Healthy White Male Volunteers Research Articles

Effect of Lacosamide on the Steady-State Pharmacokinetics of Digoxin: Results from a Phase I, Multiple-Dose, Double-Blind, Randomised, Placebo-Controlled, Crossover Trial

Recent data suggest that P-glycoprotein may be involved in cellular transport of lacosamide. To investigate potential drug-drug interactions (DDIs) between lacosamide and digoxin, this phase I, multiple-dose, randomised, double-blind, placebo-controlled, crossover trial assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of digoxin administered in combination with lacosamide or placebo. Twenty healthy White male volunteers were randomised. After receiving digoxin 0.25 mg three times daily on day 1 (loading dose), participants received digoxin 0.25 mg once daily on days 2-22. Participants received either lacosamide (200 mg twice daily) or placebo on days 8-11 and vice versa on days 18-21, after a 6-day washout. The steady-state area under concentration-time curve over the dosing interval (AUC(24,ss)) and maximum steady-state plasma concentration (C(max,ss)) of digoxin were measured; ratios of these parameters for co-administration of digoxin + lacosamide versus digoxin alone were used to evaluate potential DDIs. Interaction was excluded if the 90 % confidence interval (CI) for the geometric mean ratio of AUC24,ss and C max,ss fell within the acceptance range for bioequivalence (0.8-1.25). The point estimates (90 % CI) of the geometric mean ratios for co-administration of digoxin with lacosamide versus digoxin alone for AUC(24,ss) [1.024 (0.979-1.071)] and C(max,ss) [1.049 (0.959-1.147)] were within the acceptance range for bioequivalence. Digoxin and lacosamide co-administration was generally well-tolerated. A small numerical increase in the mean PR interval following co-administered digoxin + lacosamide was observed versus digoxin alone and versus pre-treatment baseline values (178.5 vs. 170.4 or 166.8 ms, respectively). The RR interval increased in parallel. The change was not considered clinically relevant. Co-administration of steady-state digoxin (0.25 mg/day) with multiple-dose lacosamide (400 mg/day) versus digoxin alone revealed no differences in digoxin disposition.

Genetic Sequence Variants are Associated with Severity of Lower Urinary Tract Symptoms and Prostate Cancer Susceptibility

While a clear heritable component underlies lower urinary tract symptoms and benign prostatic hyperplasia, few studies have identified specific genetic factors. In contrast, recent genome-wide association studies identified single nucleotide polymorphisms that increase prostate cancer risk. Some of these single nucleotide polymorphisms may also predispose to surgical intervention for benign prostatic hyperplasia. We determined whether these single nucleotide polymorphisms are also associated with lower urinary tract symptom severity and benign prostatic hyperplasia medication use. The genotypes of 38 single nucleotide polymorphisms previously associated with prostate cancer risk were determined for 1,168 healthy white male volunteers. American Urological Association symptom index score and medication for benign prostatic hyperplasia were documented prospectively. Statistical analyses were done to compare the frequency of the single nucleotide polymorphisms with American Urological Association symptom index and benign prostatic hyperplasia medication use. Several single nucleotide polymorphisms, including rs2736098 on chromosome 5p15, showed a significant relationship with benign prostatic hyperplasia medication. After adjusting for the other genetic variants, patient age and medication use, rs1571801 on chromosome 9q33.2 (OR 1.31, 95% CI 1.0-1.74) and rs5945572 on chromosome Xp11 (OR 1.28, 95% CI 1.04-1.59) were significantly associated with increased urinary symptoms. In contrast, rs445114 on chromosome 8q24 was marginally associated with decreased urinary symptoms (OR 0.83, 95% CI 0.66-1.01). Of 38 single nucleotide polymorphisms that predispose to prostate cancer we identified 3 that are also associated with a well characterized lower urinary tract symptom phenotype. These single nucleotide polymorphisms may aid in the improved characterization of men with lower urinary tract symptoms/benign prostatic hyperplasia.

