Crossover Study In Healthy Subjects Research Articles

326 Co-administration of a CYP3A4 inhibitor (ketoconazole) increased the bioavailability of CS-7017 but did not affect tolerability: results from an open-label, phase I, two-way crossover study in healthy subjects

326 Co-administration of a CYP3A4 inhibitor (ketoconazole) increased the bioavailability of CS-7017 but did not affect tolerability: results from an open-label, phase I, two-way crossover study in healthy subjects

Pharmacokinetics of alogliptin when administered with food, metformin, or cimetidine: a two-phase, crossover study in healthy subjects

The dipeptidyl peptidase-4 inhibitor alogliptin, under development for treatment of Type 2 diabetes, primarily is excreted renally. This study investigated (1) the effect of food on alogliptin pharmacokinetics and tolerability and (2) pharmacokinetic interactions between alogliptin and metformin or cimetidine and tolerability of alogliptin when administered with either drug. This randomized, open-label, two-phase, crossover study recruited healthy adults. In the single-dose phase, 36 subjects received an oral dose of alogliptin 100 mg under fed or fasted conditions. In the multiple-dose phase, subjects in one arm (n = 17) received 6 days each of alogliptin 100 mg once daily (q.d.), metformin 1,000 mg twice daily (b.i.d), and alogliptin q.d. + metformin b.i.d; subjects in the other arm (n = 18) received 6 days each of alogliptin 100 mg q.d., cimetidine 400 mg q.d., and alogliptin q.d. + cimetidine b.i.d. Pharmacokinetic parameters were determined after the last dose in each period. Tolerability was assessed through adverse events and clinical findings. Food had no effect on alogliptin area under the concentration-time curve (AUC) from 0 h to infinity and a small, clinically insignificant effect on maximum plasma concentration (C(max)) (fed/fasted least squares (LS) geometric mean ratio, 0.856; 90% confidence interval (CI), 0.798 - 0.917). Metformin and cimetidine did not affect alogliptin pharmacokinetics. Alogliptin had no effect on metformin C(max) and a small, clinically insignificant effect on AUC over the dosing interval ((alogliptin + metformin)/metformin LS geometric mean ratio, 1.19; 90% CI, 1.095 - 1.291). Alogliptin did not affect cimetidine pharmacokinetics. Alogliptin tolerability was similar under all conditions. Alogliptin can be administered without regard to meals and with metformin or cimetidine without the need for dose adjustment.

Pharmacokinetic—pharmacodynamic interaction between nebicapone and controlled-release levodopa/benserazide: A single-center, phase I, double-blind, randomized, placebo-controlled, four-way crossover study in healthy subjects

