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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 of multiple doses of ABT-578. Healthy subjects randomly received placebo or ABT-578 (200, 400, or 800 microg) as daily intravenous infusions for 14 days. ABT-578 blood pharmacokinetics and urine excretion on days 1 and 14 were determined. The effect of ABT-578 on mitogen-stimulated lymphocyte proliferation was assessed. ABT-578 pharmacokinetics was described by a 3-compartment open model. The mean CL, V(ss), and t(1/2) ranges were 4.0 to 4.6 L/h, 92.5 to 118.0 L, and 24.7 to 31.0 hours, respectively. ABT-578 pharmacokinetics was dose and time invariant. Approximately 0.1% of ABT-578 was excreted in the urine. ABT-578 was well tolerated, and no systemic changes were observed in the mitogen-stimulated lymphocyte proliferation. ABT-578 was shown to be safe over a wide range of systemic exposures. [ABSTRACT FROM AUTHOR]

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 <18 years; cohort 2, ≥6 to <12 years; cohort 3, ≥2 to <6 years; cohort 4, ≥3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [≥40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0-∞) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.)., (Copyright © 2016 Bradley et al.)

Background: Avibactam is a non-β-lactam β-lactamase inhibitor that restores the in vitro activity of β-lactams, such as ceftazidime, against bacterial pathogens harboring Ambler class A, C, and some class D β-lactamases., Objective: This randomized, double-blind, placebo-controlled, phase I study (NCT01920399) evaluated the safety, tolerability, and pharmacokinetics of single and repeated doses of avibactam and ceftazidime in healthy Chinese subjects., Methods: Sixteen healthy Chinese males aged 18-45 years were randomized 3:1 to receive 2000 mg ceftazidime and 500 mg avibactam (n = 12) or matched placebo (n = 4) as a 120-min intravenous infusion, once on Days 1 and 9, and every 8 h on Days 2-8., Results: Avibactam and ceftazidime showed time-independent pharmacokinetics. Plasma exposure to avibactam and ceftazidime was similar following single and multiple dosing and accumulation of either agent was negligible. The majority of the avibactam and ceftazidime dose was recovered in urine. Adverse events were reported in three subjects (25.0%) in the ceftazidime-avibactam group and one subject (25.0%) in the placebo group. Two subjects in the ceftazidime-avibactam group had elevations in transaminases and one subject in the placebo group had elevated serum bilirubin levels that were considered causally related to study treatment. All adverse events were of mild intensity., Conclusions: Single and multiple doses of 2000 mg ceftazidime and 500 mg avibactam were well tolerated in healthy Chinese subjects, and the observed pharmacokinetics were comparable to previous studies conducted in Western subjects.