Effect of clopidogrel on circulating biomarkers of angiogenesis and endothelial activation

Angiogenic cytokines have been shown to influence vessel injury, and platelets represent a disposable circulating pool of angiogenic molecules. In the present study, objectives were to determine whether clopidogrel could have a potential effect on levels of circulating biomarkers of angiogenesis and endothelial activation. We explored 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg/day. We quantified angiogenic growth factors that have been shown to be correlated to cardiovascular risk or endothelial progenitor cell mobilization such as vascular endothelial growth factor (VEGF)-A and its soluble receptor forms VEGFR1 and VEGFR2, placenta growth factor, and stromal cell-derived factor-1. We also quantified soluble E-selectin and von Willebrand factor to evaluate endothelial activation. Blood samples were drawn just before the first clopidogrel intake on day 1, and after the last dosing (day 7). As expected, we observed a decrease in platelet reactivity in response to clopidogrel, confirmed by vasodilator-stimulated phosphoprotein phosphorylation assay. However, the 7-day intake of clopidogrel did not significantly modify the levels of the selected angiogenic factors or biomarkers of endothelial activation. These results show that circulating angiogenic factor level in healthy subjects is not driven by P2Y12 platelet receptor-induced activation and clopidogrel does not modify in a significant way the endothelial activation level.

Randomized phase II trial of first-line gefitinib, gemcitabine or docetaxel in performance status (PS) 2 or 3 non-small cell lung cancer (NSCLC) patients (IFCT-0301): elderly patients analysis

Many patients with head and neck cancer have difficulty swallowing tablet formulations ofmedications, and use of dispersion preparations may be advantageous.The aim of the present study was to determine the relative bioavailability and safety profile of asingle dose of gefitinib, an orally active inhibitor of epidermal growth factor receptor tyrosine kinase, when administered as a whole 250-mg tablet or as a dispersion preparation via drink or nasogastric tube in healthy male volunteers.This was a Phase 1, randomized, open-label, 3-period crossover study. Plasma samples obtained beforedosing to 240 hours after dosing were analyzed for gefitinib using reverse-phase high-performance liquid chromatography with tandem mass-spectrometric detection. The pharmacokinetic parameters of interest included AUC, Cmax, and the relative bioavailability of the dispersion via drink or nasogastric tube compared with the standard tablet.Eighteen healthy white male volunteers were enrolled. They had a mean age of 43 years (range, 21–59 years), mean body weight of 85.1 kg (range, 60–101 kg), and mean height of 180.3 cm (range, 171–187 cm). The geometric mean AUC was 2219 ng·h/mL for a single 250-mg dose of gefitinib administered as a whole tablet, 2233 ng·h/mL for the dispersion preparation administered by drink, and 2007 ng·h/mL for the dispersion preparation administered by nasogastric tube. The corresponding values for the geometric mean Cmax were 95.2, 96.3, and 89.9 ng/mL. The gefitinib dispersion preparation administered by drink had a mean bioavailability of 103.8% relative to the whole tablet; the dispersion preparation administered by nasogastric tube had a mean bioavailability of 99.1% relative to the whole tablet. For the drink-tablet and nasogastric tube-tablet comparisons, the estimate-of-treatment ratios for the AUC were a respective 1.006 and 0.928; for the Cmax, they were 1.012 and 0.964. There appeared to be no clinically significant differences in absorption or elimination between the preparations. Three volunteers experienced adverse events (AEs) that were considered possibly related to gefitinib (pruritus and dry skin), and 6 volunteers experienced procedure-related AEs (cannula-site reaction and rhinorrhea); these AEs were mild or moderate. No serious AEs were recorded, and no AEs led to withdrawal of any volunteer.Administration of a 250-mg dose of gefitinib as a dispersion preparation by drink or nasogastrictube achieved a systemic exposure to gefitinib that was consistent with that achieved when gefitinib was administered as a whole tablet. There was no evidence of tolerability problems associated with the routes of administration studied in these healthy volunteers.

Comparison of two marketed nifedipine modified-release formulations: An exploratory clinical food interaction study

