Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: a proof-of-mechanism study.

In this multicenter, double-blind, placebo-controlled, randomized, four way cross-over proof-of-mechanism study, we tested the effect of the positive allosteric α7 nicotinic acetylcholine receptor (nAChR) modulator JNJ-39393406 in a key translational assay (sensory P50 gating) in 39 regularly smoking male patients with schizophrenia. All patients were clinically stable and JNJ-39393406 was administered as an adjunct treatment to antipsychotics. No indication was found that JNJ-39393406 has the potential to reverse basic deficits of information processing in schizophrenia (sensory P50 gating) or has a significant effect on other tested electrophysiological markers (MMN, P300 and quantitative resting EEG). Sensitivity analyses including severity of disease, baseline P50 gating, medication and gene variants of the CHRNA7 gene did not reveal any subgroups with consistent significant effects. It is discussed that potential positive effects in subgroups not present or not large enough in the current study or upon chronic dosing are possible, but unlikely to be developed. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Prospective-retrospective biomarker analysis for regulatory consideration: white paper from the industry pharmacogenomics working group.

One approach to delivering cost-effective healthcare requires the identification of patients as individuals or subpopulations that are more likely to respond to an appropriate dose and/or schedule of a therapeutic agent, or as subpopulations that are less likely to develop an adverse event (i.e., personalized or stratified medicine). Biomarkers that identify therapeutically relevant variations in human biology are often only uncovered in the later stage of drug development. In this article, the Industry Pharmacogenomics Working Group provides, for regulatory consideration, its perspective on the rationale for the conduct of what is commonly referred to as the prospective-retrospective analysis (PRA) of biomarkers. Reflecting on published proposals and materials presented by the US FDA, a decision tree for generating robust scientific data from samples collected from an already conducted trial to allow PRA is presented. The primary utility of the PRA is to define a process that provides robust scientific evidence for decision-making in situations where it is not necessary, nor practical or ethical to conduct a new prospective clinical study.

Patterns of dioxin-altered mRNA expression in livers of dioxin-sensitive versus dioxin-resistant rats.

Dioxins exert their major toxicologic effects by binding to the aryl hydrocarbon receptor (AHR) and altering gene transcription. Numerous dioxin-responsive genes previously were identified both by conventional biochemical and molecular techniques and by recent mRNA expression microarray studies. However, of the large set of dioxin-responsive genes the specific genes whose dysregulation leads to death remain unknown. To identify specific genes that may be involved in dioxin lethality we compared changes in liver mRNA levels following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in three strains/lines of dioxin-sensitive rats with changes in three dioxin-resistant rat strains/lines. The three dioxin-resistant strains/lines all harbor a large deletion in the transactivation domain of the aryl hydrocarbon receptor (AHR). Despite this deletion, many genes exhibited a "Type-I" response-that is, their responses were similar in dioxin-sensitive and dioxin-resistant rats. Several genes that previously were well established as being dioxin-responsive or under AHR regulation emerged as Type-I responses (e.g. CYP1A1, CYP1A2, CYP1B1 and Gsta3). In contrast, a relatively small number of genes exhibited a Type-II response-defined as a difference in responsiveness between dioxin-sensitive and dioxin-resistant rat strains. Type-II genes include: malic enzyme 1, ubiquitin C, cathepsin L, S-adenosylhomocysteine hydrolase and ferritin light chain 1. In silico searches revealed that AH response elements are conserved in the 5'-flanking regions of several genes that respond to TCDD in both the Type-I and Type-II categories. The vast majority of changes in mRNA levels in response to 100 microg/kg TCDD were strain-specific; over 75% of the dioxin-responsive clones were affected in only one of the six strains/lines. Selected genes were assessed by quantitative RT-PCR in dose-response and time-course experiments and responses of some genes were assessed in Ahr-null mice to determine if their response was AHR-dependent. Type-II genes may lie in pathways that are central to the difference in susceptibility to TCDD lethality in this animal model.

Effect of CYP2D6 genetic polymorphism on the population pharmacokinetics of tipifarnib.

OBJECTIVE: Evaluate the effect of CYP2D6 genotype on the pharmacokinetics of tipifarnib. METHODS: A total of 268 subjects included in six clinical trials were treated orally with tablet formulation of tipifarnib, as a single dose or as multiple b.i.d. doses (range 50-600 mg), and/or intravenously following 1, 2, and 24 h infusions. A total of 2,575 tipifarnib concentrations were fitted to an open three-compartment linear disposition model with sequential zero-order input into the depot compartment, followed by a first-order absorption process, and lag time, using NONMEM V. The effect of CYP2D6 genotype was explored as a covariate for tipifarnib systemic clearance and absolute bioavailability. Likelihood ratio test was used to compare these parameters in homozygous extensive metabolizers (EM) (N=152), heterozygous EM (N=97), or poor metabolizers (PM) (N=19). Computer simulations were undertaken to explore the CYP2D6 genotype effect on the tipifarnib pharmacokinetics. RESULTS: The ratio of tipifarnib systemic clearance for the heterozygous EM and the PM subjects, relative to the homozygous EM group, were 0.95 (95%CI 0.87-1.03) and 0.96 (95%CI 0.82-1.11), respectively (chi2=2.376, df=2, P=0.305). The ratio of tipifarnib absolute bioavailability for the heterozygous EM and the PM, relative to the homozygous EM, were 1.06 (95%CI 0.83-1.30) and 0.95 (95%CI 0.55-1.34), respectively (chi2=1.398, df=2, P=0.497). CONCLUSIONS: These results indicate that CYP2D6 genetic polymorphism does not appreciably influence the pharmacokinetics of tipifarnib. Hence, concomitant administration of potent CYP2D6 inhibitors is anticipated to have little or no significant impact on the systemic exposure to tipifarnib.