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

Yin, Ophelia; Merante, Domenico; Truitt, Kenneth E.; Miller, Raymond

doi:10.1002/jcph.584

Cited by 15 publications

(28 citation statements)

References 27 publications

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“…The results of the current study are also supported by those derived from the population PK model, which demonstrated that total mirogabalin clearance was reduced by 25%, 54%, and 76% in white subjects with mild, moderate, and severe renal impairment, respectively, relative to normal controls . Similar results were observed in the Japanese subjects enrolled in the current study; the cumulative percentage of dose excreted into urine decreased with increasing severity of renal impairment.…”

Section: Discussionsupporting

confidence: 87%

“…Given that mirogabalin is primarily eliminated in the urine, renal function can be expected to play a significant role in its elimination and clearance . A 2‐compartment population PK model — designed to describe the concentration–time profiles of mirogabalin 15 mg once or twice daily in European subjects with varying degrees of renal function — demonstrated that in white subjects, mirogabalin exposure increased with increasing degrees of renal impairment . Therefore, the current study evaluated the PK profile of mirogabalin in a cohort of Japanese subjects with varying degrees of renal impairment.…”

Section: Discussionmentioning

confidence: 99%

“…A single 5‐mg mirogabalin tablet was administered 2 hours after a standard low‐calorie meal to subjects who had fasted for ≥8 hours. This dose was selected based on previous clinical pharmacology studies of mirogabalin . In subjects with ESRD, mirogabalin was administered 20 to 56 hours after the completion of hemodialysis so that the next hemodialysis could be conducted 24 hours after study drug administration to minimize the effect of hemodialysis.…”

Section: Methodsmentioning

confidence: 99%

“…Because individuals with diabetic peripheral neuropathic pain often have reduced renal function and mirogabalin is primarily excreted unchanged in urine, it is imperative to determine the effect of renal impairment on mirogabalin pharmacokinetics (PK). Increased mirogabalin exposure concomitant with worsening renal function was observed in white subjects, leading to a dose adjustment in subjects with moderate or severe renal impairment …”

mentioning

confidence: 99%

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Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment

Kato

Tajima

Shimizu

et al. 2017

The Journal of Clinical Pharma

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Mirogabalin (DS‐5565) is a novel preferentially selective α2δ‐1 ligand being developed for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia. The current multicenter open‐label study determined the effect of varying degrees of renal impairment on the pharmacokinetics and safety of a single dose of mirogabalin 5 mg in Japanese subjects. A total of 30 subjects (6 subjects per renal function category [normal, mild, moderate, or severe impairment; and end‐stage renal disease (ESRD)]) were enrolled and completed the study. The AUClast increased with severity of renal impairment; the geometric least‐squares mean ratios of AUClast compared with subjects with normal renal function were 1.3, 1.9, 3.6, and 5.3 for patients with mild, moderate, and severe impairment and ESRD, respectively. In accordance with this AUClast increase, apparent total body clearance (CL/F), renal clearance (CLr), and the cumulative percentage of mirogabalin dose excreted into urine all decreased with severity of renal impairment. There were no deaths and no severe treatment‐related adverse events (TEAEs), serious TEAEs, or TEAEs resulting in study discontinuation. Mirogabalin was well tolerated in Japanese subjects with normal renal function and those with mild to severe renal impairment. It was also tolerated in subjects with ESRD but with a higher incidence of TEAEs. The most frequently reported TEAEs were dizziness (ESRD, n = 3), somnolence (ESRD, n = 2), and vomiting (ESRD, n = 2). Based on these data, a mirogabalin dose adjustment will be considered in Japanese subjects with moderate to severe renal impairment and those with ESRD.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment

Kato

Tajima

Shimizu

et al. 2017

The Journal of Clinical Pharma

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“…When administered to healthy human subjects, it was also shown to exhibit linear absorption and plasma protein binding of 25% (Table 1) [30].…”

Section: Mirogabalinmentioning

confidence: 98%

Alpha₂delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use

Calandre

Rico‐Villademoros

Slim

2016

Expert Review of Neurotherapeutics

180

128

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The first two alphadelta ligands - gabapentin (GBP) and pregabalin (PGB) - were initially synthesized as antiepileptics; however, they were later also found to be useful for the treatment of additional conditions. Areas covered: Relevant publications describing potential underlying mechanisms, clinical pharmacokinetics/pharmacokinetics, and clinical efficacy and safety of these drugs in various disease conditions were searched in PubMed and Scopus and included in this review. Expert commentary: GBP and PGB are effective for the treatment neuropathic pain, fibromyalgia and epilepsy; in addition, they may be useful for the reduction of postoperative pain. PGB is also effective for the treatment of generalized anxiety disorder and GBP for the treatment of restless legs syndrome. GBP may be considered a treatment option for pain associated with Guillain-Barré Syndrome and phantom limb and for the management of uremic pruritus. Mirogabalin (MGB), recently developed, is being investigated for the treatment of peripheral neuropathic pain and fibromyalgia, showing promising results in patients with diabetic peripheral neuropathy. Their most frequent adverse reactions are of neuropsychiatric nature and include fatigue, dizziness, sedation, somnolence, and ataxia; peripheral edema and weight gain are also frequently described. Pharmacokinetic interactions are scarce; however, pharmacodynamic interactions have been described in association with drugs with CNS-depressant effects.

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A Randomized, Placebo‐Controlled, Double‐Blind Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeated Doses of Mirogabalin in Healthy Asian Volunteers

Jansen

Warrington

Dishy

et al. 2018

Clinical Pharm in Drug Dev

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Mirogabalin is a novel, preferentially selective α δ-1 ligand under investigation to treat neuropathic pain. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of various doses of mirogabalin in healthy subjects of different ethnicities. This randomized, placebo-controlled, double-blind, sequential, ascending-dose study evaluated single (10-40 mg) and repeated (10, 15 mg twice a day) doses of mirogabalin in Japanese subjects, and a single dose of mirogabalin in Korean, Chinese, and white subjects. Mirogabalin was rapidly absorbed, with a median time to maximum plasma concentration of 1 hour, and rapidly eliminated, with a mean elimination half-life of 2 to 3 hours. Single-dose mirogabalin pharmacokinetic parameters were comparable between Asian and white subjects. Exposure increased proportionally as mirogabalin dose increased in Japanese subjects. Mean mirogabalin steady-state clearance and volume of distribution values were comparable across dose levels. No accumulation of mirogabalin was observed on repeated dosing in Japanese subjects. Mirogabalin had an acceptable safety and tolerability profile in Asian and white subjects at doses up to 15 mg twice a day for 7 days. The most common treatment-emergent adverse events (somnolence, headache, and dizziness) were consistent with the known mechanism of action and safety profile of mirogabalin.

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

Cited by 15 publications

References 27 publications

Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment

Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment

Alpha₂delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use

A Randomized, Placebo‐Controlled, Double‐Blind Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeated Doses of Mirogabalin in Healthy Asian Volunteers

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

Cited by 15 publications

References 27 publications

Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment

Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment

Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use

A Randomized, Placebo‐Controlled, Double‐Blind Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeated Doses of Mirogabalin in Healthy Asian Volunteers

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Alpha₂delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use