Ixekizumab is an IgG4 monoclonal antibody that binds with high affinity (<3 pM) and specificity to interleukin 17A (both IL-17A and IL-17A/F). Elevated concentrations of IL-17A have been implicated in the pathogenesis of psoriasis by promoting keratinocyte proliferation and activation, as well as in the pathogenesis of psoriatic arthritis. Neutralisation of IL-17A by ixekizumab inhibits these actions. Ixekizumab does not bind to ligands IL-17B, IL-17C, IL-17D, IL-17E or IL-17F.
In vitro binding assays confirmed that ixekizumab does not bind to human Fcγ receptors I, IIa, and IIIa or to complement component C1q.
Ixekizumab modulates biological responses that are induced or regulated by IL-17A. Based on psoriatic skin biopsy data from a phase I study, there was a dose-related trend towards decreased epidermal thickness, number of proliferating keratinocytes, T cells, and dendritic cells, as well as reductions in local inflammatory markers from baseline to day 43. As a direct consequence treatment with ixekizumab reduces erythema, induration and desquamation present in plaque psoriasis lesions.
Ixekizumab has been shown to lower (within 1 week of treatment) levels of C-reactive protein, which is a marker of inflammation.
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 Ctrough,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.
From population pharmacokinetic 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 immunoglobulins.
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.
Exposure (AUC) increased proportionally over a dose range of 5 to 160 mg given as a subcutaneous injection.
The pharmacokinetic properties of ixekizumab observed in psoriatic arthritis patients were similar to those displayed in plaque psoriasis patients. The bioavailability of ixekizumab in psoriatic arthritis patients was in the range of 61-84% on the basis of the population pharmacokinetic model.
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.
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.
Non-clinical data from cynomolgus monkeys revealed no special hazards for humans based on repeatdose toxicity studies, safety pharmacology evaluations, and reproductive and developmental toxicity studies.
Ixekizumab administration to cynomolgus monkeys for 39 weeks at subcutaneous doses up to 50 mg/kg weekly produced no organ toxicity or undesirable effects on immune function (e.g. T-cell dependent antibody response and NK cell activity). A weekly subcutaneous dose of 50 mg/kg to monkeys is approximately 19 times the 160 mg starting dose of ixekizumab and in monkeys results in exposure (AUC) that is at least 61-fold higher than the predicted mean steady-state exposure in humans administered the recommended dose regimen.
Non-clinical studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ixekizumab.
No effects on reproductive organs, menstrual cycles or sperm were observed in sexually mature cynomolgus monkeys that received ixekizumab for 13 weeks at a weekly subcutaneous dose of 50 mg/kg.
In developmental toxicity studies, ixekizumab was shown to cross the placenta and was present in the blood of offspring for up to 6 months of age. A higher incidence of postnatal mortality occurred in the offspring of monkeys given ixekizumab compared to concurrent controls. This was related primarily to early delivery or maternal neglect of offspring, common findings in nonhuman primate studies, and considered clinically irrelevant.
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