Pharmacokinetics of renally excreted drug dexpramipexole in subjects with impaired renal function

He, Ping; Kerr, Doug; Marbury, Thomas; Ries, Daniel; Farwell, Wildon; Stecher, Scott; Dong, Yan; Dong, Wei; Rogge, Mark

doi:10.1002/jcph.353

Cited by 5 publications

(8 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such findings are not unexpected because renal function primarily affects the clearance and elimination of mirogabalin. Similar observations have been reported for a number of drugs that are predominantly eliminated in the urine . Similar to pregabalin, the effect of mirogabalin on chronic pain reduction is most likely to be driven by the overall systemic exposure (ie., AUC ss or average concentration over a dosing interval) rather than C max,ss .…”

Section: Discussionsupporting

confidence: 74%

Population pharmacokinetic modeling and simulation for assessing renal impairment effect on the pharmacokinetics of mirogabalin

Yin

Merante

Truitt

et al. 2015

The Journal of Clinical Pharma

View full text Add to dashboard Cite

A population pharmacokinetic model was developed to describe plasma concentrations of mirogabalin and lactam metabolite, obtained following a single oral dose of 5 mg mirogabalin to subjects with varying degrees of renal function.A 2-compartment model was used for both mirogabalin and lactam metabolite. Body weight was a significant covariate on volume of distribution of mirogabalin and lactam metabolite, whereas creatinine clearance significantly affected both renal and nonrenal clearance of mirogabalin. The total clearance of mirogabalin was decreased by 25%, 54%, and 76% in subjects with mild, moderate, and severe renal impairment, respectively, relative to normal controls. Simulation results showed that in comparison with the normal renal function group receiving mirogabalin 15 mg once or twice daily, dose reduction by 50% or 75% in subjects with moderate or severe renal impairment would produce similar AUCss values, but 37%-43% or 28%-32% lower Cmax,ss of mirogabalin. Predicted mirogabalin AUCss was 26% higher, whereas Cmax,ss was similar in subjects with mild renal impairment compared with those having normal renal function taking the same dose. Results support a dose reduction by 50% or 75% in subjects with moderate or severe renal impairment. No dose adjustment seemed necessary for subjects with mild renal impairment.

show abstract

Section: Discussionsupporting

confidence: 74%

Population pharmacokinetic modeling and simulation for assessing renal impairment effect on the pharmacokinetics of mirogabalin

Yin

Merante

Truitt

et al. 2015

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Dexpramipexole, also known as R-(+)-Pramipexole, is an enantiomer of pramipexole recently developed, and used as neuroprotective agent in amyotrophic lateral sclerosis, with pharmacokinetic features similar to those of pramipexole. In a study evaluating the impact of renal failure and HD on dexpramipexole concentration, high-flux HD decreased dexpramipexole plasma concentration by 25% [13]. In the present case, and in our other previously reported patient [8], pramipexole reduction ratios by HD were 32.5 and 44.3%, respectively, and mean dialytic clearances of pramipexole were estimated at 76.8 and 73.3 mL/min, respectively.…”

Section: Discussionsupporting

confidence: 59%

Influence of hemodialysis on pramipexole pharmacokinetics: Lessons from two cases and literature review

Hanset

Hantson

Saint-Marcoux

et al. 2019

CNCS

View full text Add to dashboard Cite

Background: Restless legs syndrome (RLS) is not a rare condition in patients on long-term dialysis. Pramipexole is a small molecule used in the treatment of idiopathic and uremic RLS. Although some information concerning the efficacy and safety of pramipexole in uremic patients is available, data concerning the pharmacokinetics of pramipexole in hemodialysis (HD) are lacking. Following the occurrence of accidental pramipexole intoxication in a chronic HD patient, we were concerned about the efficacy of HD in removing pramipexole. Our aim was thus to assess plasma pramipexole concentrations and pramipexole clearance in a stable chronic HD patient without any residual kidney function. Materials and methods: Our patient was a 63-year-old man on chronic HD for 5 years who had been treated uneventfully with oral pramipexole for uremic RLS since then. During a routine 4-hour high-flux HD session, blood, ultrafiltrate, and dialysate samples were collected every hour to determine pramipexole concentrations over time. Results: Pramipexole blood concentrations ranged from 12.1 to 23.9 µg/L. Pramipexole reduction ratio was 32.5%. Mean dialytic clearance of pramipexole was 76.8 mL/min. Postdialysis rebound was 5.6%. Conclusion: In the absence of any side effect, pramipexole blood concentrations at steady state were 2- to 4-fold higher than those observed in subjects with normal kidney function. Like other drugs with a high volume of distribution, pramipexole was poorly removed by HD. Therefore, HD is not recommended as a treatment option for pramipexole intoxication in patients with a glomerular filtration rate superior to 30 mL/min/1.73m².

show abstract

“…Hence, in order to carefully define the effects of dexpramipexole in this mouse model of progressive MS, we evaluated neurological functions and neuro/immune parameters up to 6 months after immunization. We decided to adopt a treatment schedule consisting on daily administration of dexpramipexole at 10 mgÁkg −1 , in keeping with dose regimens well tolerated in humans (Cudkowicz et al, 2011(Cudkowicz et al, , 2013He et al, 2014). The drug has been administered orally (p.o.)…”

Section: Resultsmentioning

confidence: 99%

Neuroprotection induced by dexpramipexole delays disease progression in a mouse model of progressive multiple sclerosis

Buonvicino

Ranieri

Pratesi

et al. 2020

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose: Drugs able to counteract progressive multiple sclerosis (MS) represent a largely unmet therapeutic need. Even though the pathogenesis of disease evolution is still obscure, accumulating evidence indicates that mitochondrial dysfunction plays a causative role in neurodegeneration and axonopathy in progressive MS patients. Here, we investigated the effects of dexpramipexole, a compound with a good safety profile in humans and able to sustain mitochondria functioning and energy production, in a mouse model of progressive MS. Experimental Approach: Female non-obese diabetic mice were immunized with MOG 35-55. Functional, immune and neuropathological parameters were analysed during disease evolution in animals treated or not with dexpramipexole. The compound's effects on bioenergetics and neuroprotection were also evaluated in vitro. Key Results: We found that oral treatment with dexpramipexole at a dose consistent with that well tolerated in humans delayed disability progression, extended survival, counteracted reduction of spinal cord mitochondrial DNA content and reduced spinal cord axonal loss of mice. Accordingly, the drug sustained in vitro bioenergetics of mouse optic nerve and dorsal root ganglia and counteracted neurodegeneration of organotypic mouse cortical cultures exposed to the adenosine triphosphate-depleting agents oligomycin or veratridine. Dexpramipexole, however, was unable to affect the adaptive and innate immune responses both in vivo and in vitro. Conclusion and Implication: The present findings corroborate the hypothesis that neuroprotective agents may be of relevance to counteract MS progression and disclose the translational potential of dexpramipexole to treatment of progressive MS patients as a stand-alone or adjunctive therapy.

show abstract

Pharmacokinetics of renally excreted drug dexpramipexole in subjects with impaired renal function

Cited by 5 publications

References 7 publications

Population pharmacokinetic modeling and simulation for assessing renal impairment effect on the pharmacokinetics of mirogabalin

Population pharmacokinetic modeling and simulation for assessing renal impairment effect on the pharmacokinetics of mirogabalin

Influence of hemodialysis on pramipexole pharmacokinetics: Lessons from two cases and literature review

Neuroprotection induced by dexpramipexole delays disease progression in a mouse model of progressive multiple sclerosis

Contact Info

Product

Resources

About