Background: Nebicapone is a reversible catechol-O-methyltransferase (COMT) inhibitor. Coadministration of a COMT inhibitor with levodopa and a dopa-decarboxylase inhibitor (carbidopa or benserazide) increases levodopa exposure and its therapeutic effect.Objectives: The primary objective of this study was to investigate the effect of nebicapone (50, 100, and 200 mg), compared with placebo, on levodopa pharmacokinetics when coadministered with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg. The secondary objectives were to investigate the effect of nebicapone on the erythrocyte-soluble COMT (S-COMT) activity and on the plasma levels of the levodopa 3-O-methylated metabolite (3-O-methyldopa [3-OMD]). Nebicapone's tolerability was also assessed.Methods: This was a single-center, Phase I, doubleblind, randomized, placebo-controlled, 4-way crossover study conducted in healthy adult volunteers. Each of the 4 single-dose treatment periods was separated by a washout period of ≥5 days. During the different treatment periods, subjects received a single dose of controlled-release levodopa 100 mg/benserazide 25 mg concomitantly with nebicapone 50, 100, and 200 mg or placebo. Plasma concentrations of nebicapone, levodopa, and 3-OMD were determined by HPLC. Blood samples (7 mL) for determination of plasma concentrations of levodopa, 3-OMD, and 2258 nebicapone, as well as for the assay of S-COMT activity, were collected in potassium EDTA test tubes at the following times: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose. S-COMT activity was assessed as the amount of metanephrine formed by the action of S-COMT on an epinephrine substrate. Spontaneously reported clinical adverse events (AEs) were recorded throughout the study.Results: Sixteen subjects (8 females, 8 males; mean [SD] age, 26.13 [6.29] years; weight, 69.4 [12.4] kg; body mass index, 24.0 [3.0] kg/m2) completed the 4 treatment periods and had data available for pharmacokinetic and pharmacodynamic analyses. Compared with placebo, levodopa Cmax increased 25%, 30%, and 34%, and AUC increased 14%, 37%, and 42% after administration of nebicapone 50, 100, and 200 mg, respectively. After administration of nebicapone 50, 100, and 200 mg, 3-OMD Cmax decreased 44%, 57%, and 58%, and 3-OMD AUC0–∞ decreased 33%, 37%, and 45%, respectively, compared with placebo. Extent of exposure to levodopa, as assessed by using AUC0−t, increased with all doses of nebicapone in relationship to placebo, but the difference did not reach statistical significance. This may be related to a relatively high inter-subject variability: %CVs ranged from 48.0% with nebicapone 100 mg to 66.8% with placebo. Maximum S-COMT inhibition by nebicapone occurred at ~1.5 hours postdose and ranged from 57% with nebicapone 50 mg to 74% with nebicapone 200 mg. There was an inverse correlation between plasma concentrations of nebicapone and S-COMT activity; Tmax of nebicapone plasma concentrations and time to occurrence of the maximum inhibition of S-COMT activity appeared to correlate. Nineteen AEs were reported; 8 were assessed by the investigator as possibly related to treatment. All AEs were mild in severity. There were no serious AEs or discontinuations due to AEs. No abnormalities in liver enzyme levels were found.Conclusions: When administered concomitantly with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg, single doses of nebicapone 50, 100, and 200 mg were well tolerated in these healthy adult volunteers, and dose dependently inhibited S-COMT activity and reduced 3-OMD formation compared with placebo. However, there was no significant difference in levodopa bioavailability.

Drug-Drug Interaction Study of Ketoconazole and Ritonavir-Boosted Saquinavir

Saquinavir, a potent human immunodeficiency virus protease inhibitor, is extensively metabolized by CYP3A4. Saquinavir is coadministered with ritonavir, a strong CYP3A4 inhibitor, to boost its exposure. Ketoconazole is a potent CYP3A inhibitor. The objectives of this study were to investigate the effect of ketoconazole on the pharmacokinetics of saquinavir/ritonavir and vice versa using the approved dosage regimens of saquinavir/ritonavir at 1,000/100 mg twice daily and ketoconazole at 200 mg once daily. This was an open-label, randomized two-arm, one-sequence, two-period crossover study in healthy subjects. In study arm 1, 20 subjects received saquinavir/ritonavir treatment alone for 14 days, followed in combination with ketoconazole treatment for 14 days. In arm 2, 12 subjects received ketoconazole treatment for 6 days, followed in combination with saquinavir/ritonavir treatment for 14 days. The pharmacokinetics were assessed on the last day of each treatment (days 14 and 28 in arm 1 and days 6 and 20 in arm 2). The exposures C(max) and the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of saquinavir and ritonavir with or without ketoconazole were not substantially altered after 2 weeks of concomitant dosing with ketoconazole. The C(max) and AUC(0-12) of ketoconazole, dosed at 200 mg once daily, were increased by 45% (90% confidence interval = 32 to 59%) and 168% (90% confidence interval = 146 to 193%), respectively, after 2 weeks of concomitant dosing with ritonavir-boosted saquinavir (1,000 mg of saquinavir/100 mg of ritonavir given twice daily). The greater exposure to ketoconazole when given in combination with saquinavir/ritonavir was not associated with unacceptable safety or tolerability. No dose adjustment for saquinavir/ritonavir (1,000/100 mg twice daily) is required when coadministered with 200 mg of ketoconazole once daily, and high doses of ketoconazole (>200 mg/day) are not recommended.

