General
Information
This
summary contains information on dosages and dosing regimens that are
not consistent with the information contained in the paragraph 4.2
(Posology and method of administration) of the Summary of Product
Characteristics (SmPC). Please refer to the SmPC for full prescribing
information.
Absorption
Following
a single subcutaneous dose of ixekizumab in patients with psoriasis,
mean peak concentrations were achieved within 4 to 7 days,
across a dose range of 5 to 160 mg. The mean (SD)
maximum plasma concentration (Cmax)
of ixekizumab, after the 160 mg starting dose, was
19.9 (8.15) µg/ml.
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. Mean (SD)
Cmax,ss, and
Ctrough,ss
estimates are 14.6 (6.04) µg/ml, and
1.87 (1.30) µg/ml.
The
average bioavailability of ixekizumab after subcutaneous
administration was 54 % to 90 % across analyses.1
Distribution
From
population pharmacokinetic analyses, the mean total volume of
distribution at steady state was 7.11 L.1
Biotransformation
Ixekizumab
is a monoclonal antibody and is expected to be degraded into small
peptides and amino acids via catabolic pathways in the same manner as
endogenous immunoglobulins.1
Elimination
In
the population PK analysis, mean serum clearance was 0.0161 L/hr.
Clearance is independent of dose. The mean elimination half-life, as
estimated from population pharmacokinetic analysis, is 13 days
in patients with plaque psoriasis.1
Linearity/Non-Linearity
Exposure
(AUC) increased proportionally over a dose range of 5 to 160 mg
given as a subcutaneous injection.1
Pharmacokinetic
Properties Across Indications
The
pharmacokinetic properties of ixekizumab were similar across the
plaque psoriasis, psoriatic arthritis, radiographic axial
spondyloarthritis and non-radiographic axial spondyloarthritis
indications.1
Pharmacokinetics
in Elderly
Of
the 4,204 plaque psoriasis patients exposed to ixekizumab
in clinical studies, a total of 301 were 65 years of age or
older and 36 patients were 75 years of age or older. Of the
1,118 psoriatic arthritis patients exposed to ixekizumab in
clinical studies, a total of 122 patients were 65 years of age or
older and 6 patients were 75 years of age or older.
Based
on population pharmacokinetic analysis with a limited number of
elderly patients (n = 94 for age ≥ 65 years
and n = 12 for age ≥ 75 years), clearance in
elderly patients and patients less than 65 years of age was
similar.1
Pharmacokinetics
in Patients with Renal or Hepatic Impairment
Specific
clinical pharmacology studies to evaluate the effects of renal
impairment and hepatic impairment on the PK of ixekizumab have not
been conducted. Renal elimination of intact ixekizumab, an IgG MAb,
is expected to be low and of minor importance; similarly, IgG MAbs
are mainly eliminated via intracellular catabolism and hepatic
impairment is not expected to influence clearance of ixekizumab.1
Ixekizumab
is a humanized IgG4 monoclonal antibody that selectively binds with
the interleukin 17A cytokine and inhibits its interaction with the
IL-17 receptor. Theoretical considerations and case reports for other
IgG mAb suggest that renal impairment does not affect the PK and
likely not the PD of mAb-based therapeutics. However, there is only
limited published experience with regard to the use of other IgG mAb
in patients with renal impairment.2
Table
1 summarizes information
regarding the PK profile for ixekizumab.
Table
1. ADME Profile for Ixekizumab1,3
Absorption
|
Distribution
|
Biotransformation
|
Elimination
|
Following
a single SC dose of ixekizumab in patients with psoriasis:
mean
peak concentrations were achieved within 4 to 7 days across a dose
range of 5 to 160 mg,
mean (SD) Cmax
= 19.9 (8.15) µg/mL after a 160 mg starting dose,
steady
state was achieved by week 8 with the 80 mg Q2W dosing regimen
following a 160 mg starting dose.
average
SC bioavailability was estimated to be in the range of 54% to 90%
across analyses.
axSpA PK Parameters for 160 and 80
mg doses:
mean (SD) Cmax:
160
mg: 13.77 (2.59) μg/mL
80 mg: 6.91 (1.29) μg/mL
median
Time to Cmax:
160
mg: 4 days
80 mg: 4 days
time to steady state:
approximate steady state was achieved for both starting dose
regimens 8 to 12 weeks after starting treatment.
|
From
population PK analyses the mean total volume of distribution at
steady-state was 7.11 L.
|
Ixekizumab
is a monoclonal antibody and is expected to be degraded into small
peptides and amino acids via catabolic pathways in the same manner
as endogenous IgGs.
|
In
the population PK analysis, mean serum clearance was 0.0161L/hr.
Clearance is independent of dose.
The
mean elimination half-life, as estimated from population
pharmacokinetic analysis, is 13 days in plaque psoriasis patients.
|
Abbreviations:
ADME = absorption, distribution, metabolism, elimination; Cmax
= maximum concentration; IgG = immunoglobulin G; L/h = liters per
hour; µg/mL = microgram per milliliter; PK = pharmacokinetic;
SC = subcutaneous.
Note:
The table contains information on dosing that is not consistent with
the approved dosing from the label. Please refer to the Taltz Summary
of Product Characteristics for approved dosing.1
References
1.
Taltz [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
2.
Meibohm B, Zhou H. Characterizing the impact of renal impairment on
the clinical pharmacology of biologics. J Clin Pharmacol.
2012;52(s1):54S-62S. http://dx.doi.org/10.1177/0091270011413894
3.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Glossary
AS/r-axSpA
= ankylosing spondylitis/radiographic axial spondyloarthritis
AUC(0-tlast)
= area under the concentration versus time curve, where tlast
is time of the last sample (14 days ± 24 hours)
Cmax
= maximum concentration
CrCl
= creatinine clearance
hsCRP
= high sensitivity C-reactive protein
IgG
= immunoglobulin G
IgG4
= immunoglobulin G subclass 4
IL-17
= interleukin-17
IL-17A
= interleukin-17A
nr-axSpA
= nonradiographic axial spondyloarthritis
PASI
= Psoriasis Area and Severity Index
PBO
= placebo
PD =
pharmacodynamic(s)
PK =
pharmacokinetic(s)
PsA
= psoriatic arthritis
Q2W
= every 2 weeks