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.

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview.

Glumetz (Depomed, Inc., Menlo Park, CA, USA) is a recently approved gastric retentive extended-release formulation of metformin (M-ER) that provides effective, sustained and well-tolerated glycemic control with once daily administration. Pharmacokinetic studies have demonstrated a similar bioavailability of M-ER administered once daily to immediate-release metformin given twice daily. In addition, M-ER has demonstrated a nearly linear dose proportionality with a relative bioavailability of highest dose to lowest dose of 80%, whereas with immediate-release metformin the relative bioavailability of the highest dose to the lowest dose is only 58%. M-ER demonstrated a positive food effect and should be administered with a meal, preferably the evening meal. Because metformin is only eliminated through renal mechanisms, the use of M-ER, as is the case with other formulations, is contraindicated in patients with renal impairment. Administration of M-ER with sulfonylureas (SUs) had no effect on the pharmacokinetics of metformin. In controlled clinical trials M-ER demonstrated efficacy for 24 weeks as a monotherapy or in combination with SU. Additionally, glycemic control was maintained for an extra 24 weeks in an open-label monotherapy extension study of M-ER. M-ER was well tolerated in all studies.

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.

Ocular pharmacokinetics of bimatoprost formulated in DuraSite compared to bimatoprost 0.03% ophthalmic solution in pigmented rabbit eyes.

PURPOSE: To compare the aqueous humor (AH) and iris-ciliary body (ICB) concentration of bimatoprost in rabbit eyes treated with ISV-215 (0.03% bimatoprost formulated in DuraSite) with the marketed product bimatoprost 0.03% ophthalmic solution. METHODS: The left eye of rabbits received a single topical instillation of either ISV-215 (n = 32 eyes) or bimatoprost 0.03% (n = 32 eyes). At predetermined time points, levels of bimatoprost and bimatoprost acid in the AH and the ICB were quantified by HPLC-MS/MS. RESULTS: Both bimatoprost and bimatoprost acid were detected in the AH and the ICB within 15 minutes of dosing. Bimatoprost acid concentrations in both compartments were markedly higher than bimatoprost. There was a statistically significant (P < 0.01) increase in the concentration of the prodrug in the AH and its acid form in the ICB in animals treated with ISV-215 compared to bimatoprost 0.03%. In the ISV-215-treated rabbit eyes, the highest concentrations of bimatoprost and bimatoprost acid were in the ICB and AH, respectively, while in the bimatoprost 0.03%-treated eyes, no differences in the drug content of the selected ocular tissues were observed. CONCLUSIONS: Bimatoprost 0.03% formulated in DuraSite has superior ocular distribution and area under the curve compared to bimatoprost 0.03% in rabbit eyes. This improvement in the pharmacokinetic parameters of ISV-215 may provide us with a better platform to optimize a bimatoprost formulation that offers the same degree of efficacy in lowering intraocular pressure and improved therapeutic index in glaucomatous patients by lessening the ocular side effects associated with long-term use of topical prostaglandin F2α analogs.

Aqueous humor penetration of ketorolac formulated in DuraSite or DuraSite 2 delivery systems compared to Acular LS in rabbits.

PURPOSE: To evaluate the ocular penetration of ISV-304 (ketorolac tromethamine) formulated in DuraSite(®) or DuraSite(®) 2 compared to Acular LS(®) (0.4% ketorolac ophthalmic solution) in rabbits. METHODS: The left eye of rabbits received a single topical instillation of either ISV-304 (0.2% and 0.4% ketorolac) in DuraSite, ISV-304 (0.2% and 0.4% ketorolac) in DuraSite 2, or Acular LS. At predetermined time points, aqueous humor (AH) levels of ketorolac were measured by HPLC-MS/MS, and Cmax, Tmax, and AUC0.25-24h were determined. RESULTS: The highest mean concentration of ketorolac was achieved in ISV-304 (0.4%) formulated in DuraSite 2 with a Cmax value of 1889 ± 884 ng/mL, compared to Cmax values for ISV-304 (0.4%) formulated in DuraSite (1212 ± 435 ng/mL) or Acular LS (275 ± 83 ng/mL). ISV-304 (0.2%) formulations also achieved higher AH Cmax values (801 ± 205 ng/mL and 1077 ± 415 ng/mL) compared to Acular LS. There was a significant increase in drug exposure in the ISV-304 (0.4%) formulated in DuraSite 2 or DuraSite formulations with AUC0.25-24h values 6836 ng/mL*h and 5684 ng/mL*h, respectively, compared to Acular LS with an AUC0.25-24h value of 1424 ng/mL*h. ISV-304 (0.2%) formulations also had high AUC0.25-24h values (3241 ng/mL*h and 4490 ng/mL*h), which were a 2.3-3.2-fold increase over the Acular LS AUC0.25-24h value. CONCLUSIONS: DuraSite and DuraSite 2 delivery systems markedly improved the ketorolac ocular pharmacokinetic parameters in rabbits. DuraSite formulations may lessen the side effects associated with topical nonsteroidal anti-inflammatory drug use by maintaining efficacy with a reduced dosing regimen and reduced active ingredient.

Pharmacokinetics of gabapentin in a novel gastric-retentive extended-release formulation: comparison with an immediate-release formulation and effect of dose escalation and food.

The objectives of the 3 phase I studies described herein were (1) to compare the pharmacokinetics of gabapentin delivered from a novel gastric-retentive dosage form vs an immediate-release formulation, (2) to assess the dose proportionality of the gastric-retentive extended-release formulation, and (3) to determine the effect of food on the pharmacokinetics of gabapentin delivered from this formulation. The time to reach maximum plasma concentration (t(max)) was extended for gabapentin delivered from the gastric-retentive extended-release formulation compared with the immediate-release formulation. A dose-related increase in both the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) was observed as the gabapentin dose increased from 600 to 2400 mg. Fed status and increased fat content delayed t(max) and enhanced C(max) and AUC in proportion to the fat content. The pharmacokinetics of gabapentin delivered from this extended-release formulation allows a reduced dosing frequency while maintaining bioavailability and possibly diminishing the occurrence of adverse events attributable to a slower increase to the peak concentration compared with the immediate-release dosage form.