T1080 Effects of Rabeprazole Sodium and Ranitidine Hydrochloride On Gastric Acidity for 2 Consecutive Weeks: A Randomized, Open-Label, Two-Way Crossover Study in Healthy Subjects Using BRAVO ® Capsules Fixed to the Stomach

inhibition in the early post-administration phase (48 hours) in relative to CYP2C19 genotype status. Methods: Fifteen Helicobacter pylori-positive volunteers with three different CYP2C19 genotypes were dosed with twice-daily intravenous infusions of famotidine 20 mg alone, omeprazole 20 mg alone, omeprazole 10 mg plus famotidine 10 mg (half), and omeprazole 20 mg plus famotidine 20 mg (full) for 2 days. The subjects underwent 48-hour intragastric pH monitoring. Results: With homozygous extensive metabolizers (EMs) of CYP2C19, the median first 24-hour intragastric pH with full-concomitant regimen was 4.8 (range; 4.5 5.4), which was significantly higher than that with omeprazole alone [3.9 (2.6 4.7), p = 0.043] or famotidine alone [4.4 (3.8 4.9), p = 0.043]. In heterozygous EMs and poor metabolizers, the respective median first 24-hour pHs attained by omeprazole alone [5.8 (4.3 6.3) and 6.1 (5.3 7.4)] and full-concomitant [5.8 (5.1 6.4) and 5.8 (5.4 6.2)] regimens were significantly higher than those with famotidine alone [4.1 (3.9 6.5) and 4.7 (3.7 5.7), p = all 0.043]. Conclusions: The CYP2C19 genotyping test appears to be a useful tool for determining the optimal treatment for the prevention of hemorrhage or rebleeding from peptic ulcers. If the CYP2C19 genotype status is determined before the hemorrhage, an optimal intravenous infusion regimen consisting of a PPI and an H2RA can be selected based on pharmacogenetic and pharmacogenomic status. We recommend the following intravenous infusion regimens for the faster and stronger acid inhibition: the infusion of omeprazole 20 mg alone twice-daily for PMs and heterozygous EMs, and the concomitant infusion of omeprazole 20 mg plus famotidine 20 mg twice-daily for homozygous EMs.

Effect of levetiracetam on cardiac repolarization in healthy subjects: A single-dose, randomized, placebo- and active-controlled, four-way crossover study

Background: Nonantiarrhythmic drugs may have the potential to prolong the QT interval, leading to potentially fatal ventricular tachycardias, including torsades de pointes.Objective: This study evaluated the potential of the newer-generation, multiple-action antiepileptic drug levetiracetam, which binds to the synaptic vesicle protein SV2A, to affect cardiac repolarization, as detected by prolongation of the QT/corrected QT (QTc) interval.Methods: This was a single-dose, randomized, placebo- and active-controlled, 4-way crossover study in healthy subjects. Subjects were randomly allocated to 1 of 4 different administration sequences. Each sequence included 3 double-blind treatments (levetirace-tam 1000 mg, levetiracetam 5000 mg, and placebo) and 1 open-label treatment (moxifloxacin 400 mg). Triplicate electrocardiograms (ECGs) were obtained at baseline and at various time points over 24 hours after each treatment using continuous Holter monitoring. ECGs were read centrally in a blinded manner. Blood samples for the determination of plasma concentrations of levetiracetam and moxifloxacin were collected before dosing and at 0.5, 1, 1.5, 2, 4, 6, 12, and 24 hours after dosing, within 5 minutes after the ECG recordings. The QT interval was corrected for heart rate using a sex- and study-specific correction (QTcss) as the primary outcome measure and Fridericia's correction (QTcF)as a secondary outcome measure. The primary analysis was performed on the time-matched, baseline-subtracted QTcss (ΔQTcss). The maximum ΔQTcss difference between each active treatment and placebo (ΔΔTcss) was derived from a mixed-effect analysis of variance. Clinical laboratory tests, standard 12-lead ECGs, and vital signs were monitored at regular intervals. Spontaneously reported adverse events were recorded throughout the study.Results: Fifty-two healthy, nonsmoking subjects (26 men, 26 women; 37 white, 9 black, 3 Hispanic, and 3 Asian/Pacific Islander) with a mean (SD) age of 28.4 (7.5) years (range, 18-45 years) and a mean weight of 71.5 (12.6) kg (range, 49-103 kg) participated in the study. Levetiracetam did not significantly prolong the QTcss. The upper bound of the 1-sided 95% CI for the maximum ΔΔTcss was 8.0 milliseconds for levetiracetam 1000 mg and 8.1 milliseconds for levetiracetam 5000 mg, with mean estimates of 4.0 and 4.1 milliseconds, respectively; similar results were obtained for the maximum ΔΔQTcF. Moxifloxacin significantly prolonged the QTcss, with a lower bound of the 1-sided 95% CI for the maximum ΔΔQTcss of 3.7 milliseconds and a mean estimate of 7.7 milliseconds. There was no statistically significant relationship between measured ΔQTcss and the levetiracetam plasma concentration, whereas a significant linear relationship was observed between measured ΔQTcss and the moxifloxacin plasma concentration (slope estimate: 4.4 milliseconds/[μg/mL]); 95% CI, 3.2-5.7; P < 0.001). No unexpected safety concerns arose based on reported adverse events, clinical laboratory evaluations, physical examinations, vital signs, or ECG monitoring during the course of the study.Conclusion: This randomized, placebo- and active-controlled study in healthy adult subjects found no clinically relevant changes in the QTc interval after a single levetiracetam dose of 1000 or 5000 mg.

Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, Has No Pharmacokinetic Interactions With the Antihypertensive Agents Amlodipine, Valsartan, and Ramipril in Healthy Subjects

We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.

Pharmacokinetics and Tolerability of Intramuscular, Oral and Intravenous Aripiprazole??in Healthy Subjects and in??Patients??with Schizophrenia

Patients with schizophrenia or bipolar disorder who are experiencing acute behavioural emergencies often require intramuscular injection of antipsychotics for rapid symptom resolution. The efficacy and tolerability of intramuscular aripiprazole injection has been established in agitated inpatients with schizophrenia or bipolar I disorder. The main objective of the two clinical pharmacology studies reported here was to evaluate the pharmacokinetics of aripiprazole after intramuscular dosing in healthy subjects and in patients with schizophrenia, and after intravenous and oral dosing in healthy subjects. Study 1 was an open-label, randomized, three-treatment crossover study in healthy subjects (n = 18) to assess the bioavailability and pharmacokinetics of intramuscular aripiprazole 5 mg and oral aripiprazole 5 mg relative to intravenous aripiprazole 2 mg. Study 2 was an open-label, nonrandomized, escalating-dose study in patients with schizophrenia (n = 32) to evaluate the pharmacokinetics of intramuscular aripiprazole across a range of doses (from 1 mg to 45 mg). The noncompartmental pharmacokinetic parameters for plasma concentrations of aripiprazole and its active metabolite dehydro-aripiprazole were determined. Safety and tolerability data are also summarized. In study 1, the geometric mean values for the absolute bioavailability of aripiprazole following oral and intramuscular administration were 0.85 and 0.98, respectively. Intramuscular aripiprazole demonstrated more rapid attainment of plasma aripiprazole concentrations than oral aripiprazole (78% and 5% of peak plasma concentration [C(max)] values at 0.5 hours postdose, respectively). The area under the plasma concentration-time curve (AUC) in the first 2 hours was 90% higher after intramuscular administration than after oral administration. For dehydro-aripiprazole, the AUC over the collection interval values were higher, the times to reach the C(max) values were later and the C(max) values were similar for the intramuscular and oral formulations. In study 2, the proportionality of the C(max) and AUC to doses ranging from 1 mg to 45 mg suggests a linear pharmacokinetic profile for intramuscular aripiprazole. More rapid absorption was observed following intramuscular aripiprazole injection than following oral dosing. These results support the recently reported efficacy of intramuscular aripiprazole for managing agitation in patients with schizophrenia or bipolar I disorder.

Pharmacokinetic-Pharmacodynamic Interaction between Nebicapone, a Novel Catechol-O-Methyltransferase Inhibitor, and Controlled-Release Levodopa/Carbidopa 200 mg/50 mg

Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but its use is often associated with development of motor complications. These adverse responses to fluctuations in dopaminergic stimulation can be reduced by concomitant administration of a catechol-O-methyltransferase (COMT) inhibitor. Nebicapone is a new COMT inhibitor currently being developed for use as an adjunct to levodopa/dopa decarboxylase inhibitor in the treatment of PD. This article aimed to investigate the effect of single oral doses (50 mg, 100 mg and 200 mg) of nebicapone on levodopa pharmacokinetics and erythrocyte-soluble COMT (S-COMT) activity when coadministered with a single dose of controlled-release (CR) levodopa/carbidopa 200 mg/50 mg (Sinemet((R)) CR 200/50) in healthy subjects (n = 16). This was a randomized, double-blind, placebo-controlled, four-way crossover study in healthy subjects, with at least 5 days of washout between treatment periods. There was a dose-dependent and significant increase in levodopa extent of exposure (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)]) without a significant change in peak exposure (maximum plasma concentration; [C(max)]). Using placebo as a reference, levodopa geometric mean ratios (GMRs) and 90% CIs following nebicapone 50 mg, 100 mg and 200 mg were, respectively, 1.13 (0.98, 1.30), 1.04 (0.90, 1.19) and 1.10 (0.96, 1.27) for C(max) and 1.26 (1.16, 1.34), 1.37 (1.27, 1.75) and 1.47 (1.42, 1.65) for AUC(infinity). For 3-O-methyldopa (3-OMD), the GMRs and 90% CIs were, respectively, 0.61 (0.55, 0.67), 0.45 (0.41, 0.50) and 0.33 (0.30, 0.36) for C(max) and 0.69 (0.61, 0.78), 0.53 (0.41, 0.61) and 0.41 (0.37, 0.47) for AUC(infinity). Nebicapone dose dependently and significantly decreased COMT activity. Maximum COMT inhibition occurred at 1.5-2.4 hours post-dose and ranged from 56% to 73% with nebicapone 50 mg and 200 mg, respectively. There was a good correlation between plasma concentrations of nebicapone and inhibition of S-COMT activity. Treatments were well tolerated. Following concomitant administration with levodopa/carbidopa CR 200 mg/50 mg, single doses of nebicapone 50 mg, 100 mg and 200 mg significantly and dose-dependently inhibited S-COMT activity, increased systemic exposure to levodopa, and reduced 3-OMD formation.

Dose Proportionality and the Effect of Food on Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, in Healthy Volunteers

Vildagliptin is a potent and selective dipeptidyl peptidase IV inhibitor in development for the treatment of type 2 diabetes that improves glycemic control by enhancing alpha- and beta-cell responsiveness to glucose. Two open-label, single-dose, randomized, crossover studies in healthy subjects (ages 18-45 years) investigated the dose proportionality of vildagliptin pharmacokinetics (n = 20) and the effect of food (n = 24) on vildagliptin pharmacokinetics. There was a linear relationship (r(2) = 0.999) between vildagliptin doses of 25, 50, 100, and 200 mg and area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)). Dose proportionality was assessed using a statistical power model [X = alpha x (dose)(beta)]. The 90% confidence intervals of the proportionality coefficient, beta, for AUC(0-infinity) (1.15-1.19) and C(max) (1.04-1.14) indicated that deviations from dose proportionality were small (<7.7%). Doubling of dose led to 2.1- to 2.3-fold increases in AUC(0-infinity) and C(max) but no dose-dependent changes in time to reach C(max) or terminal elimination half-life. Administration of vildagliptin 100 mg following a high-fat meal decreased C(max) by 19% and AUC(0-infinity) by 10%. Vildagliptin displays approximately dose-proportional pharmacokinetics over the 25- to 200-mg dose range, and administration with food has no clinically relevant effect on vildagliptin pharmacokinetics.

Relative bioavailability of tizanidine 4-mg capsule and tablet formulations after a standardized high-fat meal: A single-dose, randomized, open-label, crossover study in healthy subjects

Background: An immediate-release, multiparticulate capsule formulation of tizanidine has been developed to modify tizanidine pharmacokinetic characteristics in an attempt to decrease adverse events (AEs) while maintaining effectiveness in the management of spasticity. Objective: This study was designed to compare the pharmacokinetic properties and tolerability of a single dose (4 mg) of an immediate-release, multiparticulate tizanidine capsule versus a commercially available tablet (reference) administered after a standardized high-fat meal. Methods: This single-dose, randomized, open-label, 2-way crossover study in healthy, nonsmoking adult subjects was conducted at MDS Pharma Services, Belfast, United Kingdom. Subjects were randomly assigned to receive the capsule-tablet or tablet-capsule treatment. The 2 treatment periods were separated by a 6-day washout period. All treatments were administered after a standardized high-fat meal. To determine plasma tizanidine pharmacokinetic properties, blood samples were collected over 24 hours after administration. The predetermined bioequivalence range for the test drug (capsule) was 80% to 125% of the reference drug (tablet). Drug tolerability was assessed using routine physical examination, including vital-sign measurements; laboratory analysis (hematology, biochemistry, and urinalysis); 12-lead electrocardiography; direct observation; spontaneous reporting; and non specific questioning. Results: This study included 18 subjects (12 men, 6 women; mean [SD] age, 26 [7] years). The mean height and body weight of the subjects were 176 (8) cm and 70.1 (9.6) kg, respectively. The peak exposure, as measured by mean natural logarithm-transformed C max values, was significantly lower with the capsule compared with the tablet (2.7 vs 4.0 ng/mL; P < 0.019), and mean TmaX was significantly longer (2.6 vs 1.2 hours; P < 0.001). The 90% CIs for the capsule:tablet treatment ratios were 70.55 to 121.94 for AUC 0-lat and 70.12 to 118.75 for AUC 0−∞. The capsule did not achieve the protocol-defined definition of bioequivalence when given after a high-fat meal. All AEs were transient and mild in intensity, with asthenia being the most common event with the capsule and tablet formulations, occurring in 5 (28%) and 8 (44%) subjects, respectively. Conclusions: In this small study in healthy volunteers, after a single oral dose was administered following a high-fat meal, the mean C max was significantly lower and mean T max was significantly longer with the capsule formulation of tizanidine compared with the tablet. The capsule formulation was found not to be bioequivalent to the tablet when given with food. Based on these findings, caution is needed when a patient is switched between the capsule and tablet formulations of tizanidine, or when the timing of administration of either formulation is changed in relation to food ingestion.