For patients with normal renal function, the recommended ceftaroline fosamil dose is a 600 mg 1-h intravenous (i.v.) infusion every 12 h (q12h). In patients with a creatinine clearance of ≤30 mL/min, including those with end-stage renal disease (ESRD), the recommended dose is a 200 mg 1-h i.v. infusion q12h. This phase 1 study (NCT01664065) evaluated the pharmacokinetics, safety and tolerability of ceftaroline fosamil 200 mg 1-h i.v. infusion in patients with ESRD. Patients with ESRD (n=8) participated in two treatment periods (ceftaroline fosamil 200 mg administered pre- and post-haemodialysis) separated by >1 week. Healthy volunteers (n=7) received a single 600 mg dose of ceftaroline fosamil. Blood (pre- and post-haemodialysis) and dialysate samples were obtained for pharmacokinetic analysis. In patients with ESRD, the geometric mean [coefficient of variation (%CV)] plasma ceftaroline area under the plasma concentration-time curve from zero to infinity (AUC0-∞) following post-haemodialysis ceftaroline fosamil 200 mg infusion was 64.8 (38.9)μg·h/mL, similar to that in volunteers following a 600 mg infusion [62.7 (9.4)μg·h/mL]. Ceftaroline AUC0-∞ decreased by ca. 50% when infusion was initiated pre-haemodialysis. In the pre-haemodialysis treatment period, 80% of the ceftaroline fosamil dose was recovered in dialysate as ceftaroline (73%) and ceftaroline M-1 (7%). The frequency of adverse events was similar across patients with ESRD (pre- and post-haemodialysis) and volunteers (43%, 50% and 43% of subjects, respectively). Ceftaroline fosamil 200 mg 1-h i.v. infusion q12h, administered post-haemodialysis on dialysis days, is an appropriate dosage regimen for ESRD patients., (Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Objectives: The aim of this Phase 1, open-label study (NCT01395420) was to measure and compare concentrations of ceftazidime and avibactam in bronchial epithelial lining fluid (ELF) and plasma, following administration of two different dosing regimens in healthy subjects., Patients and Methods: Healthy volunteers received 2000 mg of ceftazidime + 500 mg of avibactam (n = 22) or 3000 mg of ceftazidime + 1000 mg of avibactam (n = 21), administered intravenously every 8 h for 3 days (total of nine doses). Bronchoscopy with bronchoalveolar lavage was performed once per subject, 2, 4, 6 or 8 h after the last infusion. Pharmacokinetic parameters were estimated from individual plasma concentrations and the composite ELF concentration-time profile. Safety was assessed., Results: Forty-three subjects received treatment (2000 mg of ceftazidime + 500 mg of avibactam, n = 22; 3000 mg of ceftazidime + 1000 mg of avibactam, n = 21). Plasma and ELF concentrations increased dose-proportionally for both drugs, with 1.5- and 2-fold increases in AUCτ, for respective components. Ceftazidime Cmax and AUCτ in ELF were ∼ 23%-26% and 31%-32% of plasma exposure. Avibactam Cmax and AUCτ in ELF were ∼ 28%-35% and 32%-35% of plasma exposure. ELF and plasma elimination were similar for both drugs. No serious adverse events were observed., Conclusions: Both ceftazidime and avibactam penetrated dose-proportionally into ELF, with ELF exposure to both drugs ∼ 30% of plasma exposure., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We assessed pharmacokinetic and safety profiles of ceftazidime-avibactam administered ± metronidazole, and whether drug-drug interactions exist between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. The first study (NCT01430910) involved two cohorts of healthy subjects. Cohort 1 received ceftazidime-avibactam (2000-500 mg) as a single infusion or as multiple intravenous infusions over 11 days to evaluate ceftazidime-avibactam pharmacokinetics. Cohort 2 received ceftazidime, avibactam, or ceftazidime-avibactam over 4 days to assess drug-drug interaction between ceftazidime and avibactam. The second study (NCT01534247) assessed interaction between ceftazidime-avibactam and metronidazole in subjects receiving ceftazidime-avibactam (2000-500 mg), metronidazole (500 mg), or metronidazole followed by ceftazidime-avibactam over 4 days. In all studies, subjects received a single-dose on the first and final days, and multiple-doses every 8 h on intervening days. Concentration-time profiles for ceftazidime and avibactam administered as single- or multiple-doses separately or together with/without metronidazole were similar. There was no evidence of time-dependent pharmacokinetics or accumulation. In both interaction studies, 90% confidence intervals for geometric least squares mean ratios of area under the curve and maximum plasma concentrations for each drug were within the predefined interval (80-125%) indicating no drug-drug interaction between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. There were no safety concerns. In conclusion, pharmacokinetic parameters and safety of ceftazidime, avibactam, and metronidazole were similar after single and multiple doses with no observed drug-drug interaction between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole.

Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been shown to restore the in vitro activity of ceftazidime against pathogens producing Ambler class A, C, and some class D β-lactamases. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of avibactam alone or with ceftazidime in healthy Japanese subjects. In this Phase I, double-blind study (NCT01291602), 16 healthy Japanese males, mean age 28.8 years, were randomized in a 2:2:1 ratio to receive avibactam 500 mg (n = 6), ceftazidime 2000 mg plus avibactam 500 mg (n = 7), or placebo (n = 3), each administered as a 100 ml intravenous infusion over 2 h, once on Day 1, every 8 h on Days 3-6, and once on Day 7. There were no deaths or serious adverse events. Nine treatment-emergent adverse events were reported in three subjects in the avibactam group - including one elevation in transaminase levels, and three vital signs events (tachycardia, palpitations, and orthostatic hypotension) - and one in the ceftazidime-avibactam group. All events were considered mild. After single or multiple dosing, plasma concentrations of avibactam and ceftazidime declined in a multi-exponential manner. No plasma concentration accumulation was observed, and the majority of avibactam was excreted unchanged in urine within 24 h. No clinically relevant changes in intestinal bacterial flora were observed. In conclusion, avibactam alone and ceftazidime-avibactam were generally well tolerated in healthy male Japanese subjects, and avibactam pharmacokinetics were comparable whether administered alone or in combination with ceftazidime., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: Two phase I studies in healthy Chinese (NCT01458743) and Western (NCT01612507) subjects evaluated the pharmacokinetics (PK) and safety of single and multiple ceftaroline fosamil 600 mg infusions administered every 8 or 12 hours (q8h or q12h)., Methods: Each study enrolled subjects sequentially into 1 of 2 cohorts (cohort 1: 60-minute infusions; cohort 2: 120-minute infusions). All subjects in the Chinese (n = 26) study received open label ceftaroline fosamil; in the Western study, subjects (n = 41) in each cohort were randomized 3 : 1 to ceftaroline fosamil or placebo infusions. Single infusions were administered on days 1 and 8. On days 2 - 7 (3 - 7 for Chinese study, cohort 1) subjects received q12h or q8h infusions. Plasma and urine were collected on days 1 and 8 for PK analysis., Results: Ceftaroline PK was linear and time-independent following single and multiple doses of ceftaroline fosamil. The magnitude and timing of peak plasma concentrations of ceftaroline (active metabolite), ceftaroline fosamil (prodrug), and ceftaroline M-1 (inactive metabolite) varied according to the ceftaroline fosamil dosing schedule (q12h or q8h) and infusion duration (60 minutes or 120 minutes), but overall plasma ceftaroline exposures within the respective dosing intervals were broadly similar across cohorts. The most frequent adverse events were rash/drug eruption, most of which were of mild-moderate intensity and considered related to treatment., Conclusions: Ceftaroline PK was broadly similar in healthy Chinese and Western subjects receiving equivalent dose regimens. The tolerability profile of ceftaroline fosamil in Chinese and Western subjects was consistent with previous clinical trials.

