RIDER: leading the way for the development of change-analysis software
Early and accurate determination of tumor response is required for clinical evaluation of effective novel therapies for lung cancer. The current approach to approving lung cancer therapies is based on patient survival compared against a "best therapy" standard in a randomized controlled study, an approach that withholds access to potentially useful agents from the general population. Armato et al. discuss the Reference Image Database to Evaluate Response (RIDER) project and its goal of developing a consensus approach to optimizing and benchmarking software tools for the assessment of tumor response to therapy and how it will reduce sources of uncertainty in vital clinical decisions. See page 448
The effect of ABCB1 haplotypes on simvastatin and atorvastatin
Although ABCB1 is associated with the efficacy of simvastatin and atorvastatin, whether the ABCB1 haplotypes affect their pharmacokinetics remains unclear. Keskitalo et al. investigate the frequencies of ABCB1 single-nucleotide polymorphisms in the Finnish population and compare the effects of haplotypes c.1236C-c.2677G-c.3435C (CGC) and c.1236T-c.2677T-c.3435T (TTT) on the pharmacokinetics of simvastatin and atorvastatin. Their findings indicate that the pharmacokinetics of statins in humans can be significantly affected by ABCB1 haplotypes. See page 457
Effect of moxifloxacin on QTc
Several concerns with the design of thorough QT-interval studies remain to be addressed. Drug-induced prolongation of the QT interval associated with torsade de pointes has resulted in the withdrawal or restriction of the use of several drugs. Bloomfield and coauthors use a randomized, placebo-controlled, two-period crossover study to analyze within-subject variability of QTc intervals. Moxifloxacin 400 mg was found to be associated with an increase of 7.5–12.5 ms in the mean placebo- and baseline-corrected QTc interval, supporting moxifloxacin as a positive control in thorough QT studies. See page 475
Methadone pharmacokinetics and pharmacodynamics
Methadone is a widely used treatment for drug addiction and for acute and chronic pain, but an increasing number of fatalities have resulted from its poorly understood kinetics. Similarly, although ritonavir is the most widely used HIV/AIDS drug, the mechanism by which it decreases methadone plasma concentrations has not been identified. Kharasch et al. investigate the short-term and steady-state effects of ritonavir on intravenous methadone disposition; concurrent intravenous and oral methadone disposition; the metabolism, renal excretion, and pharmacodynamics of methadone; first-pass P-glycoprotein activity; and both hepatic and first-pass CYP3A activity. The authors report findings that will have broad implications for dosing guidelines and drug labels for both methadone and ritonavir. See pages 497 and 506
Improving understanding of lung cancer response to treatment
In contrast to that of many other types of cancer, the survival rate for lung cancer patients has barely improved over the past 30 years; it remains steady at about 15%. Although early detection of lung nodules has been made possible by the development of imaging technologies such as multi-row detector computerized tomography (MDCT), only a small portion of these nodules are lung cancer. The delay between detection and diagnosis, known as the lung cancer paradox, requires MDCT observation over a period of months to assess potential nodule growth. New methods to advance understanding of lung cancer biomass are slowly emerging and being implemented in the clinical setting. See page 517