Objective: The objective of this study was to compare the in vitro and in vivo characteristics of 2 nifedipine modified-release tablet formulations for once-daily dosing marketed in the European community, which were expected to be bioequivalent. Methods: In vitro dissolution was tested at different pH values prior to the clinical part of the study. Either 1 tablet of a test formulation or of the reference formulation, both containing 30 mg nifedipine, were administered to healthy white male volunteers immediately after a high-fat breakfast in a randomized, open-label, 2-period crossover design. Plasma samples obtained over the subsequent period of 48 hours were analyzed using a validated LC-MS/MS method. Safety profile and tolerability of the study medications were assessed by analysis of adverse events obtained by vital sign measurements, electrocardiography, and clinical laboratory analysis. Results: Twelve volunteers were enrolled (median age, 28.0 years [range, 21-42 years]; mean body mass index, 24.2 kg/m 2 [range, 19.3–27.0 kg/m 2]). In vitro dissolution experiments revealed a significant pH dependency in drug release from the investigational tablets, while the reference tablets were found to have pH-independent dissolution. After oral administration of both tablet formulations in the fed state, marked differences in rate and extent of bioavailability were observed. Geometric mean of AUC 0-last(test, 504.21 h · ng/mL; reference, 361.28 h · ng/mL) was significantly higher for the test product, with a point estimate of 140% and a corresponding 90% CI of 121% to 161%. For the comparison of Cmax values, geometric means were: test, 76.46 ng/mL; reference, 19.20 ng/mL, with a point estimate of 398% and a CI of 316% to 503%. Thus, a significant difference in rate and extent of bioavailability was observed between the 2 products. Conclusions: Although both treatments were well tolerated by all volunteers, the test and reference tablets were found to have different pharmacokinetic properties when administered after a high-fat meal.

A single bolus infusion of C-reactive protein increases gluconeogenesis and plasma glucose concentration in humans

Recently, we reported that C-reactive protein (CRP) elicits inflammatory and procoagulant responses in humans. In addition, CRP has been associated with the development of type 2 diabetes mellitus. To further explore interactions between CRP and glucose handling, we evaluated the effects of CRP infusion on glucose metabolism in humans. Seven healthy white male volunteers (age, 39.3 ± 16.9 years) received a single bolus infusion of 1.25 mg/kg purified recombinant human (rh) CRP or CRP-free diluent in a crossover design. C-reactive protein infusion induced an inflammatory response, which was followed by increased plasma concentrations of norepinephrine (3 hours) and cortisol (4 hours). Concomitantly, plasma concentrations of insulin and C-peptide decreased transiently. These metabolic changes increased plasma glucose concentrations from 8 hours after CRP infusion, which was preceded by an increased rate of glucose appearance that was a direct consequence of increased gluconeogenesis. In conclusion, CRP infusion induces an inflammatory response followed by increased norepinephrine and cortisol levels, which results in increased gluconeogenesis. This finding implies that elevated levels of CRP in humans may in fact contribute to altered glucose metabolism and thereby may contribute to the induction of type 2 diabetes mellitus.

Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects

AbstractThe capacity of clopidogrel to inhibit ADP-induced platelet aggregation shows wide intersubject variability. To determine whether frequent functional variants of genes coding for candidate cytochrome P450 (CYP) isoenzymes involved in clopidogrel metabolic activation (CYP2C19*2, CYP2B6*5, CYP1A2*1F, and CYP3A5*3 variants) influence the platelet responsiveness to clopidogrel, we conducted a prospective pharmacogenetic study in 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg/d. We observed that pharmacodynamic response to clopidogrel was significantly associated with the CYP2C19 genotype. Twenty of the subjects were wild-type CYP2C19 (*1/*1) homozygotes, while the other 8 subjects were heterozygous for the loss-of-function polymorphism CYP2C19*2 (*1/*2). Baseline platelet activity was not influenced by the CYP2C19 genotype. In contrast, platelet aggregation in the presence of 10 μM ADP decreased gradually during treatment with clopidogrel 75 mg once daily in *1/*1 subjects, reaching 48.9% ± 14.9% on day 7 (P < .001 vs baseline), whereas it did not change in *1/*2 subjects (71.8% ± 14.6% on day 7, P = .22 vs baseline, and P < .003 vs *1/*1 subjects). Similar results were found with VASP phosphorylation. The CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet responsiveness to clopidogrel in young healthy male volunteers and may therefore be an important genetic contributor to clopidogrel resistance in the clinical setting.

