Quantitative characterization of therapeutic index: Application of mixed-effects modeling to evaluate oxybutynin dose–efficacy and dose–side effect relationships
1999; Wiley; Volume: 65; Issue: 6 Linguagem: Inglês
10.1016/s0009-9236(99)90089-9
ISSN1532-6535
AutoresSwati Gupta, Gayatri Sathyan, Elizabeth Lindemulder, Pak‐Leung Ho, Lewis B. Sheiner, Leon Aarons,
Tópico(s)Statistical Methods in Clinical Trials
ResumoClinical Pharmacology & TherapeuticsVolume 65, Issue 6 p. 672-684 Clinical Trial Quantitative characterization of therapeutic index: Application of mixed-effects modeling to evaluate oxybutynin dose–efficacy and dose–side effect relationships Suneel K. Gupta PhD, Corresponding Author Suneel K. Gupta PhD ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, Manchester1550 Plymouth Road, Mountain View, CA 94039–7210. E-mail: [email protected]Search for more papers by this authorGayatri Sathyan PhD, Gayatri Sathyan PhD ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, ManchesterSearch for more papers by this authorElizabeth A. Lindemulder MS, Elizabeth A. Lindemulder MS ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, ManchesterSearch for more papers by this authorPai-Ling Ho MS, Pai-Ling Ho MS ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, ManchesterSearch for more papers by this authorLewis B. Sheiner MD, Lewis B. Sheiner MD ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, ManchesterSearch for more papers by this authorLeon Aarons PhD, Leon Aarons PhD ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, ManchesterSearch for more papers by this author Suneel K. Gupta PhD, Corresponding Author Suneel K. Gupta PhD ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, Manchester1550 Plymouth Road, Mountain View, CA 94039–7210. E-mail: [email protected]Search for more papers by this authorGayatri Sathyan PhD, Gayatri Sathyan PhD ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, ManchesterSearch for more papers by this authorElizabeth A. Lindemulder MS, Elizabeth A. Lindemulder MS ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, ManchesterSearch for more papers by this authorPai-Ling Ho MS, Pai-Ling Ho MS ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, ManchesterSearch for more papers by this authorLewis B. Sheiner MD, Lewis B. Sheiner MD ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, ManchesterSearch for more papers by this authorLeon Aarons PhD, Leon Aarons PhD ALZA Corporation, Palo Alto University of California, San Francisco, San Francisco University of Manchester, ManchesterSearch for more papers by this author First published: 17 June 1999 https://doi.org/10.1016/S0009-9236(99)90089-9Citations: 11Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract Background Describing a therapeutic index for a drug is important for evaluating safe and effective dosage regimens. Therapeutic index can be evaluated as the relative position of the dose-efficacy and the dose-side effect curves. Oxybutynin XL (Ditropan XL), a once-daily oral controlled-release formulation for oxybutynin chloride, is being developed. Oxybutynin XL efficacy and side-effect data obtained from two parallel-group, randomized, controlled clinical trials were modeled to evaluate the therapeutic index. Methods A nonlinear mixed-effects model was used to characterize the oxybutynin dose–efficacy and dose–dry mouth relationship. Weekly urge urinary incontinence episodes, the primary efficacy variable, is a discrete variable (counts) with only non-negative integer values and was therefore modeled as a Poisson variable. The probability of dry mouth severity (the most frequently reported side effect), assessed on a categorical four-point scale, was modeled with a proportional odds model. In the modeling process, it was assumed that the time effect was the same for the active and placebo treatments and that the drug effect was additive. Results and Conclusions The urge urinary incontinence episodes declined log-linearly, and no significant difference was observed between the two formulations. However, there was a trend toward higher efficacy with oxybutynin XL than with immediate-release oxybutynin at the same dose in one study. Dose–dry mouth analysis showed that the probability of dry mouth with an increasing dose was significantly lower with oxybutynin XL than with immediate-release oxybutynin in the second study, and a similar trend was observed in the first study. By combining the dose–urge urinary incontinence and dose–dry mouth relationship, a wider therapeutic index was predicted for oxybutynin XL than for immediate-release oxybutynin. Clinical Pharmacology & Therapeutics (1999) 65, 672–684; doi: 10.1016/S0009-9236(99)90089-9 References 1Yarker, Y. E., Goa, K. L. and Fitton, A. (1995). Oxybutynin: a review of its pharmacodynamic and pharmacokinetic properties and its therapeutic use in detrusor instability. Drugs Aging 6: 243–262. 2Kachur, J. F., Peterson, J. S., Carter, J. P., Rzeszotarski, W. J., Hanson, R. C. and Noronha-Blob, L. (1988). R and S enantiomers of oxybutynin. J Pharmacol Exp Ther 247: 867–872. 3Jacquetin, B. (1997). Review of pharmacological therapy in the treatment of the unstable bladder [abstract]. Acta Obstet Gynecol Scand 76: 47. 4Tapp, A. J. S., Cardozo, L. D., Versi, E. and Cooper, D. (1990). The treatment of detrusor instability in post-menopausal women with oxybutynin chloride: a double-blind placebo-controlled study. Br J Obstet Gynaecol 97: 521–526. 5Brown, J. (June 28-July 1, 1998). Comparison of tolerability and efficacy of once-a-day vs immediate release oxybutynin chloride in patients with urge urinary incontinence. First International Consultation on Incontinence: Monaco. 6. 6Schmidt, R. A. (Sept 14–17, 1998). Efficacy of controlled release, once-a-day oxybutynin chloride for urge urinary incontinence. International Continence Society: Jerusalem. 188. 7Beal, S. L. and Sheiner, L. B. (1992). NONMEM user's guide. UCSF, NONMEM Project Group: San Francisco. 8Lindstorm, M. J. and Bates, D. M. (1990). Nonlinear mixed effects model for repeated measures data. Biometrics 46: 673–687. 9McCullagh, P. (1980). Regression models for ordinal data. J Royal Stat Soc B 42: 109–142. 10Sheiner, L. B., Beal, S. L. and Dunne, A. (1997). Analysis of nonrandomly censored ordered categorical longitudinal data from analgesic trials. J Am Stat Assoc 92: 1235–1253. 11Rubin, D. B. (1976). Inference and missing data. Biometrika 63: 581–592. 12Sheiner, L. B. (1994). A new approach to the analysis of analgesic drug trials, illustrated with bromfenac data. Clin Pharmacol Ther 56: 309–322. Citing Literature Volume65, Issue6June 1999Pages 672-684 ReferencesRelatedInformation
Referência(s)