Clinical Pharmacokinetics of XP13512, a Novel Transported Prodrug of Gabapentin

@article{Cundy2008ClinicalPO,
  title={Clinical Pharmacokinetics of XP13512, a Novel Transported Prodrug of Gabapentin},
  author={Kenneth C. Cundy and S. V. Kumara Sastry and Wendy Luo and Joan Zou and Tristen L. Moors and Daniel M. Canafax},
  journal={The Journal of Clinical Pharmacology},
  year={2008},
  volume={48}
}
Gabapentin absorption occurs in only a limited region of the small intestine and saturates at doses used clinically, resulting in dose‐dependent pharmacokinetics, high interpatient variability, and potentially ineffective drug exposure. XP13512/GSK1838262 is a novel transported prodrug of gabapentin that is absorbed throughout the entire length of the intestine by high‐capacity nutrient transporters. In 4 studies of healthy volunteers (136 subjects total), the pharmacokinetics of XP13512… Expand
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References

SHOWING 1-10 OF 23 REFERENCES
XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: II. Improved Oral Bioavailability, Dose Proportionality, and Colonic Absorption Compared with Gabapentin in Rats and Monkeys
TLDR
In clinical use, XP13512 may improve the treatment of neuropathic pain, epilepsy, and numerous other conditions by increasing efficacy, reducing interpatient variability, and decreasing frequency of dosing. Expand
A Saturable Transport Mechanism in the Intestinal Absorption of Gabapentin Is the Underlying Cause of the Lack of Proportionality Between Increasing Dose and Drug Levels in Plasma
TLDR
These findings support absorption of gabapentin by a saturable pathway, system L, shared by the large hydrophobic amino acids, L-Phe and L-Leu, made a major contribution to the lack of proportionality in plasma levels of drug with increasing dose ob-served in the clinic. Expand
Inter- and intra-subject variability in gabapentin absorption and absolute bioavailability
TLDR
The within subject variability of gabapentin is small enough that plasma drug monitoring may be used to assess gABapentin absorption for a given subject and the benefit of dose individualization. Expand
XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: I. Design, Synthesis, Enzymatic Conversion to Gabapentin, and Transport by Intestinal Solute Transporters
TLDR
Administration of the prodrug XP13512 should result in improved gabapentin bioavailability, dose proportionality, and colonic absorption compared with administration of gabapsentin, due to its substrate for several high-capacity absorption pathways present throughout the intestine. Expand
Gabapentin in the Management of Convulsive Disorders
TLDR
Gabapentin dosing must be optimized on an individual basis to achieve an adequate trial of the drug and obtain the best seizure control, as its therapeutic range is not well characterized. Expand
A summary of mechanistic hypotheses of gabapentin pharmacology
TLDR
Gabapentin prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS), and may occur by inhibition of glutamate synthesis by branched-chain amino acid aminotransferase (BCAA-t). Expand
Gabapentin (Neurontin) as Add‐on Therapy in Patients with Partial Seizures: A Double‐Blind, Placebo‐Controlled Study
TLDR
GBP is safe and effective in treating some patients with refractory partial seizures and no clinically important trends and no evidence of hepatic or hematopoietic effects are shown. Expand
The Novel Anticonvulsant Drug, Gabapentin (Neurontin), Binds to the Subunit of a Calcium Channel (*)
TLDR
[3H]Gabapentin is the first pharmacological agent described that interacts with an α subunit of a voltage-dependent Ca channel, and binding activity closely followed the elution of the α sub unit. Expand
Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial.
TLDR
Gabapentin is effective in the treatment of pain and sleep interference associated with PHN and Mood and quality of life also improve with gabapentin therapy. Expand
Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study
TLDR
The role of gabapentin as an efficacious and well‐tolerated treatment for postherpetic neuralgia is confirmed and the most common adverse events were dizziness and somnolence, particularly during the titration phase. Expand
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