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A brief historical perspective of early studies of drugs in humans

  1. Top of page
  2. A brief historical perspective of early studies of drugs in humans
  3. Contemporary Phase-I Studies:
  4. Phase-0 microdose studies; the future?
  5. REFERENCES

Between 50 and 70 AD, Dioscorides of Anazarbus, a Greek physician, described the preparation, properties and testing of many plants in his five volume text inline imageinline imageinline image(De Materia Medica) [1] and this was considered the forerunner of modern pharmacopoeias. It was not until 1542 that Leonard Fuchs gave the foxglove the name ‘digitalis’ in his book ‘De historia stirpium commentarii insignes’(notable commentaries on the history of plants) [2]. The best documented initial clinical studies of the medicinal use of the foxglove were those of William Withering in his case series entitled ‘An account of the foxglove and some of its medical uses: with practical remarks on dropsy and other diseases[3]. This was published in 1785 some ten years after Withering had started treating patients with ‘the foxglove’. Withering determined that the dried powdered foxglove leaf was more effective than other formulations and that decoction (boiling) destroyed the active principle. In his 163 patients with dropsies, many of whom had heart failure, he defined the importance of digitalis dose, observed digitalis associated diuresis, gastro-intestinal and ocular (xanthopsia) adverse effects, and noted inter-individual variability in response as some of his patients did not respond. Withering's work placed the therapeutic use of digitalis on a solid scientific footing. The fundamental principles of practical therapeutics observed and so carefully described by Withering are pertinent today, in the prescribing of approved medications but especially in the early studies of new therapeutic entities. During the mid 20th century the paradigm for early studies of novel compounds in humans focused on adverse-effect pharmacodynamics and pharmacokinetics, but recently the addition of biomarkers of therapeutic drug effect have been incorporated into such studies. This issue of the Journal contains several reports of first in human studies of new potential therapeutic agents employing contrasting study designs and cutting edge technologies.

Contemporary Phase-I Studies:

  1. Top of page
  2. A brief historical perspective of early studies of drugs in humans
  3. Contemporary Phase-I Studies:
  4. Phase-0 microdose studies; the future?
  5. REFERENCES

Bryson et al.[4] reported studies of cetilistat, a pancreatic and gastro-intestinal lipase inhibitor structurally distinct from orlistat and a potential anti-obesity agent. The researchers undertook three placebo controlled, parallel group, Phase-I studies of treatment for 5 days with oral cetilistat at doses ranging from 50 to 300 mg three times a day in healthy volunteers (n = 99; 24 placebo, 66 cetilistat and 9 orlistat). All took a standard diet (2160 calories/day, 30% from fat). The primary study endpoint was daily fecal fat excretion; other secondary pharmacodynamic endpoints were gastrointestinal and other tissue effects and effects on plasma cholesterol and triglycerides. Presumably because the therapeutic target of cetilistat is in the gastro-intestinal tract, no systemic pharmacokinetics were defined to correlate with any observed systemic ‘off target’ pharmacodynamics. Cetilistat increased fecal fat excretion relative to baseline at all doses studied. This increased fecal fat excretion was at least equivalent to that observed with orlistat 120 mg three times a day. Cetilistat caused predominantly mild to moderate gastrointestinal adverse effects (steatorrhea was 61% of all gastrointestinal adverse events). The number of episodes of steatorrhea/subject in cetilistat dosing groups (maximum 1.8) was lower than that in the orlistat group (4.1), but this data should be interpreted with caution because of the small number of subjects receiving orlistat (n = 9). Phase-II studies of cetilistat are complete and Phase-III studies planned.

Using a more traditional study design, Patat et al.[5] report the first in man study of lecozotan (a novel 5HT1A antagonist, void of intrinsic agonist activity) a potential therapy for Alzheimer's disease. They undertook three randomized, double blind, placebo-controlled sequential escalating single and multiple oral dose studies. The single doses of lecozotan that they investigated ranged from 2 to10 mg administered to groups (n = 8) of healthy young volunteers. In the ascending 14-day multiple-dose studies, young healthy subjects (n = 41) took lecozotan doses of 0.1 to 5 mg every 12 hours or placebo and the elderly healthy subjects (n = 24) took lecozotan 0.5 mg or 5 mg every 12 hours or placebo. The maximum tolerated single oral dose of lecozotan was 10 mg and for chronic dosing 5 mg every 12 hours. There were mild to moderate adverse effects of paresthesiae, dizziness and visual disturbances, which were maximal at the tmax and were reversible as the lecozotan plasma concentration declined. Lecozotan pharmacokinetics were linear over the doses studied, and it was rapidly absorbed, with a mean terminal t1/2 of 7 h in young subjects compared with 11 h in the elderly and a CL/F in elderly subjects that was on average 35% lower than in the young. Lecozotan did not have any significant effects on vital signs, electrocardiography, cognitive function or electro-encephalography. Subsequently, Phase-II and Phase-III studies of lecozotan in patients with Alzheimers disease are ongoing.

Phase-0 microdose studies; the future?

  1. Top of page
  2. A brief historical perspective of early studies of drugs in humans
  3. Contemporary Phase-I Studies:
  4. Phase-0 microdose studies; the future?
  5. REFERENCES

Of every 10 new molecular entities/biomolecules that are tested in first in man Phase-I studies three fail to go forward into further development because of their pharmacokinetic or toxicity profiles [6]. Recently, researchers have recognized the necessity to obtain more and improved pharmacokinetic-pharmacodynamic (PK-PD) data from early human studies of novel therapeutic agents and simultaneously optimize the efficiency of such studies. In theory this should better inform decision making about a novel compounds fate (go-no-go decisions) and improve the timeframe of drug development. Regulatory agencies both in Europe (EMEA) and the US (FDA) [7, 8] have published detailed guidance on Phase-0 microdose studies and the exploratory Clinical Trials Agreement (eCTA) or exploratory Investigational New Drug (eIND) mechanisms. These studies involve administration of microdoses of a drug /molecule to humans. A microdose is defined as a dose that is estimated to be 1/100th of the dose predicted to cause a pharmacologic effect, thus avoiding toxic effects, but no more than 100 micrograms.

