Studies in Healthy Volunteers

Sometimes data on side effects or on pulmonary or extrapulmonary deposition obtained in healthy volunteers are used to make predictions about what may occur iu patients with asthma or COPD, in particular if such studies in patients are not available. There is, however, some evidence that differences may exist between the behavior of an aerosolized drug in healthy volunteers and that in a patient with airflow obstruction. Although total pulmonary deposition seems to be comparable in normal subjects and asthmatic patients, pharmacokinetics (P. J. Anderson, personal communication) and regional distribution may differ (109). Indeed, recent scintigraphic studies indicate a more central distribution in patients after inhalation of budesonide via Turbuhaler (38) or of sodium CTomogly-cate administered via pMDI attached to a spacer (110). 

Although it is much easier to assess a number of aspects that pertain to aerosol therapy in healthy volunteers, extrapolation of these results to patients 

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Several studies have performed an economic evaluation of the different methods to deliver aerosolized drugs in hospitalized patients (113). Conversely, data on efficacy and cost-effectiveness of two equivalent treatments, administered via different devices to outpatients with asthma are scarce. Efficacy, measured as the total number of exacerbations, days with exacerbations and hospitalizations, and healthcare utilization were measured over a period of 52 weeks in 445 patients, treated either via pMDI or via Turbuhaler in Canada (114). In this study, effectiveness of treatment and cost differences were in favor of the DPI. 

Trials in which cost-effectiveness of treatments are compared provide extremely useful information, but a study period of several months or years is needed to obtain a realistic estimation of overall health care expenses. Indeed, such trials provide an integrated view on efficacy of the treatment provided, since efficacy takes factors such as patient compliance, efficacy of the drug, preference, acceptance, handling, and ease of use of the device into account. However, differences 

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Ferreira J. J., Galitzky M Thalamas C. et al. (2002). Effect of ropinirole on sleep onset a randomized placebo controlled study in healthy volunteers. Neurology 58(3), 460-2. 

The pharmacokinetics of rifaximin after oral administration has been studied in healthy volunteers and patients with intestinal infections or IBD. The aim of these studies was to confirm the low, if any, systemic absorption of the drug metabolism and excretion data are scant. In all these investigations a sensitive high-pressure liquid chromatographic (HPLC) method was used to measure rifaximin in body fluids. 

Berio JA, Debruyne HJ, Gortz JP A prospective study in healthy volunteers of the topical absorption of a 5% rifaximin cream. Drugs Exp Clin Res 1994,20 205-208. 

In a Phase la study in healthy volunteers, ARRY-438162 was well tolerated up to 20mg/kg q.d. oral dose. There was a dose proportional increase in plasma concentration and decrease in the production of IL-1 ft, TNFa, IL-6 and pERK in the ex-vivo-stimulated whole blood from drug treated volunteers. Array has initiated a Phase lb study of ARRY-438162 in combination with methotrexate in rheumatoid arthritis patients with the goals of assessing safety, tolerability, pharmacokinetics (PK), biomarkers and initial signs of efficacy. 

A potential drug-drug interaction has also been described for the combination of gemfibrozil with several statins. Studies in healthy volunteers have demonstrated that gemfibrozil increased the AUC and Cm ix of rosuvastatin by 1.9- and 2.2-fold, respectively [43]. These results could be confirmed in vitro using Xenopus oocytes. In these experiments, gemfibrozil inhibited OATPIBl-mediated rosuvastatin transport... 

We also conducted a combined scintigraphy and pharmacokinetic study in healthy volunteers, which allowed comparison of the in vivo rates of disintegration and gastric emptying... 

Wilson CG, Washington N, Greaves JL, Kamali F, Rees JA, Sempik AK, Lampard JF. Bimodal release of ibuprofen in a sustained-release formulation—a scintigraphic and pharmacokinetic open study in healthy volunteers under different conditions of food-intake. Int J Pharm 1989 50 155—161. 

