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This study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to

Keywords: Pharmacogenomics; ADME; PhRMA; drug-metabolizing enzymes; genotyping 849 PharmacogenomicsPhRMA White Paper on ADME Pharmacogenomics SAGE Publications, Inc.200810.1177/0091270008319329 J. AndrewWilliams PhD Pfizer Global Research and Development, San Diego, California, james.williams2@pfizer.com TommyAndersson [...]

ABT-578, a sirolimus analog, is being developed for administration from drug-eluting stents to prevent postimplantation neointimal hyperplasia. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics [...]

First-degree relatives of African-Americans with Alzheimer's disease have a higher risk of developing the disease than first-degree relative of whites but the reasons for this are not clear. Female sex and the presence of the apolipoprotein E epsilon 4 gene also increased the risk in both whites and African-Americans., Context Evidence exists that the incidence of Alzheimer disease (AD), as well as risk attributable to specific genetic factors such as apolipoprotein E(APOE) genotype, may vary considerably among ethnic groups. Family studies of probands with AD offer an opportunity to evaluate lifetime risk of dementia among relatives of these probands. Objective To compare lifetime dementia risk estimates among relatives of white and African American probands with probable or definite AD. Design and Setting Risk analysis using data collected by questionnaire and supplemental records between May 1991 and March 2001 at 17 medical centers contributing to the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study. Participants A total of 17639 first-degree biological relatives and 2474 spouses of 2339 white AD probands, and 2281 first-degree biological relatives and 257 spouses of 255 African American AD probands. Main Outcome Measures Cumulative risk of dementia by age 85 years, stratified by ethnicity and sex of relatives and by APOE genotype of probands. Results Cumulative risk of dementia in first-degree biological relatives of African American AD probands by age 85 years was 43.7% (SE, 3.1%), and the corresponding risk in first-degree biological relatives of white AD probands was 26.9% (SE, 0.8%), yielding a relative risk (RR) of 1.6(95% confidence interval [Cl], 1.4-1.9; P Conclusion First-degree relatives of African Americans with AD have a higher cumulative risk of dementia than do those of whites with AD. However, in this study, the additional risk of dementia conferred by being a first-degree relative, by being female, or by the probability of having an APOE [epsilon]4 allele appeared similar in African American and white families. These data provide estimates of dementia risk that can be used to offer counseling to family members of patients with AD.

1. The present study was designed to determine the effects of ginkgolide A, ginkgolide B and quercetin on CYP3A protein expression and enzyme activity in primary cultures of human hepatocytes. 2. Hepatocytes were pretreated with ginkgolide A, ginkgolide B and quercetin (at 1, 3, 10 and 30 µmol/L) for 48 h and then exposed to testosterone (250 µmol/L) for 30 min. Rifampin (10 µmol/L) and phenobarbital (2 mmol/L) were used as positive controls. The CYP3A activity was measured by the amount of 6β-hydroxytestosterone in the culture medium and CYP3A protein in hepatocyte lysate was semiquantified by immunoblotting. 3. Compared with the vehicle control, ginkgolides A and B, at 30 µmol/L, significantly induced CYP3A protein expression (2.1- and 2-fold, respectively; both P < 0.01) and markedly induced CYP3A-mediated testosterone 6β-hydroxylation (2.5-fold each; P < 0.05 for ginkgolide A; P > 0.05 for ginkgolide B). Quercetin had no apparent induction. 4. Ginkgolide A and ginkgolide B can induce CYP3A protein expression and enzyme activity in primary cultures of human hepatocytes at higher doses. [ABSTRACT FROM AUTHOR]

