Parameter Estimation and Reporting in Noncompartmental Analysis of Clinical Pharmacokinetic Data.

The noncompartmental analysis (NCA) of pharmacokinetic (PK) data is important throughout all phases of clinical drug development. Although there are numerous regulatory guidances and articles in the literature concerned with best practices for the modeling of PK data, there are relatively few sources of information on how to conduct a high-quality NCA. This article provides a systematic review of issues related to the estimation of plasma and urine PK parameters with the intent of encouraging rigor in the performance of NCAs so as to provide reliable and informative analysis results.

Criteria for reporting noncompartmental estimates of half-life and area under the curve extrapolated to infinity.

Various criteria have been proposed for determining the reliability of noncompartmental pharmacokinetic estimates of the terminal disposition phase half-life (t ) and the extrapolated area under the curve (AUC ). This simulation study assessed the performance of two frequently used reportability rules: the terminal disposition phase regression adjusted-r classification rule and the regression data point time span classification rule. Using simulated data, these rules were assessed in relation to the magnitude of the variability in the terminal disposition phase slope, the length of the terminal disposition phase captured in the concentration-time profile (data span), the number of data points present in the terminal disposition phase, and the type and level of variability in concentration measurement.

Performance characteristics of the adjusted r algorithm for determining the start of the terminal disposition phase and comparison with a simple r algorithm and a visual inspection method.

The adjusted r algorithm is a popular automated method for selecting the start time of the terminal disposition phase (t ) when conducting a noncompartmental pharmacokinetic data analysis. Using simulated data, the performance of the algorithm was assessed in relation to the ratio of the slopes of the preterminal and terminal disposition phases, the point of intercept of the terminal disposition phase with the preterminal disposition phase, the length of the terminal disposition phase captured in the concentration-time profile, the number of data points present in the terminal disposition phase, and the level of variability in concentration measurement. The adjusted r algorithm was unable to identify t accurately when there were more than three data points present in a profile's terminal disposition phase.

Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer.

Tremelimumab (CP-675,206) is a fully human monoclonal antibody specific for human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) in clinical development for patients with cancer. Blocking the CTLA-4 negative costimulatory receptor with the antagonistic antibody tremelimumab results in immune activation. Administration of tremelimumab to patients with locally advanced and metastatic melanoma has resulted in a subset of patients with durable objective tumor regressions.

A phase I open label study of the farnesyltransferase inhibitor CP-609,754 in patients with advanced malignant tumors.

Purpose: The purpose of this phase I clinical trial was to determine the maximum-tolerated dose and toxicity of CP-609,754 in patients with solid tumors refractory to standard therapies, to determine the cellular effects of CP-609,754 on its molecular target (farnesyltransferase), and to determine the recommended phase II dose (RP2D) of this agent.

Experimental Design: Consenting patients with adequate bone marrow, liver, and renal function were enrolled with an accelerated dose strategy with single-patient parallel cohorts in whom the drug was given orally either once or twice daily. Once a dose-limiting toxicity was encountered or two patients developed Common Toxicity Criteria > or = grade 2 toxicities, a modified Fibonacci sequence was initiated.

A phase I and pharmacologic study of pyrazoloacridine and cisplatin in patients with advanced cancer.

Pyrazoloacridine (PZA, NSC366140, PD115934) is an acridine derivative currently undergoing clinical evaluation. In preclinical testing, PZA has shown selectivity for solid tumor cell lines, activity in hypoxic, noncycling, and multidrug-resistant cell lines, and synergy with cisplatin in a variety of lung cancer cell lines. In early phase I clinical studies PZA has shown modest activity in ovarian, cervical, and colon cancer.

A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus autoantigen.

Antibodies against a conserved RNA-binding protein, the Ro 60-kDa autoantigen, occur in 24-60% of all patients with systemic lupus erythematosus. Anti-Ro antibodies are correlated with photosensitivity and cutaneous lesions in these patients and with neonatal lupus, a syndrome in which mothers with anti-Ro antibodies give birth to children with complete congenital heart block and photosensitive skin lesions. In higher eukaryotes, the Ro protein binds small RNAs of unknown function known as Y RNAs.