Intranasal loteprednol etabonate in healthy male subjects: pharmacokinetics and effects on endogenous cortisol

Loteprednol etabonate (LE) is a glucocorticoid soft drug that is currently in development for intranasal use. The main objectives of this study were to examine the pharmacokinetics and potential effects on systemic cortisol of two intranasal suspension formulations of LE and to compare these findings with placebo and fluticasone propionate (FP, Flonase) control treatments. In this randomized, double-blind (except for FP), parallel-group study (n = 8/group), all subjects received for 14 days once daily in the morning two puffs of the following nasal spray formulations into each nostril: LE 0.1% (400 microg/day), LE 0.2% (800 microg/day), FP 0.05% (200 microg/day), and placebo. Drug trough levels were determined on days 1, 5, 12, 13, and 14, and a full pharmacokinetic profile was established on day 14, and 24-hour serum cortisol profiles were assessed prior to treatment (i.e., at baseline) and after the last dose. All subjects completed the protocol without treatment-emergent adverse findings. All formulations were rapidly absorbed (t(max) less than 1 h). The rather short mean terminal half-lives of 2.2 +/- 1.5 hours and 1.8 +/- 1.0 hours for LE 400 microg and LE 800 microg, respectively, and 4.2 +/- 1.8 hours for the 200-microg FP treatment explained the lack of any accumulation. Mean peak concentrations (C(max)) were 139 +/- 57 pg/mL with LE 400 microg and 164 +/- 54 pg/mL with LE 800 microg and thus fairly independent from dose. The 200-microg FP treatment resulted in a C(max) of only 15.5 +/- 5.9 pg/mL. Mean measured AUC(0-t) values (193 +/- 87 pg/h/mL(-1), 300 +/- 183 pg/h/mL(-1), and 40 +/- 34 pg/h/mL(-1) for LE 400 microg, LE 800 microg, and FP 200 microg, respectively) showed high variability and suggested nonlinear pharmacokinetics for the LE formulations, indicative of a less complete systemic uptake of LE from the 0.2% concentration. None of the treatments (LE 400 microg, LE 800 microg, and FP 200 microg) showed evidence for serum cortisol suppression when compared with placebo, respectively. The uptake and systemic exposure appears less complete from the 0.2% LE concentration, which principally favors this formulation for further clinical development.     

Pharmacokinetics of beclomethasone 17-monopropionate from a beclomethasone dipropionate extrafine aerosol in adults with asthma

OBJECTIVE: The objectives of this study were to test the dose and strength proportionalities of beclomethasone dipropionate (BDP) delivered from two strengths of a pressurized extrafine solution formulation. METHODS: Thirty adults with mild, stable asthma, aged between 18 years and 70 years, completed the study; written informed consent was obtained from all patients. Each patient received, according to a randomized four-period crossover design, 100 microg BDP as two inhalations from 50-microg/actuation strength, 100 microg BDP as one inhalation from 100-microg/actuation strength, 400 microg BDP as eight inhalations from the 50-microg/actuation strength, and 400 microg BDP as four inhalations from the 100-microg/actuation strength. Patients self-administered all inhalations at the same time of day during the study. Blood samples were collected for 12 h during each period to assay for the presence of BDP and metabolites. The log-transformed pharmacokinetic data were compared for proportionality equivalence using a confidence-interval approach. RESULTS: Almost all the BDP-derived material in the plasma was the active metabolite beclomethasone 17-monopropionate (17-BMP). Due to low levels, neither elimination half-life ( t(1/2)) nor the area under the plasma concentration-time curve (AUC) for 17-BMP could be calculated for the 100-microg BDP doses. Dose proportionality of the 100-microg and 400-microg BDP doses, using 17-BMP maximum plasma concentration (C(max)) was demonstrated for each strength. Strength proportionality of the 50-microg and 100-microg/actuation strengths was observed for C(max) at both dose levels and for AUC at the higher dose level. The t(1/2) of 17-BMP was found to be approximately 2.8 h. CONCLUSION: This study demonstrated both the strength and dose proportionalities of the BDP extrafine aerosol. This important information will allow physicians maximum flexibility in prescribing this aerosol product.     

