Dose-finding

Like other parties of the kind, it was first silent, then talky, then argumentative, then disputatious, then unintelligible, then altogethery, then inarticulate, and then drunk. 

Drink deep, or taste not the Pierian Spring There shallow Draughts intoxicate the Brain And drinking largely sobers us again 

Statistical Issues in Drug Development 2nd Edition. Stephen Senn 2007 John Wiley Sons, Ltd. ISBN 978-0-470-01877-4 

With some drugs, the point at which efficacy fails to improve is reached before the maximum tolerated dose is reached. In that case, the concept of the maximum useful dose (International Conference on Harmonisation, 1995) may be relevant, although this concept can also be ambiguous as it may be the dose for which some utility reflecting a trade-off between efficacy and tolerability is a maximum. (See section 20.2.13 for a discussion.) 

The difference between direct and indirect assays is relevant here (Finney, 1978). In a direct assay a given response is targeted and the dose is adjusted until it is reached. In indirect assays the response is studied as a function of the dose and in consequence a useful dose is chosen. An issue that then arises is whether the dose that is eventually chosen should be limited to being one of those that has been studied or whether interpolation (or even extrapolation) can be considered. This relates to Issues regarding the way that dose-response is modelled, which are covered in Section 20.2.1. 

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Staessen JA, Kuznetsova T, Acceto R et al (2005) OASIS-HT design of a pharmacogenomic dose-finding study. Pharmacogenomics 6 755-775... 

Teal P, Silver EL, Simard D. The brains study safety, tolerability, and dose-finding of repinotan in acute stroke. Can J Neurol Sci 2005 32 61-67. 

A dose-finding study of duloxetine based on duloxetine-associated SERT occupancy was recently reported using PET [61]. SERT occupancies increased dose responsively and correlated well with the plasma concentration of duloxetine. It was found that 40 mg or more duloxetine was needed to attain 80% occupancy, and 60 mg of duloxetine could maintain a high level of SERT occupancy with once-a-day dosing. 

In the development of cytotoxic drugs in oncology, dose-finding usually means establishing a maximum tolerated dose (MTD). This is the dose associated with serious but reversible side effects in a sizable proportion of patients and the one that... 

F. L. Roder, Preliminary feasibihty investigation — explosives detection by dual-energy computerized tomography, The Aerospace Corporation, El Segundo, CA, ATR-78(3860-06)-IND. Security Intelligence Report, Micro-dose finds objects under clothes, 11 March (1991) 3. Aviation Week Space Technology, Personnel scanner, 10 June (1991) 11. 

Schmidt R. Dose-finding studies in cUnical drug development. Eur J Clin Pharmacol 1988 34 15-19. 

Senn SJ. Cross-over, Sequential and Dose Finding Studies. Statistical Issues in Drug Development. Chichester John Wiley, 1997 237-9 257-64 275-7. 

Fujii M, Nameki H, Kawaura M, et al. A dose finding study of carboplatin (CBDCA) + UFT in head and neck cancer. ProcAm Soc Clin Oncol 1998 18 406a (abstr 1564). 

Typically, later phase trials tend to have the confirmatory elements while the earlier phase studies proof of concept, dose-finding etc. are viewed as exploratory. Indeed an alternative word for confirmatory is pivotal. It is the confirmatory elements of our trials that provide the pivotal information from a regulatory perspective. 

Available pharmacokinetic (PK) studies of medications with potential to treat pediatric anxiety disorders have been open studies that examine PK parameters and monitor adverse effects in children and adolescents. None of the pediatric PK studies described below were designed as dose finding studies, and none of the studies were able to describe a clear association between dose or exposure and specific adverse effect. However, pediatric PK data can be useful to guide dosing and adverse effect monitoring to the extent that the weight-adjusted PK parameters inform extrapolation based on comparable studies of adult PK. The following summary of PK studies is based on multiple-dose PK studies. 

Proof-of-efficacy trials these studies should provide, within a limited time frame and with a low-cost program, sufficient information for a go/no-go decision concerning efficacy and safety aspects of a new compound. The traditional approaches are Phase lib trials based on placebo-controlled dose-finding designs. These studies need relatively high power, which means the inclusion of several dozen to several hundred patients. 

No pharmacokinetic, dose-finding, controlled efficacy, or safety studies of buspirone in children or adolescents have been conducted. Although b -blockers have been used to treat anxiety and aggressive dyscontrol in children and adolescents, no controlled studies and no pharmacokinetic data exist. 

Lesko U The critical path of warfarin dosing Finding an optimal dosing strategy using pharmacogenetics. Clin Pharmacol Ther 2008 84 301 http //www.fda.gov/cder/genomics/publications.htm... 

Martin CW, Riley SC, Everington D, Groome NP, Riemersma RA, Baird DT, Anderson RA. Dose-finding study of oral desogestrel with testosterone pellets for suppression of the pituitary-testicular axis in normal men. Hum Reprod 2000 15(7) 1515-24. 

Toogood AA, Shalet SM. Growth hormone replacement therapy in the elderly with hypothalamic-pituitary disease a dose-finding study. J Clin Endocrinol Metab 1999 84(l) 131-6. 

Prior to undertaking efficacy studies, baseline pharmacokinetic (PK) and toxicity data are needed, including an initial analysis of cellular/organ toxicity. It should be noted that the toxicity and therapeutic profile can differ significantly between push and continuous infusion. Thus, PK studies can help focus the initial dose finding and toxicological studies. 

PK data for cetuximab were derived from 19 clinical studies performed up to 2003 [16]. Ten of these studies were conducted as dose-escalation/dose-finding studies, while the remaining nine were conducted at the approved dosing regimen of 400 mg/m2 initially, followed by weekly doses of 250 mg/m2. 

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