Objective: 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.Methods: Atrasentan uptake was measured in HeLa cells transfected to express major alleles of organic anion transporting polypeptide 1B1 (OATP1B1). The results were used to classify individuals as extensive, intermediate, or poor OATP1B1 transporters according to their SLCO1B1 genotypes. Analysis of covariance including genotype, study, age, weight, sex, and ethnicity was used to identify factors influencing atrasentan single-dose (n = 44) and steady-state (n = 38) pharmacokinetic parameters. Genotypes for cytochrome P450 3A5, uridine diphosphate–glucuronosyltransferase (UGT) 1A1, UGT2B4, UGT2B15, adenosine triphosphate–binding cassette subfamily B (ABCB) 1, solute carrier organic anion transporter (SLCO) 1B1, and solute carrier family 22 (SLC22) A2 were each assessed.Results: Single-dose atrasentan exposure (P = .0244), steady-state atrasentan exposure (P = .0108), and maximum postdose plasma concentration (P = .0002) were associated with OATP1B1 activity classified by SLCO1B1 genotype. No other tested genotypes were observed to be associated with both single-dose and steady-state atrasentan pharmacokinetics.Conclusions: OATP1B1 is a meaningful factor for atrasentan disposition. Individuals may be classified as having extensive, intermediate, or poor OATP1B1 transport phenotypes according to SLCO1B1 genotypes. Increased exposures of OATP1B1 substrates might be expected in individuals who have the poor transporter phenotype or are treated with an OATP1B1 inhibitor.Clinical Pharmacology & Therapeutics (2006) 79, 186–196; doi: 10.1016/j.clpt.2005.11.003 [ABSTRACT FROM AUTHOR]

Objective: To screen the inhibitory effects of H1-antihistamines on hepatic bufuralol 1′-hydroxylation and on tolbutamide 4-methylhydroxylation in human liver microsomes. Methods: Bufuralol 1′-hydroxylation and tolbutamide 4-methylhydroxylation were used as index reactions for CYP2D6 and CYP2C9, respectively. The metabolites of both reactions were measured using high-performance liquid chromatography and were used as indicators of whether CYP2D6 or CYP2C9 activities were inhibited or unaffected by the agents. Results: All five H1-antihistamines studied showed a concentration-dependent inhibition of CYP2D6-mediated bufuralol 1′-hydroxylation with 50% inhibitory concentration (IC50) values of 32–109 µM. Cyclizine and promethazine showed inhibitory effects on tolbutamide 4-methylhydroxylation with IC20 values of 85 µM and 88 µM, respectively. Tripelennamine, chlorpheniramine, and diphenhydramine showed no inhibitory effects on CYP2C9. Conclusion: All five H1-antihistamines studied inhibited CYP2D6 markedly, but only cyclizine and promethazine inhibited CYP2C9 at concentrations above that usually seen in plasma. Promethazine and chlorpheniramine inhibited CYP2D6 at concentrations that are very close to their therapeutic plasma concentrations. Further studies in humans, especially in poor metabolizers of CYP2D6, will be required to confirm these findings. [ABSTRACT FROM AUTHOR]

1. The effects of four individual ginsenosides (Rb1, Rb2, Rc and Rd), two ginkgolides (A and B) and one flavonoid (quercetin) on CYP2C19-dependent S-mephenytoin 4'-hydroxylation and CYP2D6-mediated bufuralol 1'-hydroxylation were evaluated in human liver microsomes. 2. Increasing concentrations of each test compound were added to microsomal incubation mixtures containing a well-characterized marker substrate ( S-mephenytoin for CYP2C19 or bufuralol for CYP2D6) to determine their IC50 values (compound concentration yielding 50% inhibition of a marker enzyme activity), which were estimated by graphical inspection. 3. For CYP2C19, the IC50 values were 46, 46 and 62 mmol/L for ginsenoside Rd, quercetin and ginsenoside Rb2, respectively, whereas only ginsenoside Rd had an IC50 value of 57 mmol/L for CYP2D6. 4. The data suggest that the tested compounds are not likely to inhibit the metabolism of the concurrent use of a given drug whose primary route of elimination is through CYP2C19 or CYP2D6. [ABSTRACT FROM AUTHOR]

A 40-year-old black male with scleroderma lung disease presented with blurry vision and headache. His presenting hemoglobin was 22.3 g/dL and his serum erythropoietin level was surprisingly low. Although nocturnal hypoxemia was evident, his daytime resting arterial oxygen saturation was normal. The patient's symptoms of hyperviscosity improved after phlebotomy, as his hemoglobin gradually decreased to 18.3 g/dL. Repeat serum erythropoietin levels were in normal and high ranges. Patients with chronic interstitial lung disease and erythrocytosis could have normoxemia at rest and a normal or low serum erythropoietin level at the peak of erythrocytosis. A repeat sampling of serum erythropoietin and monitoring of oxygen saturation during sleep and exertion may help in diagnosis. Physicians should prescribe continuous oxygen therapy for patients with chronic interstitial lung disease and erythrocytosis, even if diurnal resting hypoxemia is absent. [ABSTRACT FROM AUTHOR]