Pharmacokinetics of gabapentin after a single day and at steady state following the administration of gastric-retentive- extended-release and immediate-release tablets: a randomized, open-label, multiple-dose, three-way crossover, exploratory study in healthy subjects.

BACKGROUND: Gabapentin absorption is mediated by a saturable transporter system located in the upper gastrointestinal tract, indicating a short window of absorption. Therefore, conventional sustained formulations would likely result in decreased bioavailability, as the dosage form would pass through the window of absorption before the drug could be completely released. OBJECTIVE: The aim of this study was to compare the pharmacokinetics of an oral, gastric-retentive, gabapentin extended-release (G-ER) formulation with a gabapentin immediate-release (G-IR) formulation after single and multiple daily doses in healthy subjects. METHODS: In this open-label, multiple-dose, 3-way crossover, exploratory study, healthy male and female subjects (aged 18-65 years) were randomized to receive doses of 1800 mg G-ER in accordance with the following regimens: G-ER QD (8 pm), G-ER BID in divided doses (600 mg at 8 am and 1,200 mg at 8 pm), or G-IR TID (600 mg at 8 am, 2 pm, and 8 pm) on day 1 and on days 4 through 8 of each study period. The subjects underwent a 10-day washout between study periods. Gabapentin plasma concentrations were measured in serial plasma samples collected >or=48 hours following dosing on days 1 and 8 using a validated high performance liquid chromatography/tandem mass spectrometry system with a lowest limit of quantitation of 75 ng/mL. Adverse events (AEs) were monitored and documented throughout the confinement in the clinic and washout phases of each study period. RESULTS: Of the 24 subjects enrolled in the study, 21 (11 males, 10 females; mean age, 37 years [range, 23- 60 years]; mean height, 172 cm [range, 158-188 cm], mean weight, 77 kg [range, 56-95 kg]; mean body mass index, 26.2 kg/m2 [range, 21.5-29.7 kg/m2]) completed the study. The completing subjects consisted of 8 whites, 7 blacks, 3 Asians, and 3 Hispanics. At steady state, exposure of both G-ER regimens (QD and BID) appeared similar compared with that of G-IR. However, BID dosing resulted in apparently lower C(max) (mean ratio: 81%; CI 90%, 76%-86%) and greater C(min) values (mean ratio: 118%; CI 90%, 107%-130%), while G-ER QD dosing was associated with numerically greater C(max) (mean ratio: 116%; CI 90%, 109%-123%), and lower C(min) values (mean ratio: 52%; CI 90%, 48%-56%) compared with G-IR TID during a 24-hour dosing period. A total of 47 treatment-emergent AEs occurred in 17 patients during the study. The most common AEs were headache (25% G-ER BID divided dose, 10% G-ER QD dosing, and 14% in G-IR TID dosing), dizziness (6%, 0%, and 19%), and muscle cramp (19%, 0%, and 10%). AEs were most prevalent in the G-IR study group. CONCLUSIONS: This exploratory study found that in these healthy subjects, the daily exposure provided by less frequent G-ER dosing was not significantly different from same daily dose with G-IR, administered more frequently. The G-ER BID dosing resulted in less fluctuation, while the G-ER QD dosing produced higher maximum concentrations compared with a G-IR TID regimen.

Ciprofloxacin prolonged-release tablets do not affect warfarin pharmacokinetics and pharmacodynamics.

The purpose of this study was to determine whether the pharmacokinetics of warfarin and ciprofloxacin PR (a prolonged-release formulation of ciprofloxacin) were altered after coadministration. Eighteen healthy male volunteers were given a single oral 7.5-mg dose of warfarin, a single oral 500-mg dose of ciprofloxacin PR, or both drugs administered together in a randomized, open-label, 3-way crossover study. Ciprofloxacin concentrations, warfarin (R)- and (S)-enantiomer concentrations, prothrombin time, and activated partial thromboplastin time were measured over 120 hours following study drug administration. There were no significant differences in pharmacokinetic or pharmacodynamic parameters among treatments. A slightly greater value of half-life for (R)-warfarin was observed when coadministered with ciprofloxacin PR compared with warfarin administered alone (52.6 vs 50.1 hours, P = .029). This difference is not considered clinically relevant, because the values remain similar. These results show that warfarin pharmacokinetics and pharmacodynamics are not altered with concomitant administration of ciprofloxacin PR.

Case studies in swelling polymeric gastric retentive tablets.

Swelling tablets administered in the fed state have been shown to provide therapeutic advantages in two marketed products, with the duration of delivery characterised with respect to food and tablet size. Metformin extended-release tablets are a diffusion-based swelling tablet demonstrating once-daily efficacy with good gastrointestinal solubility. Ciprofloxacin extended-release tablets are based on an erosional matrix that delivers the drug to the upper gastrointestinal tract over 6 h to provide once-daily efficacy with reduced incidences of nausea and diarrhoea. Furosemide extended-release tablets are another example of an erosional matrix designed to deliver furosemide to the duodenum and upper jejunum over 6 h to provide a more gradual diuresis and naturesis compared with the immediate-release product.

