Jerry M. Collins

Plasma and cerebrospinal fluid pharmacokinetics of 3′‐azido‐3′‐deoxythymidine: A Novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases

We investigated the clinical pharmacokinetics of azidothymidine (N3TdR) as part of a phase I/II trial in the treatment of acquired immunodeficiency syndrome and related diseases. During the 6‐week course of therapy, drug levels in plasma, cerebrospinal fluid, and urine were determined by HLPC. The plasma half‐life of N3TdR was 1.1 hour. The total body clearance was 1.3 L/kg/hr. At intravenous doses of 5 mg/kg or oral doses of 10 mg/kg, plasma levels were continuously maintained above the target level of 1 μmol/L. Oral bioavailability was 63% ± 13%. Substantial penetration of N3TdR into cerebrospinal fluid was demonstrated. At doses of 5 mg/kg intravenously or 10 mg/kg orally, cerebrospinal fluid drug levels exceeded and were maintained close to 1 μmol/L. Nineteen percent of the administered dose was excreted unchanged into the urine. Renal clearance was 0.23 L/kg/hr. N3TdR possesses pharmacokinetic properties that would facilitate the long‐term treatment of patients with acquired immunodeficiency syndrome: it can be given orally and it penetrates the central nervous system.

Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered

Induction therapy is now successful in producing a complete remission in more than 90 per cent of patients with acute lymphoblastic leukemia.1 , 2 However, maintenance of remission remains a major ...

Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies

PURPOSE We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies. PATIENTS AND METHODS ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size. RESULTS Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels. CONCLUSION Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.

Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy.

In this phase II trial, 105 eligible patients with no prior chemotherapy and advanced sarcoma received doxorubicin, ifosfamide, and dacarbazine (DTIC) with mesna uroprotection (MAID). Starting doses of these drugs were 60, 7,500, and 900 mg/m2 divided over 72 hours by continuous infusion, respectively. Mesna was given for 84 to 96 hours at 2,500 mg/m2/d. Myelosuppression was dose limiting, causing the only toxic death (sepsis). Nonhematologic toxicity consisted predominantly of anorexia and vomiting. Severe mucositis, macroscopic hematuria, renal tubular acidosis, renal failure, and CNS toxicity occurred in less than 5% of cycles. No cardiotoxicity was detected. The overall response rate (10% complete response [CR]) was 47% (95% confidence intervals, 5% to 18% and 37% to 57%, respectively). Most responses (approximately 70%) were observed within two cycles. Median times to progression were 10 and 9 months, respectively. Histologic high tumor grade, lesions less than 5 cm, and less than 1 year from diagnosis to study entry correlated with the probability of response. The median survival was 16 months. Time from diagnosis to study entry, performance status, and extent of disease, but not histologic grade, correlated with survival. Following CR, two patients remain disease-free at 32 and 16 months. Of the 15 additional patients rendered disease-free with surgery, two remain disease-free at 30 and 18 months with no further therapy. While most relapses occurred in sites of prior involvement, death from CNS metastases occurred in 11 of the 80 patients with high-grade sarcomas, of whom seven were still responding systematically (three complete responders). Because of its substantial response in this phase II trial, the MAID regimen is being compared with doxorubicin and DTIC alone in advanced sarcomas and to observation in the adjuvant treatment of high-grade sarcomas in randomized trials.

Nonlinear pharmacokinetic models for 5-fluorouracil in man: Intravenous and intraperitoneal routes

A two‐compartment physiologic pharmacokinetic model has been developed for 5‐fluorouracil (5FU). This model, which incorporates saturable whole body clearance, satisfactorily predicts disappearance kinetics after an intravenous bolus and steady‐state levels during constant intravenous infusions. A half‐saturating concentration (KM) of 15μM was determined by comparison of model simulations with literature data. Both hepatic and extrahepatic elimination can be inferred for 5FU, but the exact anatomic or compartmental location of the clearance cannot be determined from the available clinical data. The effect of venous and arterial plasma sampling is discussed. This model has been extended to include intraperitoneal and oral administration of 5FU by the addition of peritoneal fluid and liver compartments.

Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements

The rapid development of new therapeutic agents that target specific molecular pathways involved in tumour cell proliferation provides an unprecedented opportunity to achieve a much higher degree of biochemical specificity than previously possible with traditional chemotherapeutic anticancer agents. However, the lack of specificity of these established chemotherapeutic drugs allowed a relatively straightforward approach to their use in combination therapies. Developing a paradigm for combining new, molecularly targeted agents, on the other hand, is substantially more complex. The abundance of molecular data makes it possible, at least in theory, to predict how such agents might interact across crucial growth control networks. Initial strategies to examine molecularly targeted agent combinations have produced a small number of successes in the clinic. However, for most of these combination strategies, both in preclinical models and in patients, it is not clear whether the agents being combined actually hit their targets to induce growth inhibition. Here, we consider the initial approach of the US National Cancer Institute (NCI) to the evaluation of combinations of molecularly targeted anticancer agents in patients and provide a description of several new approaches that the NCI has initiated to improve the effectiveness of combination-targeted therapy for cancer.

