The discovery of fingolimod (FTY720/Gilenya; Novartis), an orally active immunomodulatory drug, has opened up new approaches to the treatment of multiple sclerosis, the most common inflammatory ...disorder of the central nervous system. Elucidation of the effects of fingolimod--mediated by the modulation of sphingosine 1-phosphate (S1P) receptors--has indicated that its therapeutic activity could be due to regulation of the migration of selected lymphocyte subsets into the central nervous system and direct effects on neural cells, particularly astrocytes. An improved understanding of the biology of S1P receptors has also been gained. This article describes the discovery and development of fingolimod, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.
Clinical pharmacokinetics of fingolimod David, Olivier J; Kovarik, John M; Schmouder, Robert L
Clinical pharmacokinetics,
2012-Jan-01, Letnik:
51, Številka:
1
Journal Article
Recenzirano
Fingolimod (FTY720), a sphingosine 1-phosphate receptor modulator, is the first in a new class of therapeutic compounds and is the first oral therapy approved for the treatment of relapsing forms of ...multiple sclerosis (MS). Fingolimod is a structural analogue of endogenous sphingosine and undergoes phosphorylation to produce fingolimod phosphate, the active moiety. Fingolimod targets MS via effects on the immune system, and evidence from animal models indicates that it may also have actions in the central nervous system. In phase III studies in patients with relapsing-remitting MS, fingolimod has demonstrated efficacy superior to that of an approved first-line therapy, intramuscular interferon-β-1a, as well as placebo, with benefits extending across clinical and magnetic resonance imaging measures. The pharmacokinetic profiles of fingolimod and fingolimod phosphate have been extensively investigated in studies in healthy volunteers, renal transplant recipients (the indication for which fingolimod was initially under clinical development, but the development was subsequently discontinued) and MS patients. Results from these studies have demonstrated that fingolimod is efficiently absorbed, with an oral bioavailability of >90%, and its absorption is unaffected by dietary intake, therefore it can be taken without regard to meals. Fingolimod and fingolimod phosphate have a half-life of 6-9 days, and steady-state pharmacokinetics are reached after 1-2 months of daily dosing. The long half-life of fingolimod, together with its slow absorption, means that fingolimod has a flat concentration profile over time with once-daily dosing. Fingolimod and fingolimod phosphate show dose-proportional exposure in single- and multiple-dose studies over a range of 0.125-5 mg; hence, there is a predictable relationship between dose and systemic exposure. Furthermore, fingolimod and fingolimod phosphate exhibit low to moderate intersubject pharmacokinetic variability. Fingolimod is extensively metabolized, with biotransformation occurring via three main pathways: (i) reversible phosphorylation to fingolimod phosphate; (ii) hydroxylation and oxidation to yield a series of inactive carboxylic acid metabolites; and (iii) formation of non-polar ceramides. Fingolimod is largely cleared through metabolism by cytochrome P450 (CYP) 4F2. Since few drugs are metabolized by CYP4F2, fingolimod would be expected to have a relatively low potential for drug-drug interactions. This is supported by data from in vitro studies indicating that fingolimod and fingolimod phosphate have little or no capacity to inhibit and no capacity to induce other major drug-metabolizing CYP enzymes at therapeutically relevant steady-state blood concentrations. Population pharmacokinetic evaluations indicate that CYP3A inhibitors and CYP3A inducers have no effect or only a weak effect on the pharmacokinetics of fingolimod and fingolimod phosphate. However, blood concentrations of fingolimod and fingolimod phosphate are increased moderately when fingolimod is coadministered with ketoconazole, an inhibitor of CYP4F2. The pharmacokinetics of fingolimod are unaffected by renal impairment or mild-to-moderate hepatic impairment. However, exposure to fingolimod is increased in patients with severe hepatic impairment. No clinically relevant effects of age, sex or ethnicity on the pharmacokinetics of fingolimod have been observed. Fingolimod is thus a promising new therapy for eligible patients with MS, with a predictable pharmacokinetic profile that allows effective once-daily oral dosing.
Purpose
To describe the adverse events associated with brolucizumab, in particular the sequence of intraocular inflammation (IOI), retinal vasculitis (RV), and/or retinal vascular occlusion (RO).
...Methods
This was an unmasked post hoc analysis of the randomized HAWK/HARRIER clinical trials. Patients with neovascular AMD in the brolucizumab arms of the trials were included. IOI-related adverse events reported by study investigators were analyzed to determine early signs and the time course of IOI-related adverse events, using a subgroup of patients with definite/probable IOI cases identified in an independent unmasked post hoc review by an external safety review committee. A limited literature review on IOI following anti-VEGF therapy was also conducted.