Steady-state pharmacokinetic properties of aripiprazole 10 mg PO g12h in Han Chinese adults with schizophrenia: A prospective, open-label, pilot study

Objectives: The aims of this study were to investigate the pharmacokinetic (PK) properties of aripiprazole in the steady state in Han Chinese adults with schizophrenia and to compare them between Han Chinese and white populations described in the literature. Methods: This prospective, open4abel, pilot study was conducted at the Mental Health Institute, Xiang-ya Second Hospital, Central South University, Changsha, China. Male and female hospitalized patients aged 18 to 45 years diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-defined schizophrenia, with a Positive and Negative Syndrome Scale (PANSS) total score ⩾60 (indicating schizophrenia of at least mild severity) were eligible. On study days 1 and 2, patients were pretreated with aripiprazole 10 mg PO QD, followed by 10 mg g12h on days 3 to 21. Blood samples were drawn for analysis on day 21 before dosing and 1, 3, 4, 5, 12, 24, 48, 72, 96, 144, and 192 hours after the morning dosing of aripiprazole on day 21. Patients received low-dose (25–100 mg/d) clozapine on day 25 until day 28. The samples were assessed using high-performance liquid chromatography-mass spectrometry and compartment model analysis for aripiprazole. PK properties included mean residence time (MRT) steady-state C max (C ss max), time to C ss max (T max), elimination t /12, apparent oral clearance (CL/F), and apparent volume of distribution (V/F). Adverse effects were monitored using physical examination (including vital sign measurements), electrocardiography, electroencephalography, and clinical laboratory testing (including biochemistry, hematology, and urinalysis) at baseline and at the end of the study. Patients were asked about adverse events on days 1 to 7 and at random intervals thereafter. Patients were also instructed to report any spontaneous symptoms they experienced. Results: Twelve patients were enrolled (6 men, 6 women; mean [SD] age, 26.1 [7.0] years; mean [SD] weight, 56.6 [9.0] kg; mean [SD] PANSS score, 116.8 [12.2]). Aripiprazole exhibited linear kinetic characteristics on a 2-compartment model. After multiple oral doses (10 mg g12h), the mean (SD) t 1/2, C ss max, T max, MRT, V/F, and CL/F were 62.2 (9.0) hours, 557.3 (135.5) ng/mL, 2.6 (1.1) hours, 84.5 (11.2) hours, 173 (48) L, and 1.9 (0.5) L/h, respectively. In Chinese patients, the t /12 values were numerically similar (62.2 [9.0] vs 68.1 [22.9] hours); C ss max values were numerically higher (557.3 [135.5] vs 393 [181 ] ng/mL); and V/F and CL/F values were numerically lower (V/F: 173 [48] vs 196 [66] L; CL/F: 1.9 [0.5] vs 3.4 [1.6] L/h) compared with healthy white male volunteers. Adverse effects were mild to moderate: lightheadedness (5 of 12 patients), somnolence (3), tachycardia (3), hypodynamia (2), and extrapyramidal symptoms (EPS) (1). The EPS (convulsive movement of the muscles related to the larynx) led to one patient's discontinuation of the study. Conclusions: In this small pilot study of the PK properties of aripiprazole 10 mg PO g12h in Han Chinese patients with schizophrenia, the mean t 1/2 value was numerically similar to that previously reported in a population of healthy white male volunteers. However, the mean C ss max value was numerically higher, and V/F and CL/F values were numerically lower, compared with those in healthy white male volunteers.

Relative bioavailability and safety profile of gefitinib administered as a tablet or as a dispersion preparation via drink or nasogastric tube: results of a randomized, open-label, three-period crossover study in healthy volunteers