Pharmacokinetics of DS-96, an alkylpolyamine lipopolysaccharide sequestrant, in rodents

The pharmacokinetics of DS-96, an N-alkylhomospermine analog designed to sequester bacterial lipopolysaccharides, has been determined in rodent species. The elimination half-life in mice and rats are about 400 and 500 min, respectively, with other PK parameters being quite similar in the two rodent species. Interestingly, the mouse intravenous plasma concentration time curves exhibit an apparent absorption phase. While the rat intravenous data did not exhibit a pronounced apparent absorption phase immediately following injection, plasma levels did increase between 10 and 30 min following an expected drop from time 0 to 5 min. The data are consistent with first-pass uptake, possibly by the lung, with back diffusion as a function of time. The observed C(max) values of 1.36 microg/mL in the mouse intraperitoneal model suggest that a plasma concentration of 0.5-1 microg/mL corresponds to complete protection for a 200 ng/animal dose of intraperitoneally administered LPS in the D-galactosamine-primed model of endotoxin-induced lethality.     

Single-dose and multiple-dose pharmacokinetics and safety of telbivudine after oral administration in healthy Chinese subjects

The pharmacokinetics of telbivudine, an L-nucleoside with potent activity against hepatitis B virus, was assessed in 42 healthy Chinese volunteers. Subjects were assigned to receive a single oral dose of 200, 400, or 800 mg telbivudine or repeat doses of 600 mg/d. Telbivudine was absorbed rapidly and exhibited dose-related plasma exposure. After reaching maximum concentration (C(max)) at a median time of 2.0 to 2.5 hours, plasma disposition of the drug was biphasic with a mean terminal half-life ranging from 39.4 to 49.1 hours. Telbivudine accumulated slightly after repeat doses, and steady state was reached after 5 to 6 consecutive doses of 600 mg/d. The mean steady-state C(max) and area under the plasma concentration-time curve over the dosing interval of telbivudine 600 mg were 3.7 microg/mL and 26.1 microg x h/mL, respectively. Cumulative urinary excretion of telbivudine over 32 hours represented 24.4% of the administered dose, with a mean renal clearance of 6.6 L/h. Telbivudine was well tolerated in the studied dose range in healthy Chinese subjects, with no pattern of dose-related clinical or laboratory adverse events.     

Pharmacokinetics of dexloxiglumide after administration of single and repeat oral escalating doses in healthy young males

OBJECTIVE: To assess the pharmacokinetics, safety and tolerability of dexloxiglumide, a new CCK1 receptor antagonist currently under development for the treatment of the constipation-predominant irritable bowel syndrome. SUBJECTS AND METHODS: Twelve volunteers were enrolled in the present study and received orally 100, 200 and 400 mg of dexloxiglumide as tablets as a single dose followed by repeated t.i.d. doses for 7 days according to a randomized, double-blind, double-dummy complete crossover design. Plasma and urine were collected before drug administration and up to 72 h after dosing. Dexloxiglumide plasma and urinary concentration, determined using validated HPLC methods with UV detection, were used for the pharmacokinetic analysis by standard noncompartmental methods. In addition, dexloxiglumide safety and tolerability were evaluated throughout the study period by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence and severity of adverse events. RESULTS: After a single oral administration, dexloxiglumide was rapidly bioavailable with mean t(max) ranging from 0.9 - 1.6 h at all doses. The mean peak plasma concentrations (Cmax) were 1.7+/-0.6, 5.4+/-1.7, and 11.9+/-4.7 microg/ml, and the mean area under the plasma concentration-time curves (AUC) were 4.4+/-3.3, 8.6+/-3.6, and 18.3+/-5.9 microg x h/ml at the 3 doses, respectively. Apparent plasma clearance (CL/F) was 30.8+/-13.9, 27.2+/-10.6, and 21.1+/-8.6 l/h at the 3 doses, respectively. The apparent elimination half-life from plasma (t1/2) ranged from 2.6 - 3.3 h at the 3 doses. The excretion of unchanged dexloxiglumide in 0 - 72 h urine accounted for approximately 1% of the administered dose and this was true for all doses. Dexloxiglumide renal clearance (CLR) averaged 0.4+/-0.4, 0.4+/-0.2, and 0.3+/-0.3 l/h for the 3 doses, respectively. After the last dose of the repeated dosing period dexloxiglumide Cmax occurred at 1.1 - 1.6 h after drug administration and averaged 2.4+/-1.3, 7.1+/-2.9, and 15.3+/-2.7 microg/ml for the 3 doses, respectively. The AUC values averaged 5.9+/-3.0, 16.0+/-8.8, and 50.8+/-38.1 microg x h/ml, respectively. The area under the plasma concentration-time curve calculated at steady state within a dosing interval (AUCss) averaged 4.6+/-1.6, 11.3+/-3.6, and 28.4+/-8.2 microg x h/ml, whereas CL/F averaged 20.3+/-8.3, 16.3+/-9.0, and 10.3+/-5.0 l/h at the 3 doses, respectively. Dexloxiglumide t1/2 could not be accurately calculated due to the high inter-subject variability and to sustained dexloxiglumide plasma concentrations that precluded the identification ofthe terminal phase of the plasma concentration-time profiles. However, it appeared that dexloxiglumide t1/2 was considerably prolonged at the dose of 400 mg. CLR averaged 0.4+/-0.4, 0.3+/-0.3, and 0.3+/-0.1 l/h for the 3 doses, respectively. After a single dose, the plasma pharmacokinetics of dexloxiglumide were dose-independent in the dose range 100 - 400 mg. After repeated dose the pharmacokinetics of dexloxiglumide were virtually dose-independent in the dose range 100 - 200 mg. A slight deviation from linear pharmacokinetics was found with a dose of 400 mg. Dexloxiglumide plasma pharmacokinetics were also time-independent in the dose range 100 - 200 mg with a deviation from expectation based on the superimposition principle with a dose of 400 mg. Dexloxiglumide urinary excretion and renal clearance were both dose- and time-independent in the dose range 100 - 400 mg. The safety and tolerability of dexloxiglumide administered to healthy young males was good up to the maximum investigated dose of 400 mg both after single and after repeated doses. CONCLUSIONS: The safety and pharmacokinetic profile of dexloxiglumide when the drug is administered as single and repeated doses in the dose range 100 - 400 mg provides the rationale for the choice of the treatment schedule (200 mg t.i.d.) for the efficacy trials in patients with (constipation-predominant) irritable bowel syndrome.     