Results
Among 50 patients with definite/probable IOI cases identified by the safety review committee, 12 had RV or RO adverse events reported by the investigators. For 6 of 12, IOI (other than RV) was reported before RV or RO. The duration from the first IOI adverse event to the first RV or RO adverse event ranged from 16 to 171 days for 5 patients and was 553 days for 1 patient. Four of the 6 patients received ≥ 1 brolucizumab injection on or after the date of the first IOI adverse event and before the first RV or RO adverse event.
Conclusions
IOI may precede RV or RO in some patients treated with brolucizumab.
Immunogenicity against intravitreally administered brolucizumab has been previously described and associated with cases of severe intraocular inflammation, including retinal vasculitis/retinal ...vascular occlusion (RV/RO). The presence of antidrug antibodies (ADAs) in these patients led to the initial hypothesis that immune complexes could be key mediators. Although the formation of ADAs and immune complexes may be a prerequisite, other factors likely contribute to some patients having RV/RO, whereas the vast majority do not. To identify and characterize the mechanistic drivers underlying the immunogenicity of brolucizumab and the consequence of subsequent ADA-induced immune complex formation, a translational approach was performed to bridge physicochemical characterization, structural modeling, sequence analysis, immunological assays, and a quantitative systems pharmacology model that mimics physiological conditions within the eye. This approach revealed that multiple factors contributed to the increased immunogenic potential of brolucizumab, including a linear epitope shared with bacteria, non-natural surfaces due to the single-chain variable fragment format, and non-native drug species that may form over prolonged time in the eye. Consideration of intraocular drug pharmacology and disease state in a quantitative systems pharmacology model suggested that immune complexes could form at immunologically relevant concentrations modulated by dose intensity. Assays using circulating immune cells from treated patients or treatment-naïve healthy volunteers revealed the capacity of immune complexes to trigger cellular responses such as enhanced antigen presentation, platelet aggregation, endothelial cell activation, and cytokine release. Together, these studies informed a mechanistic understanding of the clinically observed immunogenicity of brolucizumab and associated cases of RV/RO.
Purpose
Fingolimod (FTY720) is a sphingosine-1 phosphate-receptor (S1PR) modulator recently approved as a once-daily oral therapy for relapsing multiple sclerosis (MS) in many countries. As S1PRs are ...widely expressed, including in heart and lung tissues, this study investigated the possible effects of fingolimod on heart-rate circadian rhythm and pulmonary function.
Methods
Healthy volunteers (
n
= 39) were randomized to receive fingolimod 0.5 mg, 1.25 mg, or placebo for 14 days. Heart rate and measures of cardiac and pulmonary function were assessed during the study.
Results
Mean heart rate for the first 12 h postdose was lower for both fingolimod than for placebo groups (
p
< 0.001) and remained 10–15 bpm lower than placebo until day 14 (
p
< 0.05). Heart rate circadian rhythm, cardiac output, stroke volume, and systemic vascular resistance were similar among treatment groups throughout the study. There was no evidence of an effect of fingolimod on pulmonary function. Absolute lymphocyte counts decreased by approximately 70% from baseline in both fingolimod groups (day 14) and began to increase within 14 days of stopping treatment.
Conclusions
In healthy volunteers treated for 14 days, once-daily fingolimod doses of 0.5 mg and 1.25 mg had no effect on cardiac or pulmonary function beyond a transient decrease in heart rate at treatment initiation.
