Interindividual Variability in the Bioavailability of Gabapentin Enacarbil Extended Release in Healthy Adults: An Analysis of Data From 6 Phase I Studies.

BACKGROUND: The absorption and bioavailability of oral gabapentin are associated with a high degree of interindividual variability. Gabapentin enacarbil, a prodrug of gabapentin, is well absorbed and provides sustained, dose-proportional exposure to gabapentin. The aim of this analysis was to describe the interindividual variability in the bioavailability of gabapentin after gabapentin enacarbil administration in healthy subjects. METHODS: Gabapentin pharmacokinetic (PK) parameters after an oral dose of gabapentin enacarbil 1200 mg (2 600-mg tablets) were compared across 6 phase I studies in healthy adults (n = 12 per study). The distribution of bioavailability values was assessed in all studies. RESULTS: The mean PK parameters of gabapentin were consistent across the trials: maximum concentration range: 6.4-7.9 µg/mL, time to maximum concentration range: 5.2-8.2 hours, area under the plasma-concentration curve extrapolated from time 0 to infinity or at steady state range: 70.8-109.4 µg·h/mL, and bioavailability range: 64.8%-82.9%. Overall, the mean bioavailability was 74.1% (SD, 14.1; coefficient of variation, 19.1%). Individual bioavailability across all studies ranged from 42% to 100%. CONCLUSIONS: Gabapentin PK after gabapentin enacarbil administration was consistent across studies, with low interindividual variability in bioavailability. Gabapentin enacarbil may provide more consistent and predictable exposure to gabapentin than oral gabapentin formulations.

The pharmacokinetics and pharmacodynamics of dexamethasone following epidural SP-102 or intravenous dexamethasone sodium phosphate injection in subjects with lumbosacral radicular pain.

OBJECTIVES: To evaluate the pharmacokinetics, pharmacodynamics (PD), safety, and tolerability of epidural SP-102 (10 mg dexamethasone sodium phosphate injectable gel) compared to an intravenous injection of 10 mg dexamethasone sodium phosphate, USP (IV USP). MATERIALS AND METHODS: Subjects with lumbosacral radiculopathy received a single dose of epidural SP-102, followed by a single dose of IV USP 4 weeks later. Dexamethasone plasma levels, cortisol levels, white blood cells (WBC), and blood glucose levels were assessed. RESULTS: Twelve subjects entered and completed the study. The mean total dexamethasone exposure (AUClast and AUCinf) following SP-102 by epidural injection was equivalent to the total exposure following IV USP. A lower mean plasma Cmax (~ 50% lower) was observed following epidural administration compared to IV injection. PD parameters were similar between treatments. Adverse events (AEs) were mild, with no serious AEs or study discontinuations due to AEs. CONCLUSION: In this small study, epidural SP-102 injection was well tolerated, was not associated with greater systemic dexamethasone exposure than IV USP, and both treatments had similar PD effects on cortisol suppression, blood glucose, and WBC levels.

Pharmacokinetics of immediate release, extended release, and gastric retentive gabapentin formulations in healthy adults
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OBJECTIVE: Gabapentin immediate release (GBP-IR), gabapentin gastric retentive (GBP-GR), and the prodrug gabapentin enacarbil extended release formulation (GEn) have been approved for management of postherpetic neuralgia (PHN) in adults. This is the first pharmacokinetic (PK) comparison of all three formulations using FDA-recommended doses for PHN. MATERIALS: This study compared the steady-state PK of GBP-IR 600 mg t.i.d., GBP-GR 1,800 mg q.d., and GEn 600 mg b.i.d. in healthy adults. METHODS: The open-label study consisted of a 3-day lead-in of escalating doses of GBP-IR, 5 days of treatment with each formulation (GPB-IR, GPB-GR, and GEn), and a 7-day taper period on 600 mg GEn q.d.. Plasma concentrations were collected on day 5 for each formulation. PK parameters were estimated from plasma concentration data. RESULTS: 14 healthy subjects (7 men, 7 women; mean (SD) age, 46.8 (7.60) years; mean (SD) body mass index, 26.7 (1.7) kg/m2) received all doses and completed the study. GBP-GR resulted in substantially (~ 4-fold) higher peak-to-trough ratio and percent fluctuation compared to GEn. GEn resulted in more sustained and less fluctuating daily exposure relative to GBP-IR, particularly at the end of 24 hours of dosing. In contrast, gabapentin fluctuation from GBP-IR consisted of 3 distinct peaks. After dose normalization, gabapentin exposure with GEn was ~ 2.2-fold and ~ 1.4-fold higher compared to GBP-GR and GBP-IR, respectively. All treatments were well tolerated. CONCLUSION: GEn requires less frequent dosing compared with GBP-IR and fluctuates less with sustained gabapentin exposure throughout the day. These PK differences may have clinically relevant implications.
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Arbaclofen placarbil decreases postprandial reflux in patients with gastroesophageal reflux disease.

