Taltz ® (ixekizumab) injektion

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Taltz® (ixekizumab): Plackpsoriasis - Förhållande mellan läkemedelsnivå och effekt

Högre serumkoncentrationer av ixekizumab var i allmänhet associerade med högre grad av sjukdomsförbättring.

Time To Reach Steady-State Concentrations

After the 160 mg starting dose, steady state was achieved by Week 8 with the 80 mg Q2W dosing regimen. Mean (SD) Cmax,ss, and C trough,ss estimates are 21.5 (9.16) µg/ml, and 5.23 (3.19) µg/ml.

After switching from the 80 mg Q2W dosing regimen to the 80 mg Q4W dosing regimen at Week 12, steady state would be achieved after approximately 10 weeks.1

The recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg (one injection) at Weeks 2, 4, 6, 8, 10, and 12, then maintenance dosing of 80 mg (one injection) every 4 weeks.1

 Some dosing schedules mentioned in this statement are not consistent with the approved dosing schedule for plaque psoriasis in the Taltz summary of product characteristics. Please refer to the Taltz summary of product characteristics for full information of approved dosing.1

No clinical trials have directly compared administration with and without a 160-mg starting dose (ie, a 160-mg starting dose followed by 80 mg Q2W dosing during induction [approved dosing regimen] vs administration of an 80-mg dose Q2W during induction) with regards to the PK, efficacy, or safety of ixekizumab.

In the UNCOVER-3 study, patients who received an initial 160-mg starting dose followed by ixekizumab 80 mg Q2W through week 12 reached steady state serum trough concentrations quickly (median serum trough concentration at week 12, 8.84 μg/mL) and those concentrations were associated with high clinical response rates. After switching to ixekizumab Q4W, the new steady state serum trough concentrations were reached by week 24 and were stable to week 60. The median serum trough concentrations ranged from 3.03 to 3.31 μg/mL and were associated with the maintenance of high response rates through week 60.2

Relationship Between Trough Concentration and Rates of Disease Improvement

Response Rates Through Week 12 of the UNCOVER-1, -2, and -3 Studies

An integrated analysis of data evaluated the relationship between serum drug concentrations and response rates of 2888 patients with plaque psoriasis who received either placebo or ixekizumab 80 mg Q2W or Q4W following a starting dose of 160 mg in the UNCOVER-1, -2, and -3 studies. At week 12, the group of patients who received ixekizumab Q2W had higher observed ixekizumab serum concentrations and higher PASI and sPGA scores (see Table 1).3

Table 1. Observed Response Rates at Week 12 by Ixekizumab Dosing Regimens in the UNCOVER-1, -2, and -3 Studies3

End Point

Ixekizumab Q2W

Ixekizumab Q4W

sPGA (0,1), %

85

79

sPGA (0), %

41

36

PASI 75, %

92

86

PASI 90, %

72

67

PASI 100, %

39

35

Abbreviations: PASI 75 = 75% improvement from baseline in Psoriasis Area and Severity Index; PASI 90 = 90% improvement from baseline in Psoriasis Area and Severity Index; PASI 100 = 100% improvement from baseline in Psoriasis Area and Severity Index; Q2W = 80 mg every weeks; Q4W = 80 mg every 4 weeks; sPGA = Static Physician's Global Assessment.

Subgroup analyses found that while all subpopulations had high levels of response, the sPGA response rates were slightly lower in patients with higher body weight, palmoplantar involvement, lower baseline disease state, and high CRP levels at baseline, and the PASI response rates were slightly lower in patients with higher body weight, palmoplantar involvement, and lower baseline disease state. Response rates were not affected by patient age, gender, or ADA status.3

Response Rates Through Week 60 of the UNCOVER-3 Study

The figure below illustrates the serum trough concentrations of ixekizumab through week 60 in patients who received the approved dosing regimen of ixekizumab Q2W through week 12 followed by ixekizumab Q4W during the UNCOVER-3 clinical trial along with the percentage of patients who achieved PASI 75, 90, and 100, respectively (Figure 1).

Figure 1. Ixekizumab Trough Concentrations and PASI Response Rates Over Time for IXEQ2W/IXEQ4W Approved Dosing Regimen4

Abbreviations: PASI = Psoriasis Area and Severity Index; IXE = ixekizumab; Q2W = every 2 weeks; Q4W = every 4 weeks; PK = pharmacokinetics.
Note: Pharmacokinetic axis represents serum trough concentration.

Higher serum ixekizumab trough concentrations were generally associated with higher rates of disease improvement.2 The rates of disease improvement at week 60 as shown by PASI 75 and sPGA (0,1) for the ixekizumab Q2W and ixekizumab Q4W dosing regimen are shown in Table 2.

Table 2. Clinical Response Rates at Week 60 By Ixekizumab Serum Trough Concentrations in the UNCOVER-3 Study2

Clinical Response Measure

Serum Trough Concentration Quartiles

Q1a (N=69)

Q2b (N=73)

Q3c (N=71)

Q4d (N=72)

PASI 75, n (%)

62 (89.9)

72 (98.6)

69 (97.2)

72 (100.0)

sPGA 0/1, n (%)

47 (68.1)

65 (89.0)

63 (88.7)

70 (97.2)

Abbreviations: PASI = Psoriasis Area and Severity Index; Q2W = every 2 weeks; Q4W = every 4 weeks; sPGA = Static Physician's Global Assessment.

Note: Patients received an initial dose of 160 mg ixekizumab, then 80 mg ixekizumab Q2W through week 12, followed by 80 mg Q4W through week 60.

a Quartile 1 (serum trough concentration <2.18 μg/mL).

b Quartile 2 (serum trough concentration ≥2.18 and <3.20 μg/mL).

c Quartile 3 (serum trough concentration ≥3.20 and <4.35 μg/mL).

d Quartile 4 (serum trough concentration ≥4.35 μg/mL).

Therapeutic Indication

Ixekizumab is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy.1

References

1. Taltz [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Reich K, Jackson K, Ball S, et al. Ixekizumab pharmacokinetics, anti-drug antibodies, and efficacy through 60 weeks of treatment of patients with moderate-to-severe plaque psoriasis. J Invest Dermatol. 2018;138(10):2168-2173. http://dx.doi.org/10.1016/j.jid.2018.04.019.

3. Chigutsa E, Velez de Mendizabal N, Chua L, et al. Exposure-response modeling to characterize the relationship between ixekizumab serum drug concentrations and efficacy responses at week 12 in patients with moderate to severe plaque psoriasis. J Clin Pharmacol. 2018;58(11):1489-1500. http://dx.doi.org/10.1002/jcph.1268

4. Reich K, Leng S, Jackson K, et al. Time course of ixekizumab drug levels and the relationship at week 60 to efficacy in patients with moderate-to-severe plaque psoriasis (UNCOVER-3). Poster presented at: 5th International Congress on Psoriasis; July 7-9, 2016; Paris, France.

Glossary

ADA = anti-drug antibody

CRP = C-reactive protein

IXEQ2W = ixekizumab 80 mg every 2 weeks

IXEQ4W = ixekizumab 80 mg every 4 weeks

PASI = Psoriasis Area and Severity Index

PASI 100 = 100% improvement from baseline in Psoriasis Area and Severity Index

PASI 75 = 75% improvement from baseline in Psoriasis Area and Severity Index

PASI 90 = 90% improvement from baseline in Psoriasis Area and Severity Index

PK = pharmacokinetics

Q2W = every 2 weeks

Q4W = every 4 weeks

sPGA = static Physician Global Assessment

Datum fӧr senaste ӧversyn 2019 M09 20


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