Aims: The standard dose of ceftaroline fosamil for patients with normal renal function is 600 mg diluted in 250 ml by 60 min intravenous infusion every 12 h. This two part phase I trial (NCT01577589) assessed safety and local tolerability of multiple ceftaroline fosamil 50 ml and 250 ml infusions, and pharmacokinetics following single administrations of each infusion volume., Methods: Part A was a placebo-controlled, double-blind, multiple dose crossover study. Twenty-four healthy subjects were randomized to simultaneous, bilateral ceftaroline fosamil 600 mg and placebo infusions in each arm (50 ml then 250 ml or vice versa) every 12 h for 72 h, with a ≥ 4.5 day washout. Local tolerability was evaluated by the Visual Infusion Phlebitis scale, with scores ≥2 considered infusion site reactions (ISRs). Part B was an open label crossover study. Ten subjects were randomized to single 50 ml and 250 ml ceftaroline fosamil 600 mg infusions on days 1 and 3 (washout on day 2). Blood samples for pharmacokinetic analysis were taken over 24 h., Results: In part A, four subjects (16.7%) experienced ISRs, all of which were associated with placebo infusions. No ISRs were reported for either ceftaroline fosamil 50 ml or 250 ml. Plasma pharmacokinetics (ceftaroline fosamil, active ceftaroline and an inactive metabolite) were similar following single 50 ml and 250 ml infusions in part B., Conclusions: No new safety concerns were identified for ceftaroline fosamil 600 mg 50 ml compared with 250 ml. These findings suggest infusion volumes down to 50 ml may be used in patients with fluid intake restrictions., (© 2014 The British Pharmacological Society.)

Avibactam, a novel non-β-lactam β-lactamase inhibitor with activity against Ambler class A, class C, and some class D enzymes is being evaluated in combination with various β-lactam antibiotics to treat serious bacterial infections. The in vivo mass balance recovery and metabolite profile of [(14)C] avibactam (500 mg/1-h infusion) was assessed in six healthy male subjects, and a series of in vitro experiments evaluated the metabolism and drug-drug interaction potential of avibactam. In the mass balance study, measurement of plasma avibactam (using a validated liquid chromatography-tandem mass spectrometry method) and total radioactivity in plasma, whole blood, urine, and feces (using liquid scintillation counting) indicated that most of the avibactam was excreted unchanged in urine within 12 hours, with recovery complete (>97% of the administered dose) within 96 hours. Geometric mean avibactam renal clearance (158 ml/min) was greater than the product of unbound fraction of drug and glomerular filtration rate (109.5 ml/min), suggesting that active tubular secretion accounted for some renal elimination. There was no evidence of metabolism in plasma and urine, with unchanged avibactam the major component in both matrices. Avibactam demonstrated in vitro substrate potential for organic anion transporters 1 and 3 (OAT1 and OAT3) proteins expressed in human embryonic kidney 293 cells (Km > 1000 μM; >10-fold the Cmax of a therapeutic dose), which could account for the active tubular secretion observed in vivo. Avibactam uptake by OAT1 and OAT3 was inhibited by probenecid, a potent OAT1/OAT3 inhibitor. Avibactam did not interact with various other membrane transport proteins or cytochrome P450 enzymes in vitro, suggesting it has limited propensity for drug-drug interactions involving cytochrome P450 enzymes.

