Phase I study designs

Several patent applications claiming variations represented by scaffold 42 have been published [81]. A developed PET ligand from this scaffold class, [11C]-GSK931145 (43) [82], was used in a Phase I study designed to evaluate the relationship between plasma concentrations and brain occupancy of GSK1018921 in healthy individuals (structure and data not disclosed) [46],... 

The NME can now be administered to humans. The first step in clinical evaluation is one or more phase I studies designed to assess the drug s safety and pharmacokinetic profile. Phase I studies usually involve a small number of healthy volunteers who are closely monitored after receiving escalating doses of the drug candidate. Phase I studies of drugs for cancer or HIV infection must be carried out in patients, not in healthy subjects. Ordinarily, until more information is available, the minimum dose to induce side effects is stipulated as the upper dose limit for subsequent administration to human subjects. 

In this case study a simulation strategy, based on a mechanistic PK/PD model, was developed to predict the outcome of the first time in man (FTIM) and proof of concept (POC) study of a new erythropoietin receptor agonist (ERA). A description of the erythropoiesis model, along with the procedures to scale the pharmacokinetics and pharmacodynamics based on preclinical in vivo and in vitro information is presented. The Phase I study design is described and finally the model-based predictions are shown and discussed. 

Phase I The preliminary studies in humans are designed to evaluate the pharmacokinetics and the acute toxicity/tolerability of the potential dmg. Usually, phase I studies are carried out in a very small population [15—40] of healthy male volunteers. Thus, the nature of the population tested and the small number of individuals involved limits the scope of pharmacogenomics to the study of genetic variability in drug metabolism. 

Both enantiomers and the racemate of l-(3,4-dichlorophenyl)-3-azabicyclo [3.1.0]hexane, 27a-c, have been reported to be in development. The racemate, DOV 216,303, inhibits the reuptake of NE, 5-HT and DA with IC50 values of 20, 14 and 78 nM, respectively [85]. DOV 216,303 is active in tests predictive of antidepressant activity, including the mouse FST (minimum effective dose = lOmg/kg), reversal of tetrabenazine-induced ptosis and locomotor depression. DOV 216,303 was also reported to be well tolerated in phase I clinical trials [85,86], In a phase II study designed to explore safety and tolerability in depressed individuals, patients received either DOV 216,303 (50 mg, b.i.d.) or citalopram (20 mg, b.i.d.) for two weeks [85]. It was found that the side effect profile was not remarkably different between the two treatment groups. In addition, time-dependent reductions in Hamilton Depression Scores (HAM-D) were similar for both groups. 

TABLE 20.10. Design and Dosing Schedule for a First Repeat-Dose Phase I Study... 

Drugs with very low aqueous solubility usually have sizeable inter- and/or intrasubject variability in their pharmacokinetics, which makes the study design and conduct of Phase I studies very challenging, makes the assessment of dose-response and exposure-response relationships more difLcult, and makes the dose recommendation and optimization less feasible for NDA and product labeling. 

The Phase I study was designed as a randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the pharmacokinetics and pharmacodynamics of the new ERA. Cohorts of nine subjects with baseline hemoglobin levels less than 14.5 g/dl were randomized to receive ERA treatment (N= 6) or matched placebo (N= 3) at each dose level. The various dose levels considered in this study were lx, 3x, lOx, 30x, lOOx, and 300x. The objective of the study was to identify the pharmacological effective dose (PED), defined as the dose level where four or more treated subjects achieved more than 1 g/dl increase from baseline in hemoglobin within 28 days. 

This example shows that (1) the mechanistic PK/PD model developed based on literature data of rHu-EPO and predinical information of a new ERA is suitable to provide a better quantification and prediction of the drug disposition and the time course of hemoglobin in adult healthy subjects, and (2) this model can be used to optimize the design of the Phase I studies of new ERAs, with respect to key design features (number of dose levels, selection of dose levels, number of subjects per dose level, PK/PD sampling times). In this way, a quantitative risk-benefit assessment can be obtained by determining the probability of success of a Phase I study with new ERA, conditional on a certain experimental design. 

A more recent example is that of sildenafil which, as a result of observations made during Phase I studies in male volunteers, is now used to treat erectile dysfunction. Sildefanil had originally been designed as an analogue of zaprinast, and a more selective phosphodiesterase inhibitor (PDE5) for use as a cardiovascular agent (see Chapter 1-1). 

Since the prevalence of poor metabolizers for CYP 2C19 in a Caucasian population is only 2-5 %, the recruiting of those subjects became cumbersome, and the consequence for the design of the study was that some study details were more adjusted to the needs of those subjects than in a normal phase I study. 

Allometric principles may be used to answer a variety of questions relevant to the application of pre-clinical pharmacokinetic data to the design of dose regimens for humans. Two examples are the use of data from animals to estimate the human pharmacokinetic parameters needed for selecting a starting dose for Phase I studies and the design of intraperitoneal dose regimens for antineoplastic drugs. 

Some features of a Phase I study are invariant others have changed considerably over time. On a periodic basis, a set of new investigators enters the field, and almost everyone is inclined to reinvent the design features of Phase I studies. First-in-human studies are an extraordinary opportunity to integrate pharmacokinetic (PK), pharmacodynamic (PD), and toxicology information while launching the new molecule on a path for rational clinical development (1). Above all, this is a major domain for application of the principles of clinical pharmacology. 

There is a large amount of conceptual similarity in the approach to Phase I trial design, regardless of the therapeutic area however, there are some important differences. One major consideration is the selection of the population of humans for the Phase I study. For most therapeutic indications, healthy volunteers are the participants. They are compensated for the inconveniences of participating in the study, but they are not in a position to receive medical benefit. The use of healthy volunteers substantially limits the ability to observe the desired therapeutic goal. For example, if an agent is intended to correct metabolic deficiencies, or lower elevated blood pressure, there may be no detectable changes in healthy participants. 

J. M. Heyd and B. P. Carlin, Adaptive design improvements in the continual reassessment method for phase I studies. Stat Med 18 1307-1321 (1999). 

Phase I study showed the project could yield an 11.9% internal rate of return by assuming a zero cost for coke feedstock and selling electric power at market price and F-T wax as premium products. Based on this favorable result, Texaco proceeded to Phase II experimental work which validated the key design parameters used in Phase I study. The Texaco EECP project was completed in 2003 after the completion of Phases I and II (4,5). Phase III work was cancelled because of the unavailability of the project host site after the Chevron and Texaco merger. 

ISIS 5132. ISIS 5231 is a phosphorothioate oligodeoxynucleotide designed to inhibit C-raf kinase. In phase I studies, this drug vvas shown to reduce C-raf kinase levels in peripheral blood cells and displayed activity in patients with ovarian cancer (251). It too is completing phase II evaluation (for review, see Ref 247). 

Phase I human studies are designed to evaluate the absorption, distribution, metabolism, and excretion characteristics of a new molecular entity in humans. Except for potentially toxic drugs, as used in life-threatening diseases such as cancer and AIDS, phase I studies are usually undertaken in healthy volunteers. Here, the pharmacokinetic characteristics of the drug are defined as in the preclinical studies. As described previously, the extent of availability after oral dosing and the half-life... 

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