Background: Many patients with head and neck cancer have difficulty swallowing tablet formulations ofmedications, and use of dispersion preparations may be advantageous. Objective: The aim of the present study was to determine the relative bioavailability and safety profile of asingle dose of gefitinib, an orally active inhibitor of epidermal growth factor receptor tyrosine kinase, when administered as a whole 250-mg tablet or as a dispersion preparation via drink or nasogastric tube in healthy male volunteers. Methods This was a Phase 1, randomized, open-label, 3-period crossover study. Plasma samples obtained beforedosing to 240 hours after dosing were analyzed for gefitinib using reverse-phase high-performance liquid chromatography with tandem mass-spectrometric detection. The pharmacokinetic parameters of interest included AUC, C max, and the relative bioavailability of the dispersion via drink or nasogastric tube compared with the standard tablet. Results: Eighteen healthy white male volunteers were enrolled. They had a mean age of 43 years (range, 21–59 years), mean body weight of 85.1 kg (range, 60–101 kg), and mean height of 180.3 cm (range, 171–187 cm). The geometric mean AUC was 2219 ng·h/mL for a single 250-mg dose of gefitinib administered as a whole tablet, 2233 ng·h/mL for the dispersion preparation administered by drink, and 2007 ng·h/mL for the dispersion preparation administered by nasogastric tube. The corresponding values for the geometric mean C max were 95.2, 96.3, and 89.9 ng/mL. The gefitinib dispersion preparation administered by drink had a mean bioavailability of 103.8% relative to the whole tablet; the dispersion preparation administered by nasogastric tube had a mean bioavailability of 99.1% relative to the whole tablet. For the drink-tablet and nasogastric tube-tablet comparisons, the estimate-of-treatment ratios for the AUC were a respective 1.006 and 0.928; for the C max, they were 1.012 and 0.964. There appeared to be no clinically significant differences in absorption or elimination between the preparations. Three volunteers experienced adverse events (AEs) that were considered possibly related to gefitinib (pruritus and dry skin), and 6 volunteers experienced procedure-related AEs (cannula-site reaction and rhinorrhea); these AEs were mild or moderate. No serious AEs were recorded, and no AEs led to withdrawal of any volunteer. Conclusions: Administration of a 250-mg dose of gefitinib as a dispersion preparation by drink or nasogastrictube achieved a systemic exposure to gefitinib that was consistent with that achieved when gefitinib was administered as a whole tablet. There was no evidence of tolerability problems associated with the routes of administration studied in these healthy volunteers.

Effects of grapefruit juice on the pharmacokinetics of sildenafil

Because of extensive first-pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N -desmethylsildenafil, is mainly mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of grapefruit juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N -desmethylsildenafil. In a randomized crossover study, 24 healthy white male volunteers received single 50-mg doses of sildenafil. Two doses each of 250 ml grapefruit juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N -desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography-tandem mass spectrometry (limit of quantification, 1 ng/ml). Grapefruit juice changed the area under the sildenafil plasma concentration-time curve from time zero to infinity [AUC(0-infinity) from 620 [1.53] ng/ml x h to 761 [1.58] ng/ml x h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%-33%). N-Desmethyl sildenafil AUC(0-infinity) increased by 24% (90% confidence interval, 17%-32%). Maximum plasma concentrations (C(max)) of sildenafil and N -desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach C(max) during the grapefruit juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0-0.63 hour). Interindividual variability was pronounced in both periods. Grapefruit juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with grapefruit juice. Although patients usually will not be endangered by concomitant use of grapefruit juice, it seems advisable to avoid this combination.

Digoxin Pharmacokinetics and Spirapril, a New Ace Inhibitor

As concurrent use of digoxin with the novel ACE inhibitor spirapril should be common, potential for spirapril to affect steady-state digoxin kinetics was studied. Fifteen healthy white male volunteers aged 22-42 and weighing 135-225 lbs took digoxin tablets 0.25 mg every 12 hours for 5 weeks. In crossover design, each also received spirapril or matching placebo capsules during weeks 1 and 2, or 4 and 5. Dosage of spirapril was increased from 12 mg to 48 mg once daily. Spirapril produced no significant effect on mean (+/- SD) serum digoxin concentration in the steady state, area under curve for 12 hours, peak digoxin level, time to peak, or urinary digoxin excretion over 12 hours. No change in renal or whole body digoxin clearance was seen. Unlike some other cardiovascular drugs, spirapril does not alter steady-state digoxin kinetics in healthy adults.

The use of dihydroxyacetone for skin tanning.

Within the past year a number of similar cosmetic preparations have appeared on the market and have been extensively advertised for their tanning effect on the skin. In our practices we have received numerous inquiries regarding their effectiveness and safety. There seems to be a general impression on the part of the laity that the artificial tan which these agents produce will protect against sunlight. This investigation was undertaken to determine the possible sun-screening properties and effect upon melanogenesis of dihydroxyacetone, the active ingredient in these preparations. Experiment I Ten healthy white male volunteers were used. Three test areas, each measuring 1×1 inch (2.5×2.5 cm.), were marked out on the external aspect of one arm of each subject. Dihydroxyacetone lotion * was applied to one of these test sites. Twenty-four hours later this site was given a 4+ erythema dose of ultraviolet light produced by Westinghouse FS4OT-12 fluorescent ultraviolet lamp. The