title: Pharmacokinetic analysis of capsaicin after topical administration of a high-concentration capsaicin patch to patients with peripheral neuropathic pain.
abstract: Capsaicin, a pungent compound in chili peppers, is a highly selective agonist for the transient receptor potential vanilloid 1 receptor expressed in nociceptive sensory nerves. A high-concentration (640 microg/cm2) capsaicin patch, designated NGX-4010, is in clinical evaluation for the management of peripheral neuropathic pain. To determine systemic capsaicin exposure after single 60- or 90-minute NGX-4010 applications, plasma samples were collected from 173 patients with postherpetic neuralgia (PHN), painful human immunodeficiency virus-associated neuropathy (HIV-AN), and painful diabetic neuropathy (PDN). The percentages of patients with quantifiable levels of capsaicin at any time point were 31% for PHN (30 of 96), 7% for HIV-AN (3 of 44), and 3% for PDN (1 of 33). The maximum plasma concentration observed in any patient was 17.8 ng/mL. Due to the limited number of quantifiable levels, a population analysis was performed to characterize the pharmacokinetics (PK) of capsaicin. Plasma concentrations were fitted adequately using a 1-compartment model with first-order absorption and linear elimination. Capsaicin levels declined very rapidly, with a mean population elimination half-life of 1.64 hours. Mean area under the curve and C max values after a 60-minute application were 7.42 ng x h/mL and 1.86 ng/mL, respectively. Only a few correlations between calculated PK parameters and patient characteristics were observed. Duration and area of application of the patch were detected as significant covariates explaining the PK of capsaicin. Ninety-minute applications of NGX-4010 resulted in capsaicin area under the curve and Cmax values approximately 1.78- and 2.15-fold higher than those observed in patients treated for 60 minutes. Treatment on the feet (patients with HIV-AN and PDN) produced far lower systemic exposure than treatment on the trunk (patients with PHN). Finally, larger treatment areas were associated with statistically higher Vc/F values. The low systemic exposure and very rapid elimination half-life of capsaicin after NGX-4010 administration are unlikely to result in systemic effects and support the overall safety profile of this investigational cutaneous patch.
authors.affiliation: NeurogesX, Inc, San Mateo, California 94404, USA.
authors.forename: Sunita
authors.initials: S
authors.lastname: Babbar
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Marier
authors.forename: Mohamad-Samer
authors.initials: MS
authors.lastname: Mouksassi
authors.forename: Martin
authors.initials: M
authors.lastname: Beliveau
authors.forename: Geertrui F
authors.initials: GF
authors.lastname: Vanhove
authors.forename: Sanjay
authors.initials: S
authors.lastname: Chanda
authors.forename: Keith
authors.initials: K
authors.lastname: Bley
mesh_terms: D000279:Administration, Cutaneous; D000287:Administration, Topical; D002211:Capsaicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002212:Capsicum; D004304:Dosage Forms; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D010146:Pain / Q000378:metabolism*; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D004304:Dosage Forms; D002211:Capsaicin