Adaline C. Smith

Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models.

UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2–0.3 μM. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T1/2. Specific binding to human α1-acidic glyco-protein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in “real time” with phase I studies.

Effects of bis-chloronitrosourea (BCNU) on pulmonary and serum angiotensin converting enzyme activity in rats

The anticancer drug bis-chloronitrosourea (BCNU) causes potentially life-threatening lung injury in a high percentage of patients. Because changes in the activities of pulmonary and serum angiotensin converting enzyme (ACE) have been reported previously to reflect toxic pulmonary damage by certain agents, we have investigated the effects of BCNU on pulmonary and serum ACE of rats. In vitro, BCNU had a direct inhibitory effect on both serum ACE and pulmonary ACE. In vivo, a large single dose of BCNU (80 mg/kg, i.p.) did not alter pulmonary ACE nor cause histologically observable acute lung damage. However, serum ACE dropped by 25% within 1 hr after drug. A multi-dose regimen, consisting of 5 mg BCNU/kg once per week for 6 weeks, caused marked pulmonary injury, which continued to develop in severity over several weeks following the completion of dosing. Lung ACE after four doses (total of 20 mg BCNU/kg) was depressed by 40% and remained low until dosing was completed. Following the final dose, lung ACE returned to control within 2 weeks. However, after an additional 2 weeks both lung and serum ACE had decreased by 35 and 25% respectively. It appears that ACE may provide a useful biochemical monitor for BCNU-induced pulmonary toxicity, but careful attention must be given to the time-course of changes in the enzyme activity.

Chloroquinoxaline sulfonamide: A sulfanilamide antitumor agent entering clinical trials

SummaryChloroquinoxaline sulfonamide (CQS) has been developed to the clinical trial stage based on its activity in the Human Tumor Colony Forming Assay (HTCFA). In the HTCFA, CQS demonstrated inhibition of colony formation against breast, lung, melanoma and ovarian carcinomas. The mechanism of action of CQS is unknown. It does not appear to inhibit folate metabolism as does the structurally similar sulfaquinoxaline. Preclinical toxicology studies in dogs and rats have shown that CQS is toxic to lymphoid organs, bone marrow, gastrointestinal tract, pancreas, CNS, adrenal glands and testes. Toxicity was generally reversible with the exception of testicular atrophy in dogs and rats which occurred late and was not reversible within the study time frame.The pharmacokinetic data indicate that CQS binds to serum proteins in a dose and species specific manner. Terminal half-lives appear to vary between species from 60 hours in mice, 15 hours in rats, and 45–132 hours in dogs. Preliminary data indicate a longer terminal half-life in humans.Two phase I trials are ongoing using a 60 min infusion schedule once every 28 days. The starting dose for each trial was 18 mg/m2.

CHAPTER 17 – RELEVANCE OF PRECLINICAL PHARMACOLOGY AND TOXICOLOGY TO PHASE I TRIAL EXTRAPOLATION TECHNIQUES: RELEVANCE OF ANIMAL TOXICOLOGY

The chapter reviews the studies of a wide variety of anticancer drugs investigated by the U.S. National Cancer Institute (NCI) to prove the relevance of preclinical pharmacology and toxicology to Phase I trial extrapolation techniques. The development of drugs for the treatment of patients with cancer is perhaps more difficult than that of drugs for other non-life-threatening indications as cancer drugs tend to be the most toxic agents intentionally administered to man. This is further complicated by the fact that the typical patient in a Phase I trial is not a healthy human volunteer but a very ill, terminal cancer patient for whom all other therapeutic interventions have failed. Thus, the starting dose (SD) that is selected for the first human trial of cancer drugs must not only be safe but also offer some hope of benefit to the patient. However, it can also be extremely difficult to select a high enough dose so that the number of dose escalations is kept to a minimum to achieve either a maximum tolerated dose (MTD) or a biologically effective dose in humans. The results of the NCI studies that used agent directed techniques for the pharmacologic and toxicologic evaluation of antitumor agents in preclinical animal models are impressive in their prediction of human MTDs.