OBJECTIVES: Arbaclofen placarbil (AP), previously designated as XP19986, is an investigational prodrug of the active R-isomer of baclofen, a gamma-aminobutyric acid agonist reflux inhibitor. The aim of this study was to assess the efficacy and safety of AP for decreasing meal-induced reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: We conducted a multicenter, randomized, double-blind, crossover study comparing single doses of AP with placebo. Different patients were enrolled at each of four escalating AP doses: 10, 20, 40, and 60 mg. Enrolled patients had GERD symptoms at least three times a week and 20 reflux episodes on impedance/pH monitoring over a period of 2 h. During study visits separated by periods of 3-7 days, patients received single doses of AP or placebo, followed by high-fat meals 2 and 6 h after treatment. The primary end point was the number of reflux episodes over 12 h after treatment. RESULTS: A total of 50 patients were treated; efficacy analysis included 44 patients who received both AP and placebo and had technically satisfactory impedance/pH data. For the combined data from all dose cohorts, there was a statistically significant (P=0.01) decrease in reflux episodes over 12 h after treatment with AP compared with placebo. The mean (s.d.) number of reflux episodes over 12 h after AP treatment was 50.5 (27.2), with a mean reduction of 10.4 (23.9) episodes (17%) compared with placebo, for which a mean (s.d.) number of 60.9 (35.3) episodes was observed. Heartburn events associated with reflux were reduced during treatment with AP compared with placebo. AP seemed to be the most efficacious in the 60-mg dose group, and was well tolerated at all dose levels. CONCLUSIONS: AP decreased reflux and associated symptoms with good tolerability in patients with GERD.

Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine.

AIM: Gabapentin enacarbil, a transported prodrug of gabapentin, provides sustained, dose-proportional exposure to gabapentin. Unlike gabapentin, the prodrug is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). Once absorbed, gabapentin enacarbil is rapidly hydrolyzed to gabapentin, which is subsequently excreted by renal elimination via organic cation transporters (OCT2). To examine the potential for drug-drug interactions at these two transporters, the pharmacokinetics of gabapentin enacarbil were evaluated in healthy adults after administration alone or in combination with either naproxen (an MCT-1 substrate) or cimetidine (an OCT2 substrate). METHODS: Subjects (n= 12 in each study) received doses of study drug until steady state was achieved; 1200 mg gabapentin enacarbil each day, followed by either naproxen (500 mg twice daily) or cimetidine (400 mg four times daily) followed by the combination. RESULTS: When gabapentin enacarbil was co-administered with naproxen, gabapentin C(ss,max) increased by, on average, 8% and AUC by, on average, 13%. When gabapentin enacarbil was co-administered with cimetidine, gabapentin AUC(ss) increased by 24% and renal clearance of gabapentin decreased. Co-administration with gabapentin enacarbil did not affect naproxen or cimetidine exposure. Gabapentin enacarbil was generally well tolerated. CONCLUSIONS: No gabapentin enacarbil dose adjustment is needed with co-administration of naproxen or cimetidine.

Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen.