Potential effects of supratherapeutic doses of intravenous (IV) ceftazidime-avibactam and ceftaroline fosamil-avibactam on cardiac repolarization were assessed in a thorough QT/QTc study. This was a double-blind, randomized, placebo-controlled, four-period crossover Phase I study (NCT01290900) in healthy males (n = 51). Subjects received, in randomized order and separated by ≥3 days washout: single doses of IV ceftaroline fosamil 1,500 mg with avibactam 2,000 mg; IV ceftazidime 3,000 mg with avibactam 2,000 mg; oral moxifloxacin 400 mg (open-label positive control); and IV placebo (saline). Least square mean and two-sided 90% confidence intervals (CI) for change from baseline in Fridericia-corrected QT interval (ΔQTcF) for active treatments versus placebo were estimated at 10 time points over 24 hours. The upper bound of the two-sided 90% CI for placebo-corrected ΔQTcF did not exceed 10 milliseconds at any time point over 24 hours for ceftaroline fosamil-avibactam or ceftazidime-avibactam. The lower bound of the two-sided 90% CI for the difference between moxifloxacin and placebo in ΔQTcF over 1-4 hours was >5 milliseconds, confirming assay sensitivity. Pharmacokinetics results confirmed achievement of supratherapeutic plasma concentrations. No safety concerns were raised. In conclusion, supratherapeutic doses of ceftaroline fosamil-avibactam or ceftazidime-avibactam were not associated with QT/QTc prolongation in this study population., (© 2013, The American College of Clinical Pharmacology.)

Introduction: Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters., Methods: In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo., Results: Seventy patients received AZD9773 (n=47) or placebo (n=23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment., Conclusions: The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies.

The FDA guidance on exploratory IND studies is intended to enable sponsors to move ahead more efficiently with the development of promising candidates. A survey of PhRMA member companies was conducted in 2007 to obtain a cross-sectional industry perspective on the current and future utility of exploratory IND studies. About 56% of survey responders (9 companies of 16 survey responders) conducted or were planning to conduct clinical studies under exploratory INDs. The majority of microdosing studies are performed to characterize human pharmacokinetics or to examine target organ pharmacokinetics using PET imaging techniques. On the other hand, the majority of pharmacological end point studies conducted under exploratory IND are performed to determine whether the compound modulated its pharmacological target or to evaluate the degree of saturation of a target receptor. The present survey suggests that although the merits of exploratory INDs are still being debated, the diversity in the applications cited, the potential for early clinical guidance in decision making and the increasing pressure on containing drug development costs, suggest that the exploratory IND/CTA will be a valuable option with evolving and possibly more specific applications for the future.

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.

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 cent-hydroxylation and CYP2D6-mediated bufuralol 1 cent-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 IC(50) values (compound concentration yielding 50% inhibition of a marker enzyme activity), which were estimated by graphical inspection. 3. For CYP2C19, the IC(50) values were 46, 46 and 62 micromol/L for ginsenoside Rd, quercetin and ginsenoside Rb2, respectively, whereas only ginsenoside Rd had an IC(50) value of 57 micromol/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.

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.

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.

Objective: This study was conducted to evaluate the potential for pharmacokinetic interaction between fenofibrate and ezetimibe in healthy subjects., Methods: This was a Phase I, open-label, multiple-dose,3-period crossover study conducted in healthy adult men and women. Subjects received fenofibrate 145 mg alone, fenofibrate 145 mg with ezetimibe 10 mg, and ezetimibe 10 mg alone for 10 consecutive days, in an order determined by computerized randomization schedule. Blood samples were collected for up to 24 hours after dosing on study day 1 and up to 120 hours after dosing on study day 10 for determination of plasma concentrations of fenofibric acid, unconjugated (free) ezetimibe, and total (conjugated and unconjugated) ezetimibe using validated high-performance liquid chromatography methods with mass-spectrometric detection. Ezetimibe glucuronide concentrations were estimated by subtracting free ezetimibe concentrations from total ezetimibe concentrations., Results: Eighteen healthy adults (12 men, 6 women; 17 white, 1 black) were enrolled in the study. Their mean age was 43.4 years (range, 27-55 years), their mean weight 78.7 kg (range, 60-98 kg), and their mean height 174.9 cm (range, 156-194 cm). Coadministration of multiple doses of fenofibrate and ezetimibe produced no statistically significant effect on the pharmacokinetics of fenofibric acid but significantly increased exposures to total ezetimibe and ezetimibe glucuronide (P < 0.05). Using point estimates, co-administration of fenofibrate and ezetimibe increased AUC central values for total ezetimibe and ezetimibe glucuronide by 43% (90% CI, 29-59) and 49% (90% CI, 34-65), respectively., Conclusion: In these healthy volunteers, coadministration of multiple doses of fenofibrate and ezetimibe had no statistically significant effect on the pharmacokinetics of fenofibric acid but was associated with a significant increase in exposure to total ezetimibe and its metabolite ezetimibe glucuronide.