Basotti G, Betti C, Imbimbo BP, Pelli MA, Morelli A. Colonic high-amplitude propogated contractions (mass movements) repeated 24 h manometric studies in healthy volunteers. J Gastrointest Mot 1992 4 187-191. 

The ED plan should lead to one or more decision milestones at which an agreed body of information will be provided in a defined time. The plan may consist of as few as one or two studies in healthy volunteers, which will deliver in 6-9 months, or it may involve a complex series of studies in healthy volunteers and patients, which might take 2 years. Whatever is appropriate, the information available at the decision milestones should enable the company to compare the actual profile with the previously agreed MAP. The company will then be in a position to make a well-founded decision on whether to continue development with a much reduced risk of failure or whether to stop and concentrate precious resources elsewhere. 

A protocol for the first and other early studies with a NME in man is similar to those for later studies in healthy volunteers and patients but has some particular features that are worth special consideration. The protocol should be written to satisfy not only the needs of regulatory authorities and personnel who will be involved in conduct of the study but also to facilitate the work of the lEC, which bears considerable responsibility in such cases. The nature of the scientific material contained in the protocol is often complex, highly specialised and quite unlike most protocols for clinical trials handled by such committees. 

In the report of the Royal College of Physicians on studies in healthy volunteers, a healthy volunteer is described as an individual who is not known to suffer any significant illness relevant to the proposed study, who should be within the ordinary range of body measurements such as weight, and whose mental state is such that he is able to understand and... 

In summary, studies in healthy volunteers are an integral part of the development of most drugs because they are capable of rapidly providing a large amount of data that are not confounded by other variables and that can thereby expedite the subsequent evaluation of the drug in patients. 

A preliminary assessment of the effect of food on pharmacokinetics can generally be studied in a single-dose, two-arm, randomised, crossover design. Preliminary information can often be obtained by including a fed occasion in the first, dose-escalating study. This will be insuffi-cent for registration purposes, which require an adequately powered study performed with the final formulation, but the information should be sufficient to indicate whether there is need for restrictions on dosing relative to meals in repeat-dose studies in healthy volunteers and patient clinical trials. 

Participation in a clinical study should be voluntary and there will be no pa)mient unless the study provides no therapeutic benefit, such as tolerability/pharmacokinetic studies in healthy volunteers. When the new GCP was introduced, there was substantial discussion if patients were required to visit study sites more often than usual, for example, to attend additional examinations or treatments would it be fair to put aU financial burden on the patients. 

Drug abuse and dependence Studies in healthy volunteers, subjects with a history of multiple drug abuse, and depressed patients showed some increase in motor activity and agitation/excitement. In individuals experienced with drugs of abuse, a single dose of 400 mg bupropion produced mild amphetamine-like activity as compared with placebo. 

There are only isolated reports on studies in healthy volunteers with the old nootropics. On the basis of a report by Hindmarch et al. (1990) on pyrilinol... 

King, D. J., Henry, G. The affect of neuroleptics on cognitive and psychomotor function a preliminary study in healthy volunteers. Br. 3. Psychiatry 160, 647-653, 1992. 

In vitro data and studies in healthy volunteers suggest a role for protease inhibitors in insulin resistance... 

Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE. 2007. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev 16 1246-1252. 

Portoles, A., Terleira, A., Almeida, S., et al. Bioequivalence study of two formulations of enalapril, at a single oral dose of 20 mg (tablets) A randomized, two-way, open-label, crossover study in healthy volunteers. Curr. Ther Res. 65(1) 34—46, 2004. 

Staner L, Linker T, Toussaint M, Danjou P, Roegel JC, Luthringer R, Le Fur G, Macher JP (2001) Effects of the selective activation of 5-HT3 receptors on sleep a ploysomno-graphic study in healthy volunteers. Eur Neuropsychopharmacol 11 301-305... 

Aalders AL, Schmidt FJ, Schoonen AJ, Broek IR, Maessen AG, Doorenbos H. Development of a wearable glucose sensor studies in healthy volunteers and in diabetic patients. The International Journal of Artificial Organs 1991, 14, 102-108. 

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