Metformin extended release for the treatment of type 2 diabetes mellitus.

Metformin extended release (ER) (Glumetza, Depomed, Inc.) is a recently approved formulation that provides effective and well-tolerated glycaemic control with once-daily dosing. Metformin ER has similar bioavailability to conventional immediate-release (IR) formulations. In controlled clinical trials, metformin ER provided effective glycaemic control for 24 weeks when administered either as monotherapy or in combination with sulfonylurea. Good glycaemic control was maintained for an additional 24 weeks during an open-label extension study. Once-daily dosing with metformin ER 1500 mg/day was as effective as twice-daily dosing with metformin IR at the same total daily dose. Metformin ER was well tolerated at doses of 1500 or 2000 mg/day, with no increase in the frequency or severity of adverse events at the higher dose.

Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes.

OBJECTIVE: The purpose of this study was to determine the efficacy and safety of a novel extended-release metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes (newly diagnosed, treated with diet and exercise only, or previously treated with oral diabetic medications) were randomly assigned to receive one of three extended-release metformin treatment regimens (1,500 mg/day q.d., 1,500 mg/day twice daily, or 2,000 mg/day q.d.) or immediate-release metformin (1,500 mg/day twice daily) in a double-blind 24-week trial. RESULTS: Significant decreases (P < 0.001) in mean HbA(1c) (A1C) levels were observed by week 12 in all treatment groups. The mean changes from baseline to end point in the two groups given 1,500 mg extended-release metformin (-0.73 and -0.74%) were not significantly different from the change in the immediate-release metformin group (-0.70%), whereas the 2,000-mg extended-release metformin group showed a greater decrease in A1C levels (-1.06%; mean difference [2,000 mg extended-release metformin - immediate-release metformin]: -0.36 [98.4% CI -0.65 to -0.06]). Rapid decreases in fasting plasma glucose levels were observed by week 1, which continued until week 8, and were maintained for the duration of the study. The overall incidence of adverse events was similar for all treatment groups, but fewer patients in the extended-release metformin groups discontinued treatment due to nausea during the initial dosing period than in the immediate-release metformin group. CONCLUSIONS: Once- or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment.

Effect of omeprazole on bioavailability of an oral extended-release formulation of ciprofloxacin.

PURPOSE: The effect of omeprazole on the oral bioavailability and urinary exposure of the Depomed formulation of extended-release (ER) ciprofloxacin was studied. METHODS: A two-way crossover study was conducted in healthy subjects. Subjects received either a single dose of ER ciprofloxacin 1000 mg or a single dose of ER ciprofloxacin 1000 mg following three days of treatment with omeprazole 40 mg. Blood and urine samples were collected over 36 hours, and ciprofloxacin concentrations were determined using high-performance liquid chromatography. RESULTS: Twenty-seven subjects (16 men, 11 women) received both treatments. The mean maximum concentration, mean area under the plasma-versus-concentration curve, and mean amount of ciprofloxacin excreted in urine were similar between the two treatments and met strict bioequivalence criteria. CONCLUSION: Omeprazole did not affect the plasma or urinary pharmacokinetics of an oral ER formulation of ciprofloxacin.

Pharmacokinetics and pharmacodynamics of a novel extended-release ciprofloxacin in healthy volunteers.

Two open-label, randomized, 2-way crossover studies (1 single-dose and 1 steady-state) were conducted in healthy volunteers to compare the pharmacokinetics and pharmacodynamics of a novel extended-release ciprofloxacin (ciprofloxacin ER; 500 mg once daily) and immediate-release ciprofloxacin (ciprofloxacin IR; 250 mg twice daily). For both studies, mean ciprofloxacin maximum concentration (Cmax) values after once-daily ciprofloxacin ER were significantly greater than those after the first daily dose of ciprofloxacin IR (P < .0001) but were lower than those after the second daily dose of ciprofloxacin IR (P < .05). The relative bioavailability of ciprofloxacin ER compared to ciprofloxacin IR was 93.8% in the single-dose study and 97.7% in the steady-state study. Mean urinary ciprofloxacin concentrations and excretion rates after either treatment were substantially greater than the minimum inhibitory concentrations (MICs) for susceptible uropathogens in both studies. The area under the concentration-time curve (AUC)/MIC, Cmax/MIC, amount excreted (Ae)/MIC, and Ae24/MIC ratios with ciprofloxacin ER were similar to or slightly greater than with ciprofloxacin IR for all susceptible organisms.