Herbal medicines are widely consumed by patients in different clinical settings in the United States and all over the world. In this study, 7 herbal components ginsenosides Rb1, Rb2, Rc, and Rd (from ginseng quercetin) ginkgolides A and B (from ginkgo biloba) were investigated for their inhibitory effects on hepatic CYP2C9 and CYP3A4 catalytic activities in human liver microsomes. Tolbutamide 4-methylhydroxylation and testosterone 6beta-hydroxylation were used as index reactions of CYP2C9 or CYP3A4 catalytic activities, respectively. The metabolites of both reactions were measured by high-performance liquid chromatography and used as indicators of whether enzymes were inhibited or unaffected by these agents. Herbal components were studied at various concentrations (0.1, 1, 10, 100, 200 micromol/L). The herbal compounds investigated were capable of inhibiting CYP2C9 and CYP3A4 catalytic activities, but the potencies differed. Quercetin showed marked inhibitory effects on both tolbutamide 4-methylhydroxylation and testosterone 6beta-hydroxylation with IC(50) values of 35 and 38 micromol/L, respectively. Ginsenoside Rd also had significant inhibitory potency on both CYP2C9- and CYP3A4-mediated index reactions with IC(50) values of 105 and 62 micromol/L, respectively. Ginsenosides Rb1, Rb2, and Rc had limited inhibitory activities on both enzyme reaction systems, whereas the effects of ginkgolides A and B appeared negligible. It is concluded that the components of ginseng and ginkgo biloba screened are capable of inhibiting CYP2C9- and CYP3A4-mediated metabolic reactions. Our findings suggest that quercetin and ginsenoside Rd have the potential to interact with conventional medicines that are metabolized by CYP2C9 and CYP3A4 in vivo.

Background: Depression symptoms may be associated with the development of Alzheimer disease (AD)., Objectives: To evaluate the association between depression symptoms and risk of AD, and to explore the temporal aspects of this association., Setting: Academic institutions with specialized memory clinics., Design: Cross-sectional, family-based, case-control study with standardized self- and proxy questionnaires to collect information on depression symptoms and other risk factors., Participants: A total of 1953 subjects with AD and 2093 of their unaffected relatives enrolled in the Multi-institutional Research in Alzheimer's Genetic Epidemiology Study., Main Outcome Measures: Odds ratios (ORs) of AD were estimated with and without depression symptoms, adjusted for age, sex, education, history of head trauma, and apolipoprotein E status., Results: There was a significant association between depression symptoms and AD (adjusted OR, 2.13; 95% confidence interval [CI], 1.71-2.67). In families where depression symptoms first occurred within 1 year before the onset of AD, the association was higher (OR, 4.57; 95% CI, 2.87-7.31), while in the families where the depression symptoms first occurred more than 1 year before the onset of AD, the association was lower (OR, 1.38; 95% CI, 1.03-1.85). In families where depression symptoms first occurred more than 25 years before the onset of AD, there was still a modest association (OR, 1.71; 95% CI, 1.03-2.82)., Conclusions: Depression symptoms before the onset of AD are associated with the development of AD, even in families where first depression symptoms occurred more than 25 years before the onset of AD. These data suggest that depression symptoms are a risk factor for later development of AD.

Background: The association between Alzheimer disease (AD) and genotypes at the apolipoprotein E (APOE) locus has been confirmed in numerous populations worldwide, but appears to be inconsistent in African American subjects., Objective: To investigate the association between APOE genotypes and AD in elderly African American subjects., Design: Clinic-based, multicenter case-control study and a family study., Participants: A total of 338 African American probands meeting criteria for probable or definite AD, 301 cognitively healthy, elderly unrelated control subjects (spouses and community volunteers), and 108 siblings of 88 AD probands., Main Outcome Measures: Odds of AD according to APOE genotype., Results: Compared with individuals with the APOEepsilon3/epsilon3, the odds of having AD were significantly increased among those with 1 or more copies of the epsilon4 allele; the odds ratio (OR) for the epsilon3/epsilon4 genotype was 2.6 (95% confidence interval [CI], 1.8-3.7), and the OR for the epsilon4/epsilon4 genotype was 10.5 (95% CI, 5.1-21.8). These risks decreased substantially after 68 years of age. The risk for AD was lower among individuals with the epsilon2/epsilon3 genotype (OR, 0.41; 95% CI, 0.22-0.79). The patterns of association were similar in men and women. These results obtained from comparisons of unrelated AD patients and controls were bolstered by results of analysis of family data that showed preferential transmission of the epsilon4 allele to demented siblings (P<<.001) and of the epsilon2 allele to nondemented siblings (P=.005)., Conclusions: The presence of 1 or 2 epsilon4 alleles is a determinant of AD risk in African American subjects. The age-related risk for decline associated with the epsilon4 allele and the apparent protective effect of the epsilon2 allele are similar to patterns observed in white subjects.

