SUMMARY

• Please refer to the enclosed Full Prescribing Information, including the DRUG INTERACTIONS section, for more information.¹
• In a phase 1 study, there were no clinically relevant changes in the systemic exposure (maximum observed plasma concentration [C_max] and area under the plasma concentration versus time curve from time 0 to infinity with extrapolation of the terminal phase [AUC_inf]) of midazolam, S-warfarin, omeprazole, dextromethorphan, and caffeine (probe substrates of cytochrome P [CYP]3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2, respectively) after a single subcutaneous (SC) dose of TREMFYA 200 mg in patients with moderate to severe plaque psoriasis.²

PRODUCT LABELING

Drug Interactions

CYP450 Substrates

The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (eg, interleukin [IL]-1, IL-6, IL-10, tumor necrosis factor [TNF]α, and interferon) during chronic inflammation.¹

Results from an exploratory drug-drug interaction study in subjects with moderate to severe plaque psoriasis suggested a low potential for clinically relevant drug interactions for drugs metabolized by CYP3A4, CYP2C9, CYP2C19, and CYP1A2, but the interaction potential cannot be ruled out for drugs metabolized by CYP2D6. However, the results were highly variable because of the limited number of subjects in the study.¹

Upon initiation of TREMFYA in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and consider dosage adjustment as needed.¹

Clinical Pharmacology

Pharmacokinetics

Drug Interactions

Population pharmacokinetic analyses indicated that concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), oral corticosteroids, and conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX), azathioprine (AZA), and 6-mercaptopurine (6-MP), did not affect the clearance of guselkumab.¹

Cytochrome P450 Substrates

The effects of guselkumab on the pharmacokinetics (PK) of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), dextromethorphan (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in an exploratory study with 6-12 evaluable subjects with moderate to severe plaque psoriasis. Changes in AUC_inf of midazolam, S-warfarin, omeprazole, and caffeine after a single dose of guselkumab were not clinically relevant. For dextromethorphan, changes in AUC_inf after guselkumab were not clinically relevant in 9 out of 10 subjects; however, a 2.9-fold change in AUC_inf was observed in 1 individual.¹

clinical data

Zhu et al (2020)² evaluated the potential effect of a single SC dose of TREMFYA 200 mg on the PK of a cocktail of representative probe substrates of CYP isoenzymes in patients with moderate to severe plaque psoriasis.

Study Design/Methods

• This was a phase 1, open-label, multicenter drug interaction study.
• Eligible patients were ≥18 years of age with a diagnosis of moderate to severe plaque-type psoriasis (with or without psoriatic arthritis) for ≥6 months before day 1, had a Psoriasis Area Severity Index (PASI) score ≥12, an Investigator’s Global Assessment (IGA) score ≥3, an involved body surface area ≥10% at screening, and were candidates for phototherapy or systemic treatment for psoriasis (either naïve or history of previous treatment).
• Genetically determined poor metabolizers of CYP2C9, CYP2C19, or CYP2D6 substrates (ie, patients who did not have at least 1 functional allele for CYP2C9, CYP2C19, and CYP2D6) were excluded from the study.
• Probe substrates included midazolam (CYP3A4), S-warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and caffeine (CYP1A2).
• The probe cocktail consisted of oral doses of 0.03 mg/kg midazolam, 10 mg warfarin (+10 mg vitamin K), 20 mg omeprazole, 30 mg dextromethorphan, and 100 mg caffeine.
• Patients received a single SC dose of TREMFYA 200 mg on day 8 and the oral probe cocktail on days 1, 15, and 36.
• Blood samples were collected for measuring plasma concentrations of probe substrates on days 1, 15, and 36.
• Efficacy assessments were conducted through day 64 for all patients who received at least 1 dose of TREMFYA.
• Safety assessments were conducted through day 92 for all patients who received at least 1 dose of probe cocktail or TREMFYA.

Results

Patient Characteristics

• A total of 16 patients enrolled in the study and received the probe cocktail on day 1.
• Patients had a mean age of 43 years (range, 18-68), body weight of 96 kg (range, 58-150), and body mass index of 35 kg/m² (range, 21-51).
• A total of 14 patients received TREMFYA, and 12 completed the study.
• Four patients discontinued; 1 due to physician decision (difficulty in blood draw) on day 7, 1 due to adverse event on day 17, 1 due to pregnancy on day 20, and 1 was lost to follow-up on day 87.

Pharmacokinetics

• The descriptive statistics for the derived PK parameters of each probe CYP-substrate before and after probe cocktail administrations are summarized in Table: PK Parameters of Probe CYP450 Substrates Before and After Treatment with TREMFYA.

• The geometric mean ratios (GMRs) (day 15/day 1 and day 36/day 1) with 90% confidence intervals (CIs) for exposure parameters (C_max and AUC_inf) of each probe substrate are summarized in Table: GMRs of Exposure Parameters of Probe CYP450 Substrates After Treatment with TREMFYA.

Efficacy

• A majority of the patients experienced clinical improvement in their psoriasis as measured by the PASI and IGA responses after a single administration of TREMFYA 200 mg SC through day 64, as shown in Table: Efficacy Results.

Safety

• A total of 10 patients reported at least 1 treatment-emergent adverse event (TEAE).
• TEAEs were reported in 38.5% of patients during the period of treatment with probe cocktail in combination with TREMFYA and 25.0% of patients treated with probe cocktail alone.
• The majority of TEAEs were mild or moderate.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 13 September 2024.