Baclofen is a racemic GABA(B) receptor agonist that has a number of significant pharmacokinetic limitations, including a narrow window of absorption in the upper small intestine and rapid clearance from the blood. Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen designed to be absorbed throughout the intestine by both passive and active mechanisms via the monocarboxylate type 1 transporter. Arbaclofen placarbil is rapidly converted to R-baclofen in human and animal tissues in vitro. This conversion seems to be primarily catalyzed in human tissues by human carboxylesterase-2, a major carboxylesterase expressed at high levels in various tissues including human intestinal cells. Arbaclofen placarbil was efficiently absorbed and rapidly converted to R-baclofen after oral dosing in rats, dogs, and monkeys. Exposure to R-baclofen was proportional to arbaclofen placarbil dose, whereas exposure to intact prodrug was low. Arbaclofen placarbil demonstrated enhanced colonic absorption, i.e., 5-fold higher R-baclofen exposure in rats and 12-fold higher in monkeys compared with intracolonic administration of R-baclofen. Sustained release formulations of arbaclofen placarbil demonstrated sustained R-baclofen exposure in dogs with bioavailability up to 68%. In clinical use, arbaclofen placarbil may improve the treatment of patients with gastroesophageal reflux disease, spasticity, and numerous other conditions by prolonging exposure and decreasing the fluctuations in plasma levels of R-baclofen.

Pharmacodynamics and tolerability of repository corticotropin injection in healthy human subjects: A comparison with intravenous methylprednisolone.

Repository corticotropin injection (porcine adrenocorticotropic hormone [ACTH] analog) and intravenous methylprednisolone (IVMP) are used to treat inflammatory conditions such as multiple sclerosis (MS) exacerbations and rheumatoid arthritis. This multiple-dose, randomized, crossover, open-label study evaluated and compared pharmacodynamic outcomes in subjects who received ACTH analog (80 U subcutaneously) or IVMP (1 g) daily for 5 days. Specific outcome measures included IVMP and cortisol concentrations, total cortisol-equivalent exposure, immune cell population changes, and tolerability. IVMP and ACTH analog increased granulocyte numbers and decreased lymphocyte counts; effects on both were significantly less pronounced with ACTH analog. Based on total cortisol-equivalent exposure (assuming linearity), administration of 80 U of ACTH analog equates to 30 mg IVMP. Because IVMP doses significantly higher than 30 mg are usually required to treat MS exacerbations, the lower cortisol-equivalent exposure of 80 U ACTH analog supports the hypothesis that efficacy of ACTH analog results from both steroid-dependent and -independent properties. Adverse events were mild in severity; subject incidence for adverse-event reporting was similar following both regimens. The clinical relevance of these findings in autoimmune disease populations is unknown and requires further evaluation.

Single- and multiple-dose pharmacokinetics of levovirin valinate hydrochloride (R1518) in healthy volunteers.

R1518 is a valine ester prodrug of levovirin as an investigational new drug for the treatment of hepatitis C virus. Two phase 1, single- and multiple-dose studies were conducted to investigate the pharmacokinetics of R1518 in healthy volunteers. After oral dosing, R1518 was rapidly and exclusively converted to levovirin. Levovirin plasma concentrations peaked at 2 hours, with T(1/2) ranging from 6 to 8 hours. The T(1/2) of R1518 was less than 1 hour, with relative exposures (R1518/levovirin) less than 6%. A high-fat meal did not affect the pharmacokinetics. The female groups in both studies had higher plasma levels than males did due to age and renal function difference. An accumulation ratio of 1.3 to 1.5 was observed with the twice-daily regimen. About 75% to 90% of the levovirin equivalent dose was recovered in urine. Increase in exposure was slightly disproportionate to increase in dose. Significantly improved oral absorption of levovirin was achieved following administration of R1518.

Population pharmacokinetics and pharmacodynamics of gabapentin after administration of gabapentin enacarbil.

Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained dose-proportional exposure to gabapentin and predictable bioavailability. Gabapentin enacarbil is approved by the US Food and Drug Administration for the treatment of moderate-to-severe primary restless legs syndrome (RLS) in adults. Using plasma gabapentin concentration data obtained after administration of GEn in 12 phase 1 to 3 GEn studies in healthy adults or patients with RLS (dose range, 300-2400 mg/d), a population pharmacokinetic (PK) model was developed by nonlinear mixed-effect modeling using NONMEM. Data were similar in subjects with and without RLS. Population PK-pharmacodynamic (PD) models were evaluated using gabapentin exposure and change from baseline in investigator- or patient-rated Clinical Global Impression of Improvement (CGI-I) or International Restless Legs Scale (IRLS) total score. Potential PK-PD models for sleep outcomes and safety parameters were also explored. The CGI-I response increased with increasing GEn dose, whereas the IRLS total score was similar at all exposures tested. Early adverse events of dizziness or somnolence/sedation were more frequent for GEn 600 mg than higher doses; however, this is confounded by the fact that all subjects received the 600-mg dose for 3 days prior to titration to higher dosages.

Clinical pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study.

BACKGROUND: Gabapentin enacarbil, a transported acyloxyalkylcarbamate prodrug of gabapentin, provides predictable and dose-proportional gabapentin exposure (AUC). Gabapentin is cleared via renal excretion, and its elimination is proportional to creatinine clearance (CrCL); CrCL can, therefore, be used as a predictor of gabapentin renal clearance. Gabapentin produced from hydrolysis of gabapentin enacarbil is also eliminated via the renal clearance pathway. It was, therefore, anticipated that the pharmacokinetics of gabapentin derived from gabapentin enacarbil would also be affected by renal function. OBJECTIVE: The objective of this study was to describe a population pharmacokinetic analysis of gabapentin enacarbil in patients with varying degrees of renal function, using data from an open-label study of gabapentin enacarbil in patients with renal impairment (XenoPort, Inc. protocol XP066), to determine whether dosage adjustments are necessary in patients with renal impairment. METHODS: Men and women >18 years of age with a body mass index ≤34 kg/m(2) and who were, in general, healthy with the exception of renal impairment were enrolled All patients received a single 600-mg gabapentin enacarbil extended-release tablet under fed conditions. After dosing, plasma, urine, and dialysate samples were analyzed. Safety profile evaluations included adverse events, vital signs, ECGs, and laboratory values. Pharmacokinetic data were compared with those from Phase I-III studies in subjects with normal renal function to evaluate the relationship between gabapentin oral clearance (CL/F) and CrCL. RESULTS: Fifteen patients (11 men and 4 women) were enrolled. One patient had moderate renal impairment (CrCL 30-59 mL/min), 7 patients had severe renal impairment (CrCL <30 mL/min), and 7 patients had end-stage renal disease (CrCL <15 mL/min). Ten patients were white, 4 were African American, and 1 was American Indian or Alaskan Native. Their mean (range) age was 55 (28-76) years, weight was 85.6 (62-134) kg, and body mass index was 28.3 (22-34) kg/m(2). Mean maximum plasma gabapentin concentration was 5.77 µg/mL in patients with moderate and severe renal impairment, and 5.59 µg/mL in patients with end-stage renal disease who were undergoing hemodialysis. Based on the population pharmacokinetic analysis, gabapentin CL/F after administration of gabapentin enacarbil was proportionally related to CrCL, with an approximately 1.6-fold decrease in CL/F for every 2-fold decrease in CrCL. The most frequent adverse event was dizziness (4 of 15 patients). Other adverse events that were assessed as possibly or probably related to treatment were defecation urgency, extremity pain, feeling of relaxation, and muscle weakness; each occurred in 1 patient only. All events were mild or moderate and resolved without sequelae. CONCLUSIONS: The data suggest that dosage adjustment for gabapentin enacarbil is necessary in patients with impaired renal function. Gabapentin enacarbil, 600 mg, seemed to be well tolerated in this small selected population.

Actively transported levodopa prodrug XP21279: a study in patients with Parkinson disease who experience motor fluctuations.