Efficacy and safety of a novel once-daily extended-release ciprofloxacin tablet formulation for treatment of uncomplicated urinary tract infection in women.

The efficacy and safety of a novel once-daily extended-release ciprofloxacin (ciprofloxacin ER) 500-mg dose were compared with those of an immediate-release ciprofloxacin (ciprofloxacin IR) 250-mg twice-daily dose, each administered orally for 3 days in the treatment of acute uncomplicated urinary tract infection (uUTI) in women. Adult female outpatients (mean age, 39 years) with clinical signs and symptoms of acute uUTI and a positive pretreatment urine culture (> or =10(5) CFU/ml) were enrolled in a multicenter, randomized, double-blind, noninferiority trial. Patients were assessed at a test-of-cure visit (4 to 11 days posttreatment) and a late-posttreatment visit (4 to 6 weeks posttreatment) for microbiological and clinical outcomes and safety. The primary efficacy endpoint and microbiological eradication rate at the test-of-cure visit in the ciprofloxacin ER group (254/272; 93.4%) were noninferior to those in the ciprofloxacin IR group (225/251; 89.6%) (95% confidence interval [CI] of difference, -0.99%, 8.59%). Clinical-cure rates at the test-of-cure visit were 85.7% (233/272) for ciprofloxacin ER and 86.1% (216/251) for ciprofloxacin IR (95% CI of difference, -6.37%, 5.57%). At the late-posttreatment visit, microbiological and clinical outcomes were similar for the two treatments and consistent with test-of-cure results. Both treatments were well tolerated, but the frequencies of nausea and diarrhea were lower in the ciprofloxacin ER group than in the ciprofloxacin IR group (nausea, ER, 0.6%; IR, 2.2%; P = 0.033; diarrhea, ER, 0.2%; IR, 1.4%; P = 0.037). Once-daily ciprofloxacin ER was safe, effective, and noninferior to twice-daily ciprofloxacin IR in the treatment of acute uUTI. Additionally, ciprofloxacin ER was associated with significantly reduced frequencies of nausea and diarrhea.

Buccal permeation of buspirone: mechanistic studies on transport pathways.

The transport of buspirone across porcine buccal mucosa in vitro was investigated to elucidate the mechanisms of transport and permeation enhancement. The apparent permeability increased with an increase in pH to a lesser degree than the dependence of the partition coefficient. Whereas the lipophilic or apparent transcellular pathway was found to be the dominant buccal transport route for buspirone, ionized species contributed significantly to transport at acidic pH. At neutral pH, bile salts did not increase the flux of the lipophilic species of buspirone, and in contrast to its effect on stratum corneum, aqueous propylene glycol alone did enhance the flux of buspirone across buccal mucosa in vitro. The use of an enhancer combination containing 5% oleic acid, 40% propylene glycol in buffer resulted in the greatest flux, and this was consistent with the effect of this combined enhancer on the flux of lipophilic drugs across stratum corneum and the dominance of the transcellular pathway for buspirone at neutral pH.

A novel method for determination of drug solubility in polymeric matrices.

Crystallization of drugs in metastable, supersaturated adhesive polymeric matrices in transdermal drug delivery devices can be avoided by determination of the solubility of the drug in the adhesive polymer. A novel method is described to determine the solubility of the drug in polymeric matrices. Unlike existing methods, this method does not require a long and uncertain experimental time, and is accurate. In this study, an easy and accurate method is presented for the determination of solubility of drugs in polymers based on the relationship between thermodynamic activity of drugs and steady-state flux. In particular, the steady-state flux from a reference saturated solution across a test membrane was compared to an experimentally determined relationship between the polymeric loading concentration and the observed steady-state fluxes. The validity of this method was demonstrated by comparing the results to microscopic observation of crystallization and the study of aged drug-loaded adhesives for lidocaine as a model drug and an acrylate pressure-sensitive adhesive as a model polymer. The solubility of lidocaine was 20.8 +/- 0.5% (w/w) in the acrylate polymer.

Gastric retentive dosage forms: a review.

Gastric retentive dosage forms have been investigated to provide controlled release therapy for drugs with reduced absorption in the lower gastrointestinal (GI) tract or for local treatment of diseases of the stomach or upper GI tract. Gastric retentive dosage forms rely on either natural GI physiology, such as floating or large tablets that depend on delayed emptying from the fed stomach, or those dosage forms that are designed to fight the physiology and avoid emptying in the fasted state through dosage forms of even larger sizes with or without flotation or bioadhesion. To understand the behavior of the dosage forms, an introduction to GI motility and its measurement is provided. Because the fed mode underlies the successful development of dosage forms that rely on size or flotation, the emptying of these dosage forms in the fed mode and identification of the key factors influencing the variability of gastric retention are discussed. The design and limitations of size or density-based fed mode, and mucoadhesive and expandable fasting-state gastric retentive systems are presented.