Drug delivery performance of the mometasone furoate dry powder inhaler.

The mometasone furoate dry powder inhaler (MF-DPI) is a multiple-dose, breath-actuated inhaler that uses agglomerates of micronized MF and lactose. In vitro analyses evaluated dose uniformity, variability, and particle size distribution of the MF-DPI. Tests of first, middle, and end doses from 10 inhalers each of the 200-microg MF/inhalation and 400-microg MF/inhalation dose sizes found that delivered doses (doses emitted from the inhaler) ranged from 91% to 112% of claimed doses for all tested DPIs. The mean MF doses delivered at 28.3 L/min were 100% and 94% of the doses delivered at 60 L/min for the 200-microg and 400-microg dose sizes, respectively; the relative standard deviation of doses was < or = 6.1% within this range of inhalation rates. At a flow rate of 60 L/min, the mean delivered doses, compared to claimed doses for inspiration times of 1-3 sec, were 102-104% for the 200-microg dose size and 98.8-102% for the 400-microg dose size. The mean cumulative fraction of dose delivered at 60 L/min for 2 sec which consisted of particles of <6.5 microm in diameter was 39.9% (+/-2.5 SD; n = 9) for the 200-microg dose size and 35.6% (+/-3.4 SD; n = 9) for the 400-microg dose size. All MF-DPI inhalers tested were well within U.S. and European compendial standards and regulatory guidelines for dose uniformity. An appropriate and reproducible fraction of the delivered dose was within the optimal particle size range for therapeutic effectiveness.     

Pharmacokinetic differences between chlorofluorocarbon and chlorofluorocarbon-free metered dose inhalers of beclomethasone dipropionate in adult asthmatics

We have compared the serum pharmacokinetics of the metabolites of beclomethasone dipropionate after inhalation from chlorofluorocarbon (CFC) and hydrofluoroalkane HFA-134a (HFA) formulations in asthmatic patients. Twenty-three patients completed this open-label, randomized, single-dose, three-period crossover study. Each patient received in separate periods 200 microg or 400 microg HFA-beclomethasone dipropionate, or 400 microg CFC-beclomethasone dipropionate. Venous blood samples were collected over 24 h for the determination of beclomethasone esters and beclomethasone in the serum. Significant differences in pharmacokinetics following HFA- and CFC-beclomethasone dipropionate were observed. Following a 400 microg beclomethasone dipropionate dose, the HFA formulation gave mean maximum concentrations (Cmax) and area under the curve (AUC) values of beclomethasone esters of 1153 pg mL(-1) and 4328 pg h mL(-1), respectively, and beclomethasone Cmax and AUC values of 69 pg mL(-1) and 682 pg h mL(-1), respectively. These values were approximately 2-3-fold those seen with the CFC formulation (beclomethasone esters Cmax and AUC of 380 pg mL(-1) and 1764 pg h mL(-1), respectively; beclomethasone Cmax and AUC of 41 pg ml(-1) and 366 pg h mL(-1), respectively). Beclomethasone esters, the major component of beclomethasone dipropionate in the serum, peaked significantly earlier for the HFA formulation (0.8 h) than for the CFC formulation (2 h). Tests for dose proportionality of beclomethasone esters pharmacokinetics following HFA-beclomethasone dipropionate showed that the two hydrofluoroalkane strengths were proportional. The more rapid and greater efficiency of systemic drug delivery of the HFA formulation compared with the CFC formulation can be explained if most of each inhalation from CFC-beclomethasone dipropionate is swallowed and absorbed orally, whereas most of each inhalation from HFA-beclomethasone dipropionate is absorbed through the lungs. There is a need for comprehensive dose-response efficacy trials, with the use of the steep portion of the dose-response relationship, to evaluate the significance of these pharmacokinetic differences.     