Analysis of Food and Drug Administration–Approved Anticancer Agents in the NCI60 Panel of Human Tumor Cell Lines

Since the early 1990s the Developmental Therapeutics Program of the National Cancer Institute (NCI) has utilized a panel of 60 human tumor cell lines (NCI60) representing 9 tissue types to screen for potential new anticancer agents. To date, about 100,000 compounds and 50,000 natural product extracts have been screened. Early in this program it was discovered that the pattern of growth inhibition in these cell lines was similar for compounds of similar mechanism. The development of the COMPARE algorithm provided a means by which investigators, starting with a compound of interest, could identify other compounds whose pattern of growth inhibition was similar. With extensive molecular characterization of these cell lines, COMPARE and other user-defined algorithms have been used to link patterns of molecular expression and drug sensitivity. We describe here the results of screening current Food and Drug Administration (FDA)-approved anticancer agents in the NCI60 screen, with an emphasis on those agents that target signal transduction. We analyzed results from agents with mechanisms of action presumed to be similar; we also carried out a hierarchical clustering of all of these agents. The addition of data from recently approved anticancer agents will increase the utility of the NCI60 databases to the cancer research community. These data are freely accessible to the public on the DTP website (http://dtp.cancer.gov/). The FDA-approved anticancer agents are themselves available from the NCI as a plated set of compounds for research use. Mol Cancer Ther; 9(5); 1451–60. ©2010 AACR.

Inhibition of first-pass metabolism in cancer chemotherapy : interaction of 6-mercaptopurine and allopurinol

Earlier studies suggested that the dose of 6‐mercaptopurine (6‐MP) can be reduced substantially when the drug is given with allopurinol. We studied the effect of allopurinol on the kinetics of oral and intravenous 6‐MP. Studies conducted initially in rhesus monkeys and subsequently in man with 6‐MP doses of 100 mg/m2 and 75 mg/m2, demonstrated that allopurinol pretreatment resulted in a nearly 400% increase in peak plasma concentration of oral 6‐MP in monkeys (from a mean of 0.54 μM to a mean of 2.1 μM) and a 500% increase in man (0.74 μM to 3.7 μM). Allopurinol pretreatment also led to a 300% increase in plasma AUC in monkeys after oral 6‐MP (from a mean of 121 μM/min to a mean of 391 μM/min) and a 500% increase in AUC in man (from a mean of 142 μM/min to a mean of 716 μM/min). In contrast, allopurinol pretreatment had no effect on the kinetics of intravenous 6‐MP. This difference was found to be due to inhibition of first‐pass metabolism of oral 6‐MP as the result of the action of allopurinol on liver or intestinal xanthine oxidase. Our results indicate that, although dose reduction of oral 6‐MP given in conjunction with allopurinol is appropriate, it is not necessary when 6‐MP is injected intravenously.

Clinical Pharmacokinetics of Suramin in Patients With HTLV-III/LAV Infection

Suramin has been reported to inhibit the reverse transcriptase activity of a number of retroviruses and to reduce the in vitro infectivity and cytopathic effect of HTLV‐III/LAV, the etiologic agent of acquired immune deficiency syndrome (AIDS). The clinical pharmacokinetics of suramin were investigated as part of a pilot study to evaluate the safety and efficacy of this drug for the treatment of patients with diseases caused by HTLV‐III/LAV. A dose of suramin 6.2 g was given intravenously over a five‐week period to four patients. After the last dose, the plasma half‐life of suramin was 44 to 54 days. This is among the longest half‐lives reported for any therapeutic substance given to humans. Total plasma levels of suramin were greater than 100 μg/mL for several weeks. In vitro activity of suramin was found at concentrations as low as 50 μg/mL. Metabolites were not found in plasma, and urinary excretion accounts for elimination of most of the drug. Suramin is approximately 99.7% bound to plasma proteins. The results from these initial clinical pharmacokinetic studies might assist the design of further therapeutic trials of suramin, especially the selection of frequency of dosing and adjustments for renal impairment.

Pharmacogenetics and Pharmacogenomics in Drug Development and Regulatory Decision Making: Report of the First FDA‐PWG‐PhRMA‐DruSafe Workshop

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory “safe harbor” for exploratory genome‐based data, and to provide a forum for industry‐regulatory agency dialogue on these important issues.