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 microM. Cyclizine and promethazine showed inhibitory effects on tolbutamide 4-methylhydroxylation with IC20 values of 85 microM and 88 microM, 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.

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 17 639 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 [CI], 1.4-1.9; P<.001). The risk in spouses of African American AD probands of 18.5% (SE, 8.4%) was also higher than the risk in white spouses of 10.4% (SE, 1.7%) but did not reach statistical significance (RR, 1.8; 95% CI, 0.5-6.0; P =.34), likely due to the smaller sample size of African Americans. The proportional increase in risk of dementia among white first-degree biological relatives compared with white spouses of 2.6 (95% CI, 2.1-3.2) was similar to that of 2.4 (95% CI, 1.3-4.4) in African American first-degree biological relatives compared with African American spouses. Female first-degree biological relatives of probands had a higher risk of developing dementia than did their male counterparts, among whites (31.2% vs 20.4%; RR, 1.5; 95% CI, 1.3-1.7; P<.001) as well as among African Americans, although this was not significant among African Americans (46.7% vs 40.1%; RR, 1.2; 95% CI, 0.9-1.7, P =.30). The patterns of risk among first-degree biological relatives stratified by APOE genotype of the probands were similar in white families and African American families., 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 epsilon4 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.

Cytochrome P450 (CYP) 2C9 is the principal enzyme responsible for the metabolism of numerous clinically important drugs. Two polymorphic alleles CYP2C9*2 and CYP2C9*3 have been documented which affect the metabolism and clinical toxicity of drugs such as phenytoin, warfarin, glipizide, and tolbutamide. The present study reports the first example of a null polymorphism in CYP2C9. This mutation dramatically affects the half-life and clinical toxicity of phenytoin. The study subject was a female African-American presented to the emergency department with phenytoin toxicity evidenced by mental confusion, slurred speech, memory loss and the inability to stand. She exhibited extremely poor clearance of phenytoin with an elimination half-life of approximately 13 days. Genotyping studies demonstrated that the patient did not possess any known variant CYP2C9 alleles. Phenytoin is metabolized to a minor extent by the polymorphic CYP2C19, but this individual did not possess any variant CYP2C19 alleles. Sequencing studies revealed that the individual was homozygous for a new CYP2C9 allele (CYP2C9*6) with the deletion of an adenine at base pair 818 of the cDNA. The clearance of phenytoin in this individual is estimated to be approximately 17% of that observed in normal patients. The frequency of this allele was 0.6% (95% confidence limits of 0.1 to 3.5%) in 79 African-Americans and 0% (95% confidence limits of 0 to 1.1%) in 172 Caucasians. The study also demonstrates the severe clinical consequences to patients with a null mutation in CYP2C9 after treatment with normal doses of phenytoin.

Certain individuals have a metabolic deficiency in the metabolism of debrisoquin, sparteine, dextromethorphan, and more than 80 other clinically important drugs. Examples of such drugs include tricyclic antidepressants, neuroleptics, selective serotonin reuptake inhibitors, beta-adrenoceptor blockers, and antiarrhythmics. CYP2D6, the enzyme responsible for the metabolism of these drugs, is polymorphically distributed in different populations. Studies in different ethnic groups in particular demonstrate significant variation. CYP2D6 deficiency has important therapeutic consequences, such as increased side effects when medications that are substrates of this enzyme are prescribed for such individuals. To optimize drug therapy, physicians should therefore determine the metabolic capacity of their patients.