Systemic absorption of ketoconazole from vaginal pessaries.

Eight healthy female subjects were each given (a) ketoconazole 400 mg orally, (b) ketoconazole 400 mg as a single vaginal pessary, (c) ketoconazole 800 mg as two vaginal pessaries, and (d) ketoconazole 1200 mg as three vaginal pessaries. The area under the plasma concentration time curve (AUC) after the oral dose was 51.41 +/- 10.99 mg l-1 h (mean +/- s.d.) and the half-life of ketoconazole was 2.98 +/- 1.41 h. The AUCs after vaginal administration were 0.27 +/- 0.14, 0.52 +/- 0.25, and 0.43 +/- 0.22 mg-1 l h following the 400, 800 and 1200 mg pessaries respectively. Systemic absorption of single doses of vaginally administered ketoconazole appears to be negligible in the absence of vaginal infection. There were no local or systemic side effects related to ketoconazole in these healthy volunteers.     

Pharmacokinetics and safety of recombinant human parathyroid hormone (1-34) (teriparatide) after single ascending doses in Chinese healthy volunteers

The pharmacokinetics and safety of recombinant human parathyroid hormone (1-34) [rhPTH (1-34)] after single ascending doses were evaluated in Chinese healthy volunteers. Nine healthy volunteers (five male and four female) were recruited for an open label, randomized, three multiply three crossover, single ascending dose (10, 20, and 40 microg) study. Using a validated radioimmunoassay, we determined the plasma concentrations of rhPTH (1-34). The mean peak plasma concentration (Cmax) were 123.6, 195.6, and 318.2 pg x mL(-1) respectively, and were reached from 25.6 to 36.1 min after subcutaneous administration. After Cmax was reached, the plasma drug level decreased quickly, with elimination halflife (t(1/2)) of 53.9 to 64.1 min. The mean AUC(0-infinity) (the area under the plasma concentration versus time curve from time zero to infinite) of rhPTH (1-34) were 11794.2 +/- 974.8, 21606.7 +/- 4753.9, 33877.0 +/- 8374.4 pg x min x mL(-1), respectively. The mean AUC(0-t) (the area under the plasma concentration versus time curve from time zero to the last quantifiable concentration) of rhPTH (1-34) were 9034.4 +/- 1073.9, 17883.3 +/- 4597.1, 31693.5 +/- 6574.8 pg x min x mL(-1), respectively. Dose-related linear trend were observed for AUC(o-t) and Cmax of rhPTH (1-34). t(1/2) and Tmax (time to Cmax) of rhPTH (1-34) were independent of administered dose. rhPTH (1-34) was safe and well tolerated by all volunteers.     

Evaluation of the anti-diabetic property of Morinda lucida leaves in streptozotocin-diabetic rats

The hypoglycaemic and anti-hyperglycaemic activities of a methanol extract of Morinda lucida Benth. (Rubiaceae) leaves were studied in normal and streptozotocin-diabetic rats. In normal rats, the extract demonstrated a significant (P < 0.05) and dose-dependent hypoglycaemic activity within 4 h after oral administration. The plasma glucose level of 400 mg kg(-1) of the extract at 4 h was 42.5 +/- 0.4 mg/100 mL (control 67.4 +/- 1.2 mg/100 mL). After 12 h, the plasma glucose level of rats administered 50, 100, 200 or 400 mg kg(-1) extract fell to 51.9 +/- 1.2, 47.3 +/- 0.8, 43.1 +/- 0.4 and 40.0 +/- 0.5 mg/100 mL, respectively. In hyperglycaemic rats, the extract produced a significant (P < 0.05) anti-diabetic effect from day 3 after oral administration, with 400 mg kg(-1) extract-treated animals having a plasma glucose level of 248.7 +/- 5.3 mg/100 mL compared with glibenclamide (10 mg kg(-1))-treated animals with a plasma glucose level of 251.5 +/- 5.8 mg/100 mL. These results suggest that the leaves of Morinda lucida have a strong glucose lowering property when administered to streptozotocin-treated rats.     