Evaluation of the potential for pharmacokinetic interaction between fenofibrate and ezetimibe: A phase I, open-label, multiple-dose, three-period crossover study in healthy subjects

Objective:This study was conducted to evaluatethe 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, coadministrationof 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.

Impact of Experimentally Induced Serotonin Deficiency by Tryptophan Depletion on Saliva Cortisol Concentrations

Tryptophan depletion (TD) has been shown to induce a transient mood-lowering effect in psychiatric patients and susceptible healthy subjects. We investigated the effects of TD on cortisol secretion in psychiatric patients and healthy subjects based on the hypothesis that the potential mood-lowering effects may be associated with increased activity of the hypothalamic-pituitary-adrenal axis, thus leading to a rise of cortisol secretion. After TD at 18.00 h, salivary cortisol was sampled in the evening and on the following morning. The first study was a randomized, placebo-controlled, crossover study in healthy subjects. Two further open trials in patients with obsessive-compulsive disorder (OCD) and primary insomnia compared the effects of TD on cortisol with baseline conditions. In healthy subjects, TD significantly diminished cortisol the next morning compared with placebo. In OCD patients and primary insomniacs, cortisol the morning after TD was lowered compared with baseline. Evening cortisol was not affected by TD in any of the groups. Contrary to expectation, TD led to a comparable decrease of morning cortisol in all groups investigated. However, these findings are consistent with former studies analyzing the impact of antiserotonergic drugs on cortisol secretion. The results underline that the antiserotonergic effects caused by TD may influence cortisol secretion.

P1152 APPLICATION OF AN ALPHA-GLUCOSIDASE INHIBITOR IN THE TREATMENT OF GLYCOGEN STORAGE DISEASE TYPE 1. A FEASIBILITY STUDY IN HEALTHY SUBJECTS.

Introduction: Uncooked cornstarch (UCCS) is widely used to maintain normoglycemia in patients with glycogen storage disease type 1 (GSD1). However, compliance of the UCCS treatment is suboptimal because of the unpleasant taste of the UCCS. Acarbose, an alpha-glucosidase inhibitor supposed to delay carbohydrate digestion, added to a carbohydrate rich meal, might be an alternative approach in the treatment of GSD1. A cross-over study in healthy subjects was conducted to investigate the feasibility to apply an alpha-glucosidase inhibitor in the treatment of GSD1. This study compared the absorption profile after ingestion of UCCS with that after ingestion of corn pasta with acarbose. Methods: Seven healthy male volunteers (age: 23 ± 1 (mean ± SE) years, BMI 22 ± 1.1 kg/m2) ingested at least one week apart UCCS in 250 ml water or corn pasta with 12.5 mg of acarbose (CPac). Both test meals contained an equivalent of 50 g of glucose and were naturally enriched with 13C. During the 6 hours following consumption of the test meals plasma glucose and insulin were monitored. Using a primed continuous infusion of D-[6,6-2H2]glucose, the systemic appearance of exogenous glucose (RaE) was estimated, which reflects the intestinal carbohydrate absorption. Results: Significant higher total glucose responses were observed between 60 and 150 min after consumption of UCCS compared to CPac (p<0.04). Insulin responses between 60 and 240 min were significantly higher after ingestion of UCCS than those after ingestion of CPac (p<0.03). In the fasting state, before ingestion of the test meals, the endogenous glucose production was 2.24 ± 0.09 mg/kg/min. Between 30–180 min the mean RaE after consumption of UCCS (2.27 ± 0.24 mg/kg/min) was significantly higher than the mean RaE of CPac (1.16 ± 0.14 mg/kg/min)(p<0.02). Six hours after ingestion of UCCS the recovery of glucose was significantly higher than after ingestion of CPac (88 ± 6% and 45 ± 4% of the administered dose respectively, p<0.02). Conclusion: After ingestion of UCCS the mean RaE between 30 and 180 min equals the rate of endogenous glucose production. Addition of 12.5 mg of acarbose to corn pasta does not result in an absorption profile able to provide for the glucose requirements. The low 6 hours recovery of glucose after ingestion of CPac (45%) indicates that the digestion of corn pasta is inhibited to some extent. Acarbose applied in combination with the amount and type of carbohydrate used in this study is not a suitable alternative in the treatment of GSD1.

