David A. Katz

Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics

Our objective was to learn whether genetic polymorphisms of metabolic enzymes or transport proteins provide a mechanistic understanding of the in vivo disposition of atrasentan, a selective endothelin A receptor antagonist.

PhRMA White Paper on ADME Pharmacogenomics

Pharmacogenomic (PGx) research on the absorption, distribution, metabolism, and excretion (ADME) properties of drugs has begun to have impact for both drug development and utilization. To provide a cross‐industry perspective on the utility of ADME PGx, the Pharmaceutical Research and Manufacturers of America (PhRMA) conducted a survey of major pharmaceutical companies on their PGx practices and applications during 2003–2005. This white paper summarizes and interprets the results of the survey, highlights the contributions and applications of PGx by industrial scientists as reflected by original research publications, and discusses changes in drug labels that improve drug utilization by inclusion of PGx information. In addition, the paper includes a brief review on the clinically relevant genetic variants of drug‐metabolizing enzymes and transporters most relevant to the pharmaceutical industry.

Blockade of [11C](+)-PHNO binding in human subjects by the dopamine D3 receptor antagonist ABT-925

Dopamine D3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [11C](+)-PHNO is the first preferential D3 receptor radioligand in humans, yet there are no blockade studies with a D3 receptor antagonist in humans. This study characterized the blockade of [11C](+)-PHNO binding by ABT-925, a D3 receptor antagonist, in healthy male subjects. Sixteen subjects underwent 2-3 positron emission tomography (PET) scans, at baseline and following one or two doses of ABT-925 ranging from 50 mg to 600 mg. Receptor occupancies were estimated for globus pallidus, substantia nigra, caudate, putamen, and ventral striatum. At the 600-mg dose (n=9), ABT-925 receptor occupancy (mean+/-s.d.) was higher in substantia nigra (75+/-10%) and globus pallidus (64+/-22%) than in ventral striatum (44+/-17%), caudate (40+/-18%) and putamen (38+/-17%) (ANOVA: F4,140=15.02, p<0.001). The fractions of [11C](+)-PHNO binding attributable to D3 receptors in D3 receptor-rich regions were 100% (substantia nigra) and 90% (globus pallidus), and in D2 receptor-rich regions were 55% (caudate) and 53% (putamen). The ED50 of ABT-925 was 4.37 microg/ml across regions. Our results demonstrate that [11C](+)-PHNO binding can be blocked by a D3 receptor antagonist and confirm preclinical findings that [11C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D3 receptors. Thus, [11C](+)-PHNO seems a suitable PET radiotracer to estimate D3 receptor occupancy in humans.

Defining drug disposition determinants: a pharmacogenetic–pharmacokinetic strategy

In preclinical and early clinical drug development, information about the factors influencing drug disposition is used to predict drug interaction potential, estimate and understand population pharmacokinetic variability, and select doses for clinical trials. However, both in vitro drug metabolism studies and pharmacogenetic association studies on human pharmacokinetic parameters have focused on a limited subset of the proteins involved in drug disposition. Furthermore, there has been a one-way information flow, solely using results of in vitro studies to select candidate genes for pharmacogenetic studies. Here, we propose a two-way pharmacogenetic–pharmacokinetic strategy that exploits the dramatic recent expansion in knowledge of functional genetic variation in proteins that influence drug disposition, and discuss how it could improve drug development.

A Double-Blind, Randomized, Placebo-Controlled Study of the Dopamine D3 Receptor Antagonist ABT-925 in Patients With Acute Schizophrenia

There is substantial preclinical and clinical evidence to suggest a potential role for the dopamine D3 receptor in the treatment of schizophrenia. ABT-925 is a selective dopamine D3 receptor antagonist with an approximately 100-fold higher in vitro affinity for dopamine D3 versus D2 receptors. This double-blind, randomized, placebo-controlled, escalating-dose, parallel-group study assessed the efficacy and safety of ABT-925 in the treatment of patients with acute exacerbation of schizophrenia. One hundred fifty-five patients were assessed over a 6-week double-blind treatment period (placebo: n = 48; ABT-925 50 mg once daily [QD]: n = 53; ABT-925 150 mg QD: n = 54). The primary efficacy measure was mean change from baseline to final evaluation on the Positive and Negative Syndrome Scale total score. Secondary measures of efficacy and pharmacokinetic parameters were also assessed. Safety assessments included adverse event monitoring, laboratory tests, vital signs, movement rating scales, and electrocardiogram measures. No statistically significant treatment effect was observed with ABT-925 50 mg QD or 150 mg QD compared with placebo on primary or secondary efficacy end points. Pharmacokinetic parameter estimates increased with dose in a linear fashion. ABT-925 50 mg QD and 150 mg QD were generally well tolerated, with adverse event profiles similar to that of placebo. Findings from a concurrent positron emission tomography study among healthy volunteers suggest that the ABT-925 doses used in this study may not have been sufficient to adequately occupy D3 receptors, thereby underscoring the importance of pharmacodynamic markers, such as PET, in determining appropriate compound doses before embarking on studies in a target population.