Absolute bioavailability, rate of absorption, and dose proportionality of sulpiride in humans.

The pharmacokinetics of orally administered sulpiride was determined in a series of three studies. In the first study, 12 subjects received an oral solution (200 mg) and an iv dose (100 mg). The second study also included an iv dose, and examined the absorption of 200-, 300-, and 400-mg doses given as 50-mg capsules to six subjects. The third study compared the bioavailability of a 200-mg capsule dose with a 200-mg im dose in eight subjects. The concentration of sulpiride in plasma, red blood cells, and urine was measured by HPLC. The disposition of the drug was generally best described by a two-compartment pharmacokinetic model, with absorption appearing to occur by two sequential zero-order processes. The fraction of dose absorbed after oral administration was approximately 30% based on plasma and urine data. After the 200-mg dose, the mean elimination half-life was 7.0 h, and the mean residence time was 8.4 h. For each subject, total clearance, corrected for the fraction absorbed, and renal clearance were similar. The dose proportionality study demonstrated linear disposition kinetics.     

Bioequivalence following buccal and sublingual placement of fentanyl buccal tablet 400 microg in healthy subjects

BACKGROUND AND OBJECTIVE: The fentanyl buccal tablet (FBT) is formulated to enhance the rate and extent of fentanyl absorption across the buccal mucosa. FBT is indicated for the management of breakthrough pain (a transient flare of pain on a background of chronic pain otherwise controlled by treatment with opioids) in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. This study assessed the bioequivalence of a single 400-microg dose of FBT following buccal (i.e. above a molar tooth between the upper gum and cheek) and sublingual (i.e. placed under the tongue) placement in order to provide an alternative option to patients. METHODS: Healthy subjects were randomized to receive one FBT 400 microg buccally and sublingually (with naltrexone to minimize opioid effects) in an open-label, crossover design. Bioequivalence, as determined from the maximum plasma drug concentration (C(max)) and the area under the plasma drug concentration-time curve from time 0 to infinity (AUC(infinity)), was established if the 90% confidence interval (CI) for the ratio of the means of sublingual/buccal values fell within the range of 0.80 to 1.25. RESULTS: Ninety subjects were enrolled (67 men, 23 women; median age 24 years), and 78 completed the study. The criteria for bioequivalence were met for both C(max) and AUC(infinity) for the two sites of tablet placement: sublingual/buccal ratio for C(max) = 0.868 (90% CI 0.815, 0.924); sublingual/buccal ratio for AUC(infinity) = 0.947 (90% CI 0.901, 0.995). Buccal and sublingual placement resulted in similar values for both AUC from time 0 to t(max') (AUC(tmax')), where t(max') is the median time to C(max) of a single 400-microg dose of FBT administered buccally (mean [SD]: 0.35 [0.16] ng . h/mL buccal; 0.35 [0.16] ng . h/mL sublingual) and for time to C(max) (median [range]: 0.75 [0.33-3.13] hours buccal; 0.78 [0.17-3.00] hours sublingual). FBT was generally well tolerated following placement at both sites in healthy volunteers administered naltrexone. CONCLUSION: The results of this study support sublingual FBT placement as a viable alternative to buccal placement in patients who may require an alternate administration site.     

Inhaled mometasone furoate: a review of its use in adults and adolescents with persistent asthma