Madan et al.[9] in this issue of the Journal, report a Phase-0 open label , randomized, two period crossover study of the pharmacokinetics of single oral and intravenous microdoses (100 micrograms) of five histamine H1 receptor antagonists (four novel derivatives of R-dimethindine – NBI-1, NBI-2, NBI-3 and NBI-4 and diphenhydramine) in five groups (n = 4) of healthy volunteers. Drug concentrations were measured using HPLC accelerator mass spectroscopy. The pharmacokinetic parameters for diphenhydramine were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, and the rank order for elimination half-life was NBI-2 > NBI-1 > diphenhydramine > NBI-3 > NBI-4. This study provided estimates of the human pharmacokinetics of four structurally related novel compounds and led to the selection of NBI-2, due to its better pharmacokinetic profile, as a potential hypnotic agent, for subsequent Phase-I and recently Phase-II studies in humans.

Phase-0 studies have several potential benefits: the need for less pharmacological and toxicological data in the regulatory submission than for Phase-I studies; few subjects in these proof of concept studies; provision of a rational guide to lead compound selection and the design of Phase-I studies and a reduced drug development timeframe. However, Phase-0 studies also have limitations: not all compounds are amenable to the development of a radiolabeled compound for testing and there is no guarantee that the pharmacokinetics of the microdose will extrapolate linearly to the ultimate doses tested in Phase-I studies. So Phase-0 studies will not replace traditional Phase-I studies nor will they define a drug dose that is clinically effective in the absence of adverse effects. Furthermore, there may be no detectable pharmacodynamic effect if the agents therapeutic index is wide. If possible, it is desirable to incorporate into these studies validated and sensitive biomarkers for ‘drug target’ pharmacodynamics.

One recent example of the successful integration of Phase-0 studies into a drug development programme, but which in addition extended the pharmacodynamic information obtained [10, 11], was that of the poly (ADP-Ribose) polymerase (PARP) inhibitor ABT-888, which inhibits DNA repair. ABT-888 microdose pharmacokinetics and ‘drug target’ pharmacodynamics (inhibition of PARP in peripheral blood monocytes and tumor biopsies) were studied in patients with cancer patients [12] and these data provided the basis for the design of subsequent Phase-I studies of ABT-888 in combination with DNA damaging agents.

The use of Phase-0 (microdose) studies in drug development is in its infancy, and their role and contribution to the process have not yet been clearly substantiated. Studying the clinical pharmacology of a new drug is one of the most exciting areas of clinical translational science to be involved in today, just as it was for William Withering in the late 18th century.

REFERENCES

  1. Top of page
  2. A brief historical perspective of early studies of drugs in humans
  3. Contemporary Phase-I Studies:
  4. Phase-0 microdose studies; the future?
  5. REFERENCES
  • 1
    Dioscorides P. De Materia Medica 65 AD.
  • 2
    Fuchs L. De Historia Stirpium, Basel, 1542.
  • 3
    Aronson JK. An account of the foxglove and its medicinal uses 1785–1985. Incorporating a Facsimile of William Withering's ‘An Account of the Foxglove and Some of Its Medical Uses’(1785). Oxford University Press: Oxford. 1985.
  • 4
    Bryson A, De La Motte S, Dunk C. Reduction of dietary fat absorption by the novel gastrointestinal lipase inhibitor cetilistat in healthy volunteers. Br J Clin Pharmacol 2009; 67: 30915.
  • 5
    Patat A, Parks V, Raje S, Plotka A, Chassard D, Le Coz F. Safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of lecozotan in healthy young and elderly subjects. Br J Clin Pharmacol 2009; 67: 299308.
  • 6
    Dimasi JA. Risks in new drug development: approval success rates for investigational drugs. Clin Pharmacol Ther 2001; 69: 297307.
  • 7
    EMEA. Position Paper On Non-clinical Safety Studies to Support Clinical Trials with a Single Microdose. London: EMEA, 2004. http://www.emea.europa.eu/pdfs/human/swp/259902en.pdf (accessed Feb 9 2009).
  • 8
    FDA. Guidance for Industry Investigators and Reviewers. Exploratory IND Studies. Washington DC: Food and Drug Administration UdoHaHS, Jan. 2006. http://www.fda.gov/cder/guidance/7086fnl.htm (accessed Feb 9 2009).
  • 9
    Madan A, O'Brien Z, Wen J, O'Brien C, Farber RH, Beaton G, Crowe P, Oosterhuis B, Garner RC, Lappin G, Bozigian HP. A pharmacokinetic evaluation of five H1 antagonists after an oral and intravenous microdose to human subjects. Br J Clin Pharmacol 2009; 67: 28898.
  • 10
    Calvert AH, Plummer R. The development of phase I cancer trial methodologies: the use of pharmacokinetic and pharmacodynamic end points sets the scene for phase 0 cancer clinical trials. Clin Cancer Res 2008; 14: 36649.
  • 11
    Palma JP, Rodriguez LE, Bontcheva-Diaz VD et al. The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo. Anticancer Res 2008; 28(5A): 262535.
  • 12
    Kummar S, Kinders R, Gutierrez M et al. Inhibition of poly (ADP-ribose) polymerase (PARP) by ABT-888 in patients with advanced malignancies: results of a phase 0 trial [abstract 3518. J Clin Oncol 2007; 25: 142S.