefore, no dosage adjustments are needed for drugs that are substrates of these CYP enzymes when administered concomitantly with risankizumab in patients with moderate-to-severe psoriasis [25].…”