Mometasone furoate is a corticosteroid with relatively high in vitro potency. Recent randomised, double-blind, multicentre trials have assessed the efficacy of mometasone furoate delivered by dry powder inhaler over 12 weeks in adults and adolescents with mild to severe persistent asthma. Mometasone furoate 200 microg twice daily or 400 microg once daily in the morning or 200 microg once daily in the evening improved lung function, asthma symptom scores and use of rescue medication to a significantly greater extent than placebo in patients who had previously received only short-acting inhaled beta2-adrenoceptor agonists alone as treatment in 3 trials (n = 195 to 306). In studies in 227 to 733 patients with mild to moderate asthma who were receiving ongoing treatment with inhaled corticosteroids prior to enrolment, mometasone furoate 100 to 400 microg twice daily was consistently better at improving the above indicators of asthma than placebo. Mometasone furoate 100 to 200 microg twice daily was as effective as beclomethasone dipropionate 200 microg twice daily or budesonide 400 microg twice daily and mometasone furoate 200 microg twice daily was as effective as fluticasone propionate 250 microg twice daily. Mometasone furoate 400 or 800 microg twice daily was also consistently more effective than placebo in reducing oral corticosteroid dosages and improving lung function and asthma symptoms in 132 patients with oral corticosteroid-dependent asthma. Once daily administration of mometasone furoate 400 microg appears to be as effective at improving indicators of asthma as twice daily administration of 200 microg. Patients receiving mometasone furoate < or =800 microg/day and recipients of placebo experienced a similar overall incidence of adverse events considered to be related to treatment. The most common of these events were oral candidiasis, headache, pharyngitis and dysphonia. Mometasone furoate 100 to 400 microg twice daily, beclomethasone dipropionate 200 microg twice daily, budesonide 400 microg twice daily or fluticasone propionate 250 microg twice daily were similarly tolerated. CONCLUSION: Inhaled mometasone furoate is well tolerated, with minimal systemic activity and is equally effective when administered as a divided dose or as a single daily dose. Use of the drug can result in a decrease in requirements for oral corticosteroids in patients with oral corticosteroid-dependent asthma and is as effective as other inhaled corticosteroids currently used in the treatment of mild to moderate persistent asthma. Thus mometasone furoate is suitable for the control of mild to severe persistent asthma in adults or adolescents.     

Single-dose pharmacokinetics of roflumilast in children and adolescents

Roflumilast is an orally administered phosphodiesterase 4 inhibitor that has potential for use in pediatric patients with asthma. The pharmacokinetics of roflumilast and roflumilast N-oxide were examined in adolescents and children with stable mild to moderate asthma in an open-label crossover study with age-stratification and 2 treatment periods (100-microg dose in period 1, 250-microg dose in period 2) separated by a washout period. Plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using standard noncompartmental methods and compared between study groups and within the entire cohort. Roflumilast was well tolerated. Linear relationships were evident for dose and area under the plasma drug concentration-time curve extrapolated to infinity for both roflumilast (r(2) = 0.36, P < .01) and roflumilast N-oxide (r(2) = 0.39, P < .01). With the exception of dose-normalized maximum plasma concentration (mean 1.1 and 0.8 microg/L per 1 microg/kg dose for adolescents and children, respectively), pharmacokinetic parameters for roflumilast and roflumilast N-oxide were not different between age groups and were similar to adults.     

Pharmacokinetics and excretion of gamma-hydroxybutyrate (GHB) in healthy subjects

In Europe and the United States, the recreational use of gamma-hydroxy butyric acid (GHB) at dance clubs and "rave" parties has increased substantially. In addition, GHB is used to assist in the commission of sexual assaults. The aim of this controlled clinical study was to acquire pharmacokinetic profiles, detection times, and excretion rates in human subjects. Eight GHB-na?ve volunteers were administered a single 25-mg/kg body weight oral dose of GHB, and plasma, urine, and oral fluid specimens were analyzed by using gas chromatography-mass spectrometry (GC-MS). Liquid-liquid extraction was performed after acid conversion of GHB to gamma-butyrolactone. Limits of quantitation of 0.1 (oral fluid), 0.2 (urine), and 0.5 microg/mL (plasma) could be achieved in the selected ion monitoring mode. GHB plasma peaks of 39.4 +/- 25.2 microg/mL (mean +/- SEM) occurred 20-45 min after administration. The terminal plasma elimination half-life was 30.4 +/- 2.45 min, the distribution volume 52.7 +/- 15.0 L, and the total clearance 1228 +/- 233 microL/min. In oral fluid, GHB could be detected up to 360 min, with peak concentrations of 203 +/- 92.4 microg/mL in the 10-min samples. In urine, 200 +/- 71.8 and 230 +/- 86.3 microg/mL, were the highest GHB levels measured at 30 and 60 min, respectively. Only 1.2 +/- 0.2% of the dose was excreted, resulting in a detection window of 720 min. Common side-effects were confusion, sleepiness, and dizziness; euphoria and change of vital functions were not observed. GHB is extensively metabolized and rapidly eliminated in urine and oral fluid. Consequently, samples should be collected as soon as possible after ingestion.     

Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain

AIMS: It is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. METHODS: Eleven Caucasian patients (seven male and 4 female, aged 34-75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double-blind, cross-over trial, consisting of three 1-day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 microg, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated by noncompartment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire. RESULTS: The data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 microg) for dose adjusted AUC (F = 0.42, P = 0.6660), dose adjusted C(max) (F = 0.08, P = 0.9206) and Tmax (F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400-100microg) in dose adjusted AUC from the three-period crossover analysis was -0.016 min.ng/ml (t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25-40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. t(max) increased from 39.7 +/- 17.4 to 48.7 +/- 26.3 and 56.7 +/- 24.6 min for the 100, 200 and 400 microg doses, respectively. Adverse events were few and did not increase with increasing dose. CONCLUSION: With this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8-11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.     

Gel-forming erodible inserts for ocular controlled delivery of ofloxacin

A new application of high molecular weight (400 kDa) linear poly(ethylene oxide) (PEO) in gel-forming erodible inserts for ocular controlled delivery of ofloxacin (OFX) has been tested in vitro and in vivo. Inserts of 6 mm diameter, 20 mg weight, medicated with 0.3 mg OFX, were prepared by powder compression. The in vitro drug release from inserts was mainly controlled by insert erosion. The erosion time scale was varied by compounding PEO with Eudragit L100 (EUD) 17% neutralized (EUDNa17) or 71% neutralized (EUDNa71). The insert erosion rate depended on the strength of interpolymer interactions in the compounds, and on the hydrophilic-hydrophobic balance of compounds. Immediately after application in the lower conjunctival sac of the rabbit eyes, the inserts based on plain PEO, PEO-EUDNa17 or PEO-EUDNa71 formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. The gel residence time in the precorneal area was in the order PEO-EUDNa71 < PEO < PEO-EUDNa17. Compared to commercial OFX eyedrops, drug absorption into the aqueous humor was retarded by the PEO-EUDNa71 inserts, and both retarded and prolonged by the PEO-EUDNa17 inserts, while C(max) (maximal concentration in the aqueous) and AUC(eff) (AUC in the aqueous for concentrations > MIC) were barely altered by either insert type. On the other hand, C(max), AUC(eff) and t(eff) (permanence time in the aqueous at concentrations > MIC) were strikingly increased by plain PEO inserts with respect to commercial eyedrops (5.25 +/- 0.56 vs. 1.39 +/- 0.05 microg ml(-1); 693.6 vs. 62.7 microg ml(-1) min; and 290 vs. 148 min, respectively). Bioavailability increase has been ascribed to PEO mucoadhesion and/or increased tear fluid viscosity.     

Lack of pharmacokinetic interactions between steady-state zonisamide and valproic acid in patients with epilepsy

OBJECTIVES: This study evaluated the effect of the addition of zonisamide on valproic acid (valproate sodium) pharmacokinetics under steady-state conditions in patients with epilepsy. A second aim was to characterise zonisamide pharmacokinetics in the presence of valproic acid. METHODS: Twenty-two patients (males and females, 18-55 years of age) with their seizure disorder stabilised on valproic acid monotherapy were included in a two-centre, open-label, one-way drug-interaction trial. The zonisamide dose was gradually increased from 100 mg/day to 400 mg/day. Three pharmacokinetic profiles were obtained: on days -7 and -1, to assess pharmacokinetic parameters of oral valproic acid administered alone, and on day 35, after 14 days of zonisamide treatment at the maximal tolerated dose, to evaluate the effect of zonisamide on valproic acid pharmacokinetics and to characterise zonisamide pharmacokinetics in the presence of valproic acid. RESULTS: Seventeen patients completed the study, with 16 patients contributing to the pharmacokinetic analyses. Coadministration of zonisamide and valproic acid appeared reasonably well tolerated. Steady-state dosing of zonisamide (200mg twice daily) had no statistically significant effect on the mean (+/- SD) maximum observed plasma concentration (C(max)) [70.8 +/- 20.5 vs 69.2 +/- 27.0 microg/mL], area under the plasma concentration-time curve from the time of dosing to 12 hours post-dose (AUC(12)) [689.3 +/- 250.4 vs 661.8 +/- 251.3 microg . h/mL] or other evaluated pharmacokinetic parameters for valproic acid measured before and after zonisamide administration. Furthermore, 90% confidence intervals for the ratio of the geometric means (day 35/day -1) of valproic acid pharmacokinetic exposure measures fell only slightly outside the 'no effect' range of 0.80-1.25. In the presence of valproic acid, mean zonisamide oral clearance (1.23 L/h) and elimination half-life (52.5 hours) are generally consistent with values reported for healthy volunteers receiving zonisamide monotherapy. CONCLUSION: There is no apparent clinically significant effect of steady-state dosing of zonisamide on valproic acid pharmacokinetics, and valproic acid did not appear to affect the pharmacokinetics of zonisamide, indicating that no dosage adjustment of either drug should be required when they are used in combination in patients with epilepsy.     