FTY720 is a novel immunomodulator to be developed for use in organ transplantation. The primary objective of this study was to measure safety, single-dose pharmacokinetics, and pharmacodynamics in ...stable renal transplant patients-the first human use of FTY720. This study used a randomized, double-blind, placebo-controlled design that explored single oral doses of FTY720 from 0.25 to 3.5 mg in 20 stable renal transplant patients on a cyclosporine-based regimen. Safety assessments and blood samples were taken predose and at multiple time points during a 96-h period postdose. Standard pharmacokinetic parameters were derived from the FTY720 whole blood concentrations, measured by HPLC/MS/MS. FTY720 was well tolerated, with no serious adverse events. Transient, asymptomatic bradycardia occurred after administration in 10 of 24 doses of FTY720. Pharmacokinetics are characterized by a prolonged absorption phase; the terminal elimination phase started 36 h after the administration, with elimination half-life (t(1/2)) ranging from 89 to 157 h independent of dose. Maximum plasma concentration and AUC were proportional to dose with low intersubject variability, the apparent volume of distribution (V(d)/F) ranged from 1116 to 1737 L. FTY pharmacodynamics were characterized by a reversible transient lymphopenia within 6 h, the nadir being 42% of baseline. The lymphocyte count returned to baseline within 72 h in all dosing cohorts except the highest. Single oral doses of FTY720 ranging from 0.25 to 3.5 mg were well tolerated and caused a reversible selective lymphopenia. Transient, but asymptomatic bradycardia was the most common adverse event. The long t(1/2) suggests less frequent dosing intervals. The size of V(d)/F is in excess of blood volume, consistent with widespread tissue distribution
FTY720, a new and potent immunosuppressant, causes in animal models a rapid, reversible reduction of all subsets of peripheral blood lymphocytes, inducing their migration to secondary lymphoid ...organs. In this human phase I trial, the pharmacodynamics of single oral doses of FTY720 were evaluated. A randomized, double‐blind, placebo‐controlled, time‐lagged study of six different single ascending oral doses of FTY720 ranging from 0.25 to 3.5 mg was conducted in stable renal transplant patients receiving a cyclosporine‐based regimen. Absolute and subset lymphocyte counts, as well as absolute differential leukocyte counts, were determined by differential blood counts and flow cytometry at screening and multiple intervals thereafter. A pharmacodynamic model was established. Twenty‐four single doses of FTY720 that were administered caused a transient, reversible pan‐lymphopenia within 4 h. Lymphocyte subgroup analysis revealed that almost all subsets declined, with CD4‐ and CD45RA‐positive cells being affected the most. Natural killer cells, granulocytes and monocytes were not influenced by FTY720. The lymphocyte count returned to baseline within 72 h in all dosing cohorts except the highest. Pharmacokinetik/pharmacodynamic modelling revealed a nonlinear dose effect and resulted in a good fit with observed values. These data show that FTY720 is highly effective in humans, with single oral doses of FTY720 ranging from 0.25 to 3.5 mg causing a reversible selective panlymphopenia.
FTY720, a novel immunomodulator, displays potent immunosuppressive activity in a variety of preclinical transplant models. This study examined the safety, pharmacodynamics, and pharmacokinetics of ...multiple doses of FTY720 in stable renal transplant patients.
This randomized, multicenter, double-blind, placebo-controlled, phase I study included adults who had been maintained on a regimen of cyclosporine A (CsA) microemulsion and prednisone (or its equivalent) for at least 1 year after renal transplantation. Patients received once-daily doses of 0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg FTY720, or placebo for 28 days. After completion of study drug administration, the patients were monitored until day 56 by serial laboratory tests, clinical examinations, and recording of adverse events. The study includes 76 treatment courses (61 FTY720 and 15 placebo), with 65 patients enrolled once and 11 reenrolled.
FTY720 doses greater than or equal to 1.0 mg/day produced a significant reduction in peripheral blood lymphocyte count by up to 85%, which reversed within 3 days after discontinuation of study medication. Compared with placebo-treated patients, FTY720 subjects did not show a major increase in adverse events or a change in renal function. Pharmacokinetic measurements revealed that FTY720 displayed linear relations of doses and concentrations over a wide range, but had no effect on CsA exposure.
At doses up to 5.0 mg/day for 28 days, stable renal transplant patients treated with FTY720 in combination with CsA and prednisone displayed a dose-dependent, reversible decline in peripheral blood lymphocytes without an enhanced incidence of collateral toxicities, except possibly bradycardia.
Fingolimod (FTY720) is a sphingosine 1-phosphate receptor (S1PR) modulator currently being evaluated for the treatment of multiple sclerosis. Fingolimod undergoes phosphorylation in vivo to yield ...fingolimod phosphate (fingolimod-P), which modulates S1PRs expressed on lymphocytes and cells in the central nervous system. The authors developed a population model, using pooled data from 7 phase 1 studies, to enable characterization of fingolimod-P pharmacokinetics following oral administration of fingolimod and to evaluate the impact of key demographic variables on exposure. The fingolimod-P concentration-time course after either single or multiple doses of fingolimod was described by a 2-compartment model with first-order apparent formation and elimination, lag time in the apparent formation, and dose-dependent relative bioavailability and apparent central volume of distribution. Body weight and ethnicity were identified as demographic covariates correlated with the disposition of fingolimod-P. Model predictions indicated no need for dose adjustment of fingolimod based on body weight; the effect of ethnicity on the disposition of fingolimod requires further investigation. The accurate prediction of the pharmacokinetic profile of fingolimod-P determined empirically in 2 large phase 3 trials provides external validation of the model.
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