Interethnic difference in drug disposition is an important contributing factor to interindividual variation in drug response. Since interethnic differences in the protein binding of drugs may contribute to variation in drug disposition between ethnic groups, we conducted a study in 10 black Americans (A) and mean (plus minusSE) age 26 plus minus 6 years and weight 80 plus minus 9 kg matched against 10 white Americans (C) with a mean age of 28 plus minus 6 years and weight 81 plus minus 9 kg, all within 10% of ideal body weight. Serum alpha-1-acid glycoprotein (AGP) and albumin concentrations were measured using the auramine-O and bromcresol green methods, respectively. Verapamil, propranolol, lidocaine, disopyramide and diazepam binding in plasma were measured with the equilibrium-dialysis method, involving the determination of free and unbound drug concentrations. The unbound fraction of diazepam (A = 1.1 plus minus 0.1%; C = 1.1 plus minus 0.1%), verapamil (A = 9.5 plus minus 0.8%; C = 9.8 plus minus 0.4%), propranolol (A = 14.2 plus minus 1.0%; C = 12.6 plus minus 0.7%), lidocaine (A = 28.5 plus minus 2.1%; C = 25.7 plus minus 1.1%) and diphenhydramine (A = 42.9 plus minus 10.2; C = 30.4 plus minus 7.01%) showed no significant ethnic differences (unpaired t-test). Disopyramide measured at 7 different concentrations (1.0--20.0 &mgr;g/ml) was similar in both groups, as were the plasma concentrations of AGP (A = 100 plus minus 20 mg 100 ml; C = 120 plus minus 20 mg 100 ml) and albumin (A = 4.3 plus minus 0.1 g 100 ml; C = 4.5 plus minus 0.1 g 100 ml). It is therefore concluded that there are no interethnic differences in the protein binding of basic drugs between black Americans and white Americans and that it is not a major contributing factor to any possible interethnic variation in the disposition of responsiveness of these drugs.

Objective: Although it has been stated frequently that older people are more sensitive to benzodiazepines, the relative roles of impaired baseline performance, impaired elimination, and altered responsiveness have not been defined. We evaluated postural sway and plasma triazolam concentrations after administration of placebo and triazolam 0.375 mg in both young and older healthy subjects., Design: Double-blind placebo-controlled trial., Participants: Nine young and nine older healthy men., Intervention: All subjects received triazolam 0.375 mg or placebo on different study days, which were separated by at least 48 hours., Measurements: Postural sway, visual analog scale of drowsiness, and plasma triazolam levels., Results: The older subjects swayed more during triazolam than did the younger subjects, and this resulted in an increased number of losses of balance. This difference appeared to be caused by greater baseline sway in the older subjects rather than higher concentrations or increased responsiveness. A subset of older people had a much greater number of losses of balance during triazolam than did the rest of the subjects, and these individuals could be identified from their baseline sway., Conclusions: In this study, the increase in drug effect seen in the older subjects was of similar magnitude to that of the young, but it resulted in greater postural sway after drug administration than was seen in the young. The higher postural sway and the corresponding increased instability seen in the older subjects may put these older persons at increased risk of drug-related falls. This study also suggests that it should be possible to develop techniques that will identify individuals at particular risk of drug-induced postural instability.

The anticonvulsant drug mephenytoin is available as a racemic mixture of the S and R enantiomers. The S enantiomer is selectively 4'-hydroxylated in the liver by the cytochrome P450 enzyme, CYP2C19. This reaction has a polymorphic distribution in human populations. Racemic mephenytoin has been extensively used as a probe drug to assign metabolic phenotypes for this genetically-determined polymorphism. Specific base substitution mutations in the CYP2C19 gene are responsible for the poor metabolism (PM) phenotype which is inherited as a recessive autosomal trait. The poor metabolizers (PMs) of S-mephenytoin are homozygous for these mutations. In contrast, extensive metabolizers (EMs) are either heterozygous or homozygous for the wild-type allele(s). Poor metabolizers have the inactive enzyme and therefore have reduced ability to metabolize substrates of CYP2C19, many of which are psychotropic drugs. Genotyping an individual before treatment with substrates of CYP2C19 will reduce the risk of side effects and improve compliance in PMs. The prevalence of PMs is relatively low in African-Americans and Caucasians and is as high as 20 percent in Asian populations.

Twelve healthy subjects (6 females), who were drug-free and non alcoholic, age 21-40 years and weight 43-80 kg took part in the study which lasted about 4 weeks. The subjects were randomly assigned into 2 panels (of 6 subjects each) and took antipyrine (1,050 mg) orally either as powder made into solution or gelatin capsules on 3 consecutive trial occasions separated by 2-week intervals. Panel A had powder, powder and capsule formulations on trials 1, 2 and 3, respectively, and panel B had capsule, capsule and powder formulations on trials 1, 2 and 3, respectively. There were no significant differences in the saliva pharmacokinetic parameters of antipyrine in the 3 trials for both panels of subjects, except the half-lives in panel B which was significantly different at the 5% level. There were no significant differences in the amounts of antipyrine and its metabolites excreted in urine in the 3 trials. The saliva concentrations of antipyrine in the 3 trials were relatively comparable. The relative bioavailability of the capsule formulation of antipyrine was 97%. This study shows that the saliva pharmacokinetic parameters of antipyrine and the amounts of antipyrine metabolites excreted in urine are highly reproducible following repeated oral administration, either in solution or as capsules. The capsule formulation is fully bioavailable and should be suitable for oral administration in assessing the influence of drugs and environmental factors on antipyrine metabolism.