OBJECTIVE: The objectives of this study were to assess the pharmacokinetic profile, efficacy, and safety of XP21279 administered with carbidopa (CD) in subjects with Parkinson disease (PD) experiencing motor fluctuations and explore dose correspondence between CD-levodopa (LD) and XP21279 administered with CD. METHODS: Subjects received CD-LD 3 or 4 times daily for 2 weeks, followed by XP21279 plus CD 3 times daily for 2 weeks at fixed dosing times, allowing dose adjustment to optimize clinical response, in this multiple-dose, multicenter, open-label, 2-period, sequential-treatment study. Pharmacokinetic parameters, including LD exposure, were assessed over 16 hours on the last day of each treatment period. Levodopa exposure variability was assessed for each treatment using the absolute % deviation from average concentration (Cavg) in each subject. Efficacy assessments included daily self-ratings of OFF time, ON time, and dyskinesias. RESULTS: XP21279 provided significantly less variability in LD concentration compared with CD-LD (P < 0.05) in 10 PD subjects with motor fluctuations, consistent with lower peak-to-trough fluctuation for XP21279. Patterns of percentage of subjects OFF were consistent with the LD concentration-time profiles for each respective treatment. Compared with CD-LD treatment, 6 of 10 study completers experienced reduction of 30% or greater in average daily OFF time during the last 4 days in the XP21279 treatment period. XP21279 resulted in an increase in the time spent ON without troublesome dyskinesias, and the mean time to ON after the first morning XP21279 dose was not delayed, as compared with CD-LD. CONCLUSIONS: XP21279 provided improved pharmacokinetic performance (highlighted by reduction in variability of LD concentration) compared with CD-LD and therefore may provide better control of PD motor fluctuations.

Evaluation of gabapentin enacarbil on cardiac repolarization: a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults.

BACKGROUND: Gabapentin enacarbil, a transported prodrug of gabapentin, was recently approved by the US Food and Drug Administration for the treatment of moderate to severe restless legs syndrome. OBJECTIVE: As part of the overall safety evaluation of gabapentin enacarbil, the present definitive QT/QTc study was conducted to assess the effects of gabapentin enacarbil on cardiac repolarization in accordance with the International Conference on Harmonization E14 guidance. METHODS: This randomized, double-blind, placebo- and active-controlled, crossover study enrolled 54 healthy adults. Subjects were randomly assigned to receive a single oral dose of gabapentin enacarbil 1200, 6000 mg, moxifloxacin 400 mg (active control), and placebo in a randomized sequence, with treatment periods separated by a 7-day washout. Blood samples were collected for pharmacokinetic analysis, and continuous ECG measurements were recorded using a Holter monitor. The primary end point was the time-matched difference in individualized baseline-adjusted QTc (ddQTcIb) between gabapentin enacarbil and placebo. General tolerability was also monitored. RESULTS: Of the 54 subjects enrolled in the study (mean [SD] age, 29.2 [10.1]; 42.6% female; mean body mass index, 25.8 [3.0]), 48 (88.9%) completed the study, and 6 were discontinued prematurely after having received ≥ 1 dose of study medication. Thus, the numbers of patients in the safety population were: gabapentin enacarbil 1200 mg, 50; gabapentin enacarbil 6000 mg, 50; moxifloxacin, 50; and placebo, 51. The maximum ddQTcIb values were 0.7 msec (upper 95% confidence limit [CL], 3.0) with gabapentin enacarbil 1200 mg; 1.3 msec (upper CL, 3.6) with gabapentin enacarbil 6000 mg; and 7.4 msec (lower CL, 5.1) with moxifloxacin. A QT-concentration relationship was reported with moxifloxacin. Gabapentin exposures were dose-proportional with gabapentin enacarbil doses of 1200 and 6000 mg. The most commonly reported adverse events with gabapentin enacarbil 6000 mg were dizziness and somnolence (60.0% and 54.0%, respectively). CONCLUSION: In this population of healthy adults, gabapentin enacarbil at doses of 1200 and 6000 mg was not associated with QT prolongation and was generally well-tolerated.

A randomized, double-blind, placebo-controlled, dose-response study to assess the pharmacokinetics, efficacy, and safety of gabapentin enacarbil in subjects with restless legs syndrome.

