Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients

Park, Sung In; Felipe, Claudia Rosso; Machado, Paula Goulart Pinheiro; Garcia, R.; Skerjanec, A.; Schmouder, Robert; Tedesco-Silva, Helio; Medina-Pestana, Jose O.

doi:10.1590/s0100-879x2005000500005

Cited by 23 publications

(10 citation statements)

References 32 publications

(10 reference statements)

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“…[39][40][41] The degree of lymphopenia and its persistence after drug discontinuation were dose dependent, although the relationships were not linear. [22][23][24][39][40][41]49 In FREEDOMS, fingolimod 0.5mg reduced the mean 6 standard deviation lymphocyte count . Lymphopenia persisted at a stable reduced level with continued treatment.…”

Section: Inhibition Of Lymphocyte Recirculationmentioning

confidence: 98%

“…20,24 Steady state levels are reached after 4-8 weeks. 25,49 Pharmacokinetics are not affected by ethnicity, gender, and mild to moderate hepatic or renal impairment. 20 …”

Section: 21mentioning

confidence: 99%

“…20,24 Steady state levels are reached after 4-8 weeks. 25,49 Pharmacokinetics are not affected by ethnicity, gender, and mild to moderate hepatic or renal impairment. 20 Drug-drug interactions Fingolimod does not interact significantly with other drugs used to treat MS, including fluoxetine, paroxetine, carbamazepine, baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, and corticosteroids.…”

Section: Administrationmentioning

confidence: 99%

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Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

2011

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Until recently, all approved multiple sclerosis (MS) disease treatments were administered parenterally. Oral fingolimod was approved in September 2010 by the US Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. In the clinical trials that led to approval, fingolimod reduced not only acute relapses and magnetic resonance imaging lesion activity but also disability progression and brain volume loss, suggesting preservation of tissue. Fingolimod's mechanism of action in MS is not known with certainty. Its active form, fingolimod-phosphate (fingolimod-P), is a sphingosine 1-phosphate receptor (S1PR) modulator that inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the central nervous system (CNS). Fingolimod also readily penetrates the CNS, and fingolimod-P formed in situ may have direct effects on neural cells. Fingolimod potently inhibits the MS animal model, experimental autoimmune encephalomyelitis, but is ineffective in mice with selective deficiency of the S1P 1 S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti-inflammatory and possibly neuroprotective/ reparative effects, may contribute to its efficacy in MS. In clinical trials, fingolimod was generally safe and well tolerated. Its interaction with S1PRs in a variety of tissues largely accounts for the reported adverse effects, which were seen more frequently with doses 2.5 to 10Â the approved 0.5mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies.

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Section: Inhibition Of Lymphocyte Recirculationmentioning

confidence: 98%

“…20,24 Steady state levels are reached after 4-8 weeks. 25,49 Pharmacokinetics are not affected by ethnicity, gender, and mild to moderate hepatic or renal impairment. 20 …”

Section: 21mentioning

confidence: 99%

Section: Administrationmentioning

confidence: 99%

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Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

2011

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“…These studies are important to identify better immunosuppressive regimens for our patients, taking into account the unique demography of our transplant population, which is quite different from that reported in the US or Europe. We have been participants in of the majority of international clinical trials and have also performed local research with immunosuppressive drugs including new combi- nations of cyclosporine (19,20); reduced doses of OKT3 (21), tacrolimus (22), sirolimus (23), everolimus (24), mycophenolate mofetil (25), and mycophenolate sodium (26); and FTY720 (27,28). To implement our research program, we have developed techniques to measure blood levels of sirolimus and mycophenolic acid (16,17).…”

Section: Researchmentioning

confidence: 99%

Organization of a High-Volume Kidney Transplant Program???The ???Assembly Line??? Approach

Medina-Pestana

2006

Transplantation

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This report describes the organization of a high-volume Brazilian kidney transplant program. With use of an "assembly line" approach, 2,461 kidney transplantations were performed between 1999 and 2004, fulfilling government expectations without compromising the care of the patients. The annual number of kidney transplants increased from 428 to 656 per year. In our Organ Procurement Organization (with 7 million inhabitants), brain death notifications increased from 196 to 461, but less than 25% became actual donors. There are 3,200 patients on the waiting list and recipient selection is based of human leukocyte antigen matching (25 new listings per week). More than 700 first appointments for living donation occur every year. A significant number of recipients are of black race and have been receiving dialysis for long periods of time. The majority of patients are followed locally (100-120 appointments per day). Transplant outcomes among living-donor recipients are comparable to those of large registries, but inferior outcomes have been observed among recipients of deceased-donor organs. However, consistent improvement has been seen in more recent years. The present report also discusses issues related to local regulations and solutions to improve efficiency and outcomes.

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“…In many cases η represents the velocity of a chemical reaction, the parameter a ≥ 0 denotes the maximum velocity, the predictor x ≥ 0 reflects the concentration of a substrate and the parameter b ≥ 0 is the half-saturated constant, the concentration x where the velocity is half-maximal. Some exemplary applications of the Michaelis-Menten model in different disciplines can be found in Clench (1979) (conservation biology research), Butler and Wolkowicz (1985) (nutrient uptake study), Rong and Rappaport (1996) (environmental research), Park et al (2005) (pharmacokinetics) or Yu and Gu (2007) (agriculture) among many others. Because of its importance the problem of designing experiments for statistical analysis with the Michaelis Menten model has found considerable attention in the literature.…”

Section: Introductionmentioning

confidence: 99%

Optimal designs for the Michaelis–Menten model with correlated observations

Dette

Kunert

2013

Statistics

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In this paper we investigate the problem of designing experiments for weighted least squares analysis in the Michaelis Menten model. We study the structure of exact D-optimal designs in a model with an autoregressive error structure. Explicit results for locally D-optimal are derived for the case where 2 observations can be taken per subject. Additionally standardized maximin D-optimal designs are obtained in this case. The results illustrate the enormous difficulties to find exact optimal designs explicitly for nonlinear regression models with correlated observations.

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Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients

Cited by 23 publications

References 32 publications

Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

Organization of a High-Volume Kidney Transplant Program???The ???Assembly Line??? Approach

Optimal designs for the Michaelis–Menten model with correlated observations

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