Twelve normal volunteers were given 10 mg enalapril maleate by single and 2 weeks multiple dose administration, and blood samples were collected for the determination of enalaprilat concentration and angiotensin converting enzyme (ACE) activity. The mean terminal elimination half-life following a single administration of 10 mg enalapril, was 27 hours. The inhibition of ACE activity paralleled enalaprilat concentrations following both single and multiple dosing and the time of maximum inhibition of ACE activity was associated on both occasions with maximum concentration of enalaprilat. Emax modelling of enalaprilat concentration and ACE activity gave comparable values of Emax for both methods of administration. An accumulation factor of 1.7 was calculated from the area under the concentration time curve (AUC) of enalaprilat within a dosing interval at steady-state and the total AUC following single administration of enalapril. There were no significant differences between males and females in the accumulation factor, half-life and AUCinf.

At low doses of triazolam currently recommended increased assay sensitivity is required for measurement of low plasma concentrations. A highly sensitive capillary gas chromatographic analytical method with a limit of detection of 0.02 ng/ml was developed and used to describe the pharmacokinetics of triazolam following the oral intake of 0.125, 0.250 and 0.375 mg. Six male subjects were studied with blood sampling at the following times: 0, 15, 30 and 45 min and 1, 1.5, 2.0, 2.5, 3, 4, 5, 6 and 8 h. The mean pharmacokinetic parameters for the three doses, respectively, were as follows: half-life, 2.7 +/- 0.4, 3.2 +/- 0.5 and 3.2 +/- 0.6 h; apparent oral clearance, 302.3 +/- 59.0, 260.2 +/- 67.9 and 328.6 +/- 77.8 ml/min; apparent volume of distribution, 64.3 +/- 9.6, 62.0 +/- 12.6 and 73.3 +/- 7.7 l; time to maximum concentration, 0.7 +/- 0.2, 0.6 +/- 0.1 and 0.8 +/- 0.3 h; maximum concentration, 2.2 +/- 0.3, 4.3 +/- 0.6 and 5.0 +/- 0.5 ng/ml; and the area under the concentration-time curve (AUC) up to 8 h, 6.8 +/- 1.2, 16.8 +/- 2.9 and 19.6 +/- 3.5 ng/ml h; and AUC extrapolated to infinity, 8.5 +/- 1.7, 21.4 +/- 4.4 and 26.3 +/- 7.2 ng/ml h. There were no significant differences in the half-life, clearance, volume of distribution and time to maximum concentration among the three doses. The AUC was significantly different on the three occasions and was linearly correlated with dose: r = 0.64 (p less than 0.005).

The effects of a single 20 mg oral dose of timolol, a non-selective beta-adrenoceptor antagonist which is subject to hydroxylation in the liver, on intraocular pressure and heart rate were compared in four poor and five extensive debrisoquine metabolizers, using non-contact tonometry and bicycle ergometry. The beta blockade of timolol on exercise heart rate was significantly higher in poor than in extensive metabolisers with no significant difference on resting heart rate or intraocular pressure.

The hemodialysis blood clearance of chloroquine was studied in four patients with chronic renal failure undergoing chronic hemodialysis. The patients were administered chloroquine (600 mg base) orally after a light breakfast. Blood samples were then obtained from arterial blood entering and venous blood leaving the dialysis machine at 0.0, 0.5, 1.0, 2.0, 4.0, and 6.0 h, and at 24.0 and 48.0 h post dialysis. The blood flow rate varied between 200 and 275 ml/min, while the dialysate flow rate was maintained at 500 ml/min. The samples were analyzed for chloroquine by high pressure liquid chromatography, and the dialysis clearance was calculated utilizing the formula: ClD = QB[(CA - CV)/CA]. The mean extraction ratios for chloroquine were 0.238, 0.317, 0.207, and 0.216 in the four patients during the 6-h dialysis period. The calculated dialysis clearances were 57.2, 77.0, 56.1, and 48.3 ml/min. Chloroquine hemodialysis clearance was 14.5% of total body clearance in normal subjects and in patients with chronic renal failure not on hemodialysis.