Pharmacokinetics of modified oral calcitonin product in healthy volunteers

STUDY OBJECTIVE: To assess the preliminary pharmacokinetics, pharmacodynamics, safety, and tolerability of single oral doses of a chemically modified salmon calcitonin product, CT-025, in healthy volunteers. DESIGN: Phase I, exploratory, five-way, open-label, nonrandomized, crossover study. SETTING: Clinical research center. SUBJECTS: Twelve healthy volunteers aged 22-44 years. INTERVENTION: A single oral dose of CT-025 was administered on 5 separate days with a 72-hour washout period between doses. Each dose consisted of CT-025 160 or 320 microg in varying relative concentrations of a mixture of excipients (formulations A, B, and C). MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected for determination of plasma CT-025, total serum calcium, and ionized serum calcium concentrations during the 4-hour period after dose administration. The data are the results from four of the five dosing days, when subjects received CT-025 in high and low concentrations of excipients. The data indicate that CT-025 was rapidly absorbed from the gastrointestinal tract. Mean peak plasma concentrations ranging from 51+/-51-110+/-59 pg/ml were observed 36-54 minutes after administration. Mean terminal elimination half-lives ranged from 54-76 minutes. There was a trend for the mean maximum concentration and area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable plasma concentration to increase with dose. Single oral doses of CT-025 160 and 320 microg were pharmacologically active, inducing a statistically significant decrease in total and ionized serum calcium concentrations. The rate of decrease in ionized serum calcium concentration was significantly related to the CT-025 dose. Single ora doses were well tolerated; some subjects experienced mild and transient nausea. CONCLUSION: Single doses of CT-025 were absorbed into the systemic circulation after oral administration and were well tolerated in healthy volunteers at doses up to 320 microg. These data suggest that oral delivery of salmon calcitonin becomes feasible with this product and support further clinical investigation of CT-025 as a treatment for osteoporosis and osteoporotic bone pain.     

Carbamazepine-nefazodone interaction in healthy subjects

The pharmacokinetic interaction between nefazodone and carbamazepine was investigated in 12 healthy male volunteers. Subjects received nefazodone 200 mg twice daily for 5 days, and blood sample collection was performed on day 5 for 0- to 48-hour pharmacokinetic analysis. A 4-day wash-out phase then followed from days 6 to 9. Carbamazepine 200 mg was administered once daily from days 10 to 12, and then 200 mg was given twice daily from days 13 to 44. A 0- to 48-hour pharmacokinetic analysis was performed on day 38. Nefazodone 200 mg twice daily was added to the dosing regimen from days 40 to 44, and a subsequent 0- to 48-hour pharmacokinetic analysis was performed on day 44. Coadministration of nefazodone increased steady-state plasma area under the concentration-time curve (AUC) of carbamazepine from 60.77 (+/-8.44) to 74.98 (+/-12.88) microg x hr/mL (p < 0.001) and decreased the active carbamazepine-10,11-epoxide metabolite AUC concentration from 7.10 (+/-1.16) to 5.71 (+/-0.52) microg x hr/mL (p < 0.005). During the combination, the steady-state AUC of nefazodone decreased from 7,326 (+/-3,768) to 542 (+/-191) ng x hr/mL, and the AUCs of its metabolites (hydroxynefazodone, meta-chlorophenylpiperazine, and triazoledione) decreased significantly as well (p < 0.001). Coadministration of nefazodone 200 mg twice daily and carbamazepine 200 mg twice daily was found to be safe and well tolerated; however, the increased plasma exposure to carbamazepine may warrant monitoring of plasma carbamazepine concentrations with the combination. However, higher doses (>400 mg/day) of carbamazepine could yield more extensive induction, affecting tolerability of the combination. No change in the initial nefazodone dose is necessary, and subsequent dose adjustments should be made on the basis of clinical effects; however, the repercussion of carbamazepine induction of nefazodone metabolism on the antidepressant efficacy has yet to be studied.