Phase I clinical testing

Tesetaxel (DJ-927) is a fluoro analogue of Taxol currently undergoing Phase I clinical testing for oral treatment of tumors (cf. Chapter 4). ... 

The phase I clinical testing of enalapril began in 1980 in a study in which its efficacy to inhibit intravenously administered angiotensin I was determined. Oral doses as low as 2.5 mg produced a substantial decrease in ACE, activity and lowering was evident even 21-24 hours after the drug was given (129). Phase II and phase III trials began in 1981, and the first approval to use enalapril in hypertension came in 1984 and in heart failure in 1986. 

Drug sponsors could begin phase I clinical testing without receiving IND status from the FDA. Instead, Institutional Review Boards (IRBs) at hospitals or other medical institutions that administer the trials would review and monitor them. 

Phase I clinical testing (validation of mechanistic target)... 

Levo-BC-29l0 an anal(% of cyclazocine, has been evaluated in sub-acute toxicological testing by the NIMH in preparation for Phase I clinical testing. 

Clinical trials are usually divided into three phases. In phase I clinical trials, the new drug is tested in a small (20-80) group of healthy volunteers to evaluate its... 

The antisense oligonucleotide LErafAON against the serine/threonine kinase c-Raf has been tested in phase I clinical trials. The antisense oligonucleotides ISIS-5132, which also inhibits c-Raf, and ISIS-3521, which inhibits PKC, went through different phase clinical trials with solid tumour patients. Unfortunately, no objective responses occurred with these PKI. GEM-231, an oligonucleotide targeting the RIa subunit of protein kinase A is currently undergoing phase I/II clinical trials alone or in combination with traditional therapy for the treatment of solid cancers [3]. 

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. 

Doses should be selected that are reasonable multiples of the proposed therapeutic dose to be employed, especially since in many cases the amount of material available for testing may be limited and not available in Kg amounts. Preclinical rodent or primate studies should merely provide the flags to monitor during Phase I clinical trials. Reason should prevail, not only in the selection of methods and models for assessing the potential toxicity of the new agents, but also in the use of these data for extrapolation to humans. Whether U.S. industry succeeds or fails in the biotechnology arena will depend on the quick resolution of issues such as... 

Tests in Phase /. In Phase I clinical trials, there is the greatest need to obtain a wide variety of laboratory evaluations as part of developing the safety profile on a new medicine. This entails an evaluation of the basic hematology, clinical chemistry, and urinalysis parameters (Table 20.12). There will never be 100% agreement among investigators and/or clinical scientists as to which specific tests constitute a basic workup. 

Tests in Medical Practice. The ordering of laboratory tests in medical practice (as opposed to Phase I clinical trials) is extremely inefficient and often irrational. This suggests the need in some clinical situations to develop logical protocols and... 

Aubry, A.F., Sebastian, D., Hobson, T., Xu, J.Q., Rabel, S., Xie, M., and Gray, V., In-use testing of extemporaneously prepared suspension of second generation non-nucleoside reversed transcriptase inhibitors in support of Phase I clinical studies, /. Pharm. Biomed. Anal., 23,535,2000. 

The Phase I clinical trial is the first experiment in which a drug is tested on the human body. The primary aim of the trial is to assess the safety of the new drug. Other areas of study include pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics. 

ADEPT strategies have been described but only the carboxypeptidase G2 approach has been tested in patients so far. In a phase I clinical trial, patients with non-resectable metastatic or locally recurrent colorectal carcinoma were treated with ADEPT. Carboxypeptidase G2 activity was found in metastatic tumour biopsies. The pro-drug was converted into the active drug but leakage into the bloodstream also occurred [22,144]. 

Reproductive toxicity tests are not required to support Phase I clinical studies in men. Detailed histological evaluations of the male reproductive organs should be performed in the repeated-dose toxicity studies. Male fertility studies in the rodent, however, would be expected to support Phase III studies. 

---