OBJECTIVE: The objective of this study was to determine steady-state gabapentin exposures and corresponding relief of symptoms and safety profile produced by 4 dose levels of gabapentin enacarbil (GEn) in subjects with restless legs syndrome (RLS). METHODS: Subjects with RLS (n = 217) were randomized to receive once-daily, orally administered GEn 600 (n = 48), 1200 (n = 45), 1800 (n = 38), or 2400 mg (n = 45) or placebo (n = 41) in this 12-week, double-blind, multicenter study (NCT01332305). Clinic visits were at screening, baseline, and weeks 1, 2, 3, 4, 6, 8, 10, and 12; plasma gabapentin concentrations were measured by a validated liquid chromatography-mass spectrometry/mass spectrometry method at weeks 4 and 12. RESULTS: Exposure to gabapentin was proportional to GEn dose. Time to maximum plasma concentration was 7 to 9 hours, and elimination half-life was ~6 hours. The mean reduction from baseline to week 12 in International Restless Legs Syndrome Rating Scale total score and proportions of subjects with "much improved"/"very much improved" Clinical Global Impression-Improvement scores (investigator and patient ratings) ranged from -12.9 to -13.9 for GEn treatment groups versus -9.3 for placebo. The 2 most commonly reported adverse events were somnolence and dizziness. CONCLUSIONS: Gabapentin exposure was approximately proportional to GEn dose. Efficacy data showed that a once-daily dose of GEn 600 to 2400 mg provides greater relief of RLS symptoms than placebo; GEn was generally well tolerated with an adverse event profile consistent with gabapentin.

Pharmacokinetics and tolerability of single escalating doses of gabapentin enacarbil: a randomized-sequence, double-blind, placebo-controlled crossover study in healthy volunteers.

BACKGROUND: Gabapentin enacarbil is an actively transported prodrug of gabapentin that provides predictable dose-proportional gabapentin exposure with high (> or =68%) oral bioavailability. OBJECTIVES: The aims of this study were to investigate the pharmacokinetics and tolerability of gabapentin enacarbil up to supratherapeutic doses and the effects of gabapentin enacarbil on cardiac repolarization in healthy volunteers, and to provide a dose reference for a future definitive QT/corrected QT (QTc) study. METHODS: This was a randomized-sequence, double-blind, placebo-controlled, single escalating-dose, crossover study of gabapentin enacarbil 600-mg extended-release tablets administered as a single oral dose of 2400, 3600, 4800, or 6000 mg or placebo, with a 1-week washout between administrations. Blood samples were collected over a period of 36 hours after administration and were analyzed using a validated method of liquid chromatography/tandem mass spec-trometry. Blood gabapentin enacarbil and gabapentin concentrations were analyzed using noncompartmental methods. Tolerability was assessed by monitoring adverse events (AEs) (using subject interview/reporting), laboratory parameters, vital sign measurements, and 12-lead electrocardiography (ECG). Holter ECG was also performed. RESULTS: Thirty-two healthy volunteers were included in the study (18 women, 14 men; mean [SD] age, 31.2 [11.4] years; body mass index, 24.9 [3.04] kg/m(2)). Gabapentin enacarbil was converted rapidly to gaba-pentin after absorption. Gabapentin exposure in blood was proportional to gabapentin enacarbil dose over the range of 2400 to 6000 mg (1250-3125 mg-equivalent gabapentin). Blood concentrations of intact gabapen-tin enacarbil were low and transient (< or =0.5% of the released gabapentin concentration at all doses). The most commonly reported AEs were dizziness and nausea (50% and 25% of subjects, respectively). All but 4 AEs were mild to moderate in intensity. Two subjects experienced treatment-emergent AEs rated as severe: psychomotor retardation, vertigo, and sedation (4800-mg dose) and somnolence (6000 mg). All treatment-emergent AEs resolved without medical intervention. No serious AEs were reported, and none of the AEs led to study withdrawal. There were no clinically significant changes in laboratory parameters, vital sign measurements, or ECG values; QTc intervals did not exceed 480 msec or change from baseline >30 msec at any gabapentin enacarbil dose. CONCLUSIONS: Gabapentin enacarbil was associated with dose-proportional gabapentin exposure at doses up to 6000 mg and was generally well tolerated in these healthy subjects. These findings support the use of 6000-mg gabapentin enacarbil in a definitive QT/QTc study.