Abstract
ABT-594, a neuronal nicotinic acetylcholine receptor ligand, is 30- to 100-fold more potent than morphine in animal models of nociceptive and neuropathic pain. Efficacy and safety of ABT-594 in subjects with painful diabetic polyneuropathy was evaluated in a phase 2 study. The objective of this work was to use a nonlinear mixed effects model-based approach for characterizing the relationship between dose and response (efficacy and safety) of ABT-594. Subjects (N = 266) were randomized into four groups in a double-blind, placebo-controlled, 7-week study to receive twice daily regimens of placebo or 150, 225, and 300 μg of ABT-594. The primary efficacy variable, pain score (11-point Likert scale), was assessed on five occasions. The probability of change from baseline pain score of ≥1, ≥2, and ≥3 was modeled using cumulative logistic regression with dose and days of treatment as explanatory variables. The incidence of five most frequently occurring adverse events (AEs) was modeled using linear logistic regression. ABT-594 ED50 values (improvement in 50% of subjects) for improvement in pain scores of ≥1, ≥2, and ≥3 were 50, 215, and 340 μg, respectively, for the average number of days (33) on treatment. The rank order of ED50 values for AEs was nausea, vomiting, dizziness, headache, and abnormal dreams; nicotine users were less sensitive to AEs. Population pharmacodynamic models developed to characterize the improvement in pain score and incidence of adverse events indicate an approximately twofold separation between the ED50 values for efficacy and AEs.
Similar content being viewed by others
References
Woolf CJ. Neurobiology of disease. Pain. 2000;7:504–10.
Turk DC, Wilson HD, Cahana A. Treatment of chronic non-cancer pain. Lancet. 2011;377:2226–35.
Poncelet AN. Diabetic polyneuropathy: risk factors, patterns of presentation, diagnosis, and treatment. Geriatrics. 2003;58(6):16–30.
Cymbalta® (Duloxetine HCl) [prescribing information]. Indianapolis, IN: Eli Lilly; 2001
Lyrica® (Prebabalin) [prescribing information]. Vega Baja, PR: Pfizer Inc.; 2001
Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndrome. Pain. 1997;73:123–39.
Fishbain DA, Cutler R, Rosomoff HL, et al. Evidence-based data from animal and human experimental studies on pain relief with antidepressants: a structured review. Pain Med. 2000;1(4):310–16.
Bannon AW, Decker MW, Curzon P, et al. ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. In vivo characterization. J Pharmacol Exp Therapeut. 1998;285:787–94.
Rowbotham MC, Duan WR, Thomas J, et al. A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain. Pain. 2009;146:245–52.
Cruccu G, Anand P, Attal N, et al. EFNS guidelines on neuropathic pain assessment. Eur J Neurol. 2004;11(3):153–62.
Farrar JT, Young JP, LaMoreaux L, et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94(2):149–58.
Salaffi F, Stancati A, Silvestri CA, et al. Minimal clinically important changes in chronic musculoskeletal pain intensity measured on a numerical rating scale. Eur J Pain. 2004;8(4):283–91.
Othman AA, Garimella T, Dutta S, et al. Non-linear mixed-effects model-based meta-analyses of the efficacy at end-of-trials for drugs evaluated for treatment of diabetic neuropathic pain. Poster presented at the American Conference on Pharmacometrics; 2011 April 3–6; San Diego, CA. Abstract published in J Clin Pharmacol. 2011;51(9):1351.
Beal S, Sheiner L. NONMEM. San Francisco: NP Group; 1998.
Sheiner LB. A new approach to the analysis of analgesic drug trials, illustrated with bromfenac data. Clin Pharmacol Ther. 1994;56(3):309–22.
Mandema JW, Stanski DR. Population pharmacodynamic model for ketorolac analgesia. Clin Pharmacol Ther. 1996;60(6):619–35.
Dutta S, Diderichsen PM, Liu W. Clinical trial simulation of outcome after accounting for high dropout typical of acute pain studies. Poster presented at the American College of Clinical Pharmacology 40th Annual Meeting, 2011 September 11-13, Chicago, IL. Abstract published in J Clin Pharmacol. 2011;51(9):1367.
Moore RA, Moore OA, Derry S, et al. Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice. Ann Rheum Dis. 2010;69(2):374–9.
Moore RA, Moore OA, Derry S, et al. Numbers needed to treat calculated from responder rates give a better indication of efficacy in osteoarthritis trials than mean pain scores. Arthritis Res Ther. 2008;10(2):1–5.
Acknowledgments
The funding for this study was provided by Abbott, Abbott Park, IL. Dr. Dutta and Dr. Awni are stockholders and employees of Abbott. Dr. Hosmane is a consultant for Abbott.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dutta, S., Hosmane, B.S. & Awni, W.M. Population Analyses of Efficacy and Safety of ABT-594 in Subjects with Diabetic Peripheral Neuropathic Pain. AAPS J 14, 168–175 (2012). https://doi.org/10.1208/s12248-012-9328-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12248-012-9328-7