Clinical Development of a Cyclosporine Microemulsion in Transplantation

Current clinical difficulties in the use of cyclosporine in transplantation are in part due to its narrow therapeutic window between effective immunosuppression and adverse events and in part due to suboptimal absorption associated with wide pharmacokinetic variability. Under the assumption that the latter aspects are largely formulation-related, a clinical development program was undertaken to compare the conventional formulation (Sandimmun) with a new microemulsion preconcentrate (Neoral). After oral administration, Neoral immediately forms a microemulsion in aqueous gastrointestinal fluids yielding a homogeneous dispersion from which cyclosporine is more readily absorbed. Single-dose crossover studies in healthy subjects were initially performed to document improved bioavailability and dose linearity, lower intrasubject pharmacokinetic variability, and reduced food effect with Neoral. In a subsequent phase of the development program, questions that could only be assessed in transplant patients at steady state were addressed in small, open-label studies under a trough concentration-guided strategy. This approach was necessary to maintain effective immunosuppression while determining appropriate and safe guidelines for converting between formulations, assessing the trough: area under the curve correlation and exploring for potential differences in metabolism. Multicenter, double-blind, randomized investigations were then performed to compare the formulations in stable and de novo transplant populations. In this context, the conversion approach, the safety/tolerability profile, and the attendant pharmacokinetic advantages of the microemulsion formulation were confirmed in larger populations under clinical conditions. It is anticipated that the more precise pharmacokinetic control possible with Neoral will provide a firmer base from which to elucidate the relationship between cyclosporine exposure and graft survival to optimize cyclosporine-based immunosuppressive regimens.

The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil

The effects of alteration of gastric pH and food on the pharmacokinetics of 200 mg doses of cefpodoxime proxetil tablets were studied in two separate randomized, open label, crossover studies in healthy subjects. In the pH study (n = 17 subjects), there was a lead-in period done under fasting conditions, followed by randomization to a four-way crossover of pentagastrin (6 micrograms/kg, subcutaneously), ranitidine (150 mg orally, 10 and 2 hours before dosing with the antibiotic), sodium bicarbonate (12.6 gm), or aluminum hydroxide (120 cc). Gastric pH was determined by nasogastric aspirates before and 10 minutes after the intervention, just before the antibiotic was given. Peak plasma concentrations (Cmax) and area under plasma concentration-time curve (AUC) were highest in fasting and pentagastrin periods and were 35% to 50% lower for all of the other periods (p less than 0.0001). Gastric pH and Cmax and AUC were inversely related (r = 0.66 and r = 0.62; p less than 0.0001 for both). In the food study (n = 16 subjects), there were two lead-in periods, one done while subjects were fasting and one while they were normal diet, followed by randomization to a four-way crossover of either high or low protein diets, or high or low fat diets. There were six meals in each diet. Dosing with the antibiotic was done at the midpoint of the fourth meal. Cmax and AUC were 22% to 34% higher for all diets than for the fasting period (p less than 0.0001), whereas the time to Cmax was unchanged. These studies demonstrated that absorption of cefpodoxime proxetil is best at low gastric pH or in the presence of food, which suggests that the role of gastrointestinal function on the pharmacokinetic profile is complex.