Dual Effects of Rifampin on the Pharmacokinetics of Atrasentan

The effect of rifampin, a cytochrome P450 3A4 inducer, on the pharmacokinetics of atrasentan was assessed in 12 healthy male subjects in an open‐label study. Single doses of atrasentan 10 mg were administered orally on days 1 and 12. Rifampin 600 mg was given once daily from days 4 through 14. On day 12, atrasentan and rifampin were administered simultaneously. Blood samples were collected before and during 72 hours after each atrasentan dose. On average, rifampin increased atrasentan peak plasma concentrations by 150% and reduced its terminal half‐life by 77% (P < .05), without affecting the AUC or peak time of atrasentan. Rifampin may affect atrasentan pharmacokinetics by acting as both an inhibitor of organic anion transporting polypeptide‐mediated hepatic uptake of atrasentan and an inducer of atrasentan metabolism. The effect of rifampin on atrasentan pharmacokinetics may depend on the time of rifampin administration relative to that of atrasentan.

Efficacy and safety evaluation of HSD-1 inhibitor ABT-384 in Alzheimer's disease

In this study we assessed increased cortisol in Alzheimers disease (AD) patients. The selective 11‐β‐hydroxysteroid dehydrogenase type 1 (HSD‐1) inhibitor ABT‐384 blocked regeneration of active cortisol and this tests the hypothesis that intracellular hypercortisolism contributes to cognitive impairment.

Clinical Safety, Pharmacokinetics, and Pharmacodynamics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor ABT-384 in Healthy Volunteers and Elderly Adults.

ABT‐384 is a potent and selective inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 (HSD‐1), the enzyme that regenerates cortisol in several tissues. Two clinical studies of ABT‐384 were undertaken to assess its safety, pharmacokinetics, target engagement, and pharmacologic effects in healthy subjects. Single doses from 1 to 240 mg, and multiple doses from 1 to 100 mg once daily for 7–14 days, were administered to healthy adults. Multiple doses from 10 to 100 mg once daily for 21 days were administered to elderly subjects. A total of 103 subjects received at least 1 dose of ABT‐384. A maximum‐tolerated dose was not defined in either study. The pharmacokinetic profiles of ABT‐384 and its active metabolite support once daily dosing. Analysis of urine cortisol metabolites demonstrated full hepatic HSD‐1 inhibition with regimens from 1 mg daily, and confirmed in vitro target selectivity. Pharmacologic effects included increases of adrenocorticotrophic hormone levels, cortisol production and androgen and estradiol levels. ABT‐384 has a wide therapeutic index relative to full hepatic target engagement which is relevant for indications such as diabetes and metabolic syndrome. Its therapeutic index for other potential indications such as Alzheimers disease remains to be established.

Overview of Pharmacogenetics

Pharmacogenetics is the study of relationships between genetic variation and inter‐individual differences with respect to drug response. As the field has matured over the past 15 years, a remarkable diversity of pathways, variation types, and mechanisms have been found to be relevant pharmacogenetic factors. Today, pharmacogenetics is becoming more important in pharmacology for target validation, lead optimization, and understanding of idiosyncratic toxicity. This unit provides an overview of the history of pharmacogenetics and current research applications in drug discovery, as well as a discussion of research quality issues relevant for human subjects research in the pharmacogenetics laboratory. Curr. Protoc. Hum. Genet. 60:9.19.1‐9.19.23.

Evidence for epistasis between SLC6A4 and a chromosome 4 gene as risk factors in major depression

Linkage analysis on Utah pedigrees with strong family histories of major depression including only cases with the SLC6A4 HTTLPR short allele revealed a linkage peak on chromosome 4 (maximum HLOD = 3.5). This evidence suggests epistasis between SLC6A4 and an unknown gene as risk factors for major depression.