Effect of the gastrointestinal prokinetic agent erythromycin on the pharmacokinetics of pregabalin controlled-release in healthy individuals: a phase I, randomized crossover trial.

BACKGROUND AND OBJECTIVES: The controlled-release (CR) formulation of pregabalin is designed to remain in the stomach for a prolonged period while slowly releasing pregabalin for absorption in the small intestine. This study evaluated the effect of the gastrointestinal prokinetic agent, erythromycin, on the pharmacokinetics of a single dose of pregabalin CR 330 mg administered following an evening meal and the safety and tolerability of a single dose of pregabalin CR 330 mg when administered with and without multiple doses of erythromycin 500 mg. METHODS: This was a phase I, open-label, randomized, two-period, two-treatment crossover study. Participants received (in a randomized sequence) a single oral dose of pregabalin CR 330 mg alone and pregabalin CR 330 mg co-administered with multiple doses of erythromycin 500 mg. The CR formulation was administered immediately following a standardized 600-750 calorie 30 % fat evening meal. Erythromycin 500 mg was administered orally approximately 1 h prior to pregabalin CR, as well as 6 and 12 h following the first erythromycin dose. Blood samples were collected up to 48 h post-pregabalin CR dose. Pharmacokinetic parameters were estimated from concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout. RESULTS: Eighteen healthy participants (aged 19-52 years) received pregabalin CR. Co-administration of pregabalin CR with erythromycin resulted in a 17 % decrease in total exposure [area under the plasma concentration-time curve from zero to infinity (AUC∞)] and a 13 % decrease in peak plasma concentrations (C max) relative to pregabalin CR administered alone. The 90 % CI for the ratio of the adjusted geometric mean AUC∞ was 76.5-89.2 % (outside the 80-125 % range prespecified for bioequivalence). Adverse events were of mild to moderate severity and the adverse event profile was similar for pregabalin CR administered with and without erythromycin. CONCLUSION: Co-administration of multiple high doses of erythromycin resulted in 17 % lower pregabalin exposure for a single dose of pregabalin CR 330 mg than for pregabalin CR 330 mg administered alone. Although the two treatments did not achieve formal bioequivalence, the impact of co-administered erythromycin treatment was small and not considered clinically relevant.

Pharmacokinetics of pregabalin controlled-release in healthy volunteers: effect of food in five single-dose, randomized, clinical pharmacology studies.

BACKGROUND: The pharmacokinetic properties of the immediate-release (IR) and the recently developed controlled-release (CR) formulation of pregabalin are dose proportional. Pregabalin IR can be taken with or without food. OBJECTIVES: This analysis characterizes the effect of food on pregabalin CR. The objectives of this analysis were: (1) to evaluate the effect of administration time and fat or caloric content of an accompanying meal on the pharmacokinetic properties of a single dose of pregabalin CR (330 mg) relative to a single dose of pregabalin IR (300 mg); (2) to evaluate the pharmacokinetic properties of a single dose of pregabalin CR administered fasted relative to a single dose of pregabalin CR administered immediately after food; and (3) to determine the safety and tolerability of single-dose administration of pregabalin CR and IR with and without food. METHODS: The effect of food on the pharmacokinetic properties of pregabalin CR was determined in five phase I, open-label, single-dose, crossover studies (24-28 participants/study). Caloric and fat content of meals were varied and treatments were administered in the morning, at midday, or in the evening. Blood samples were collected up to 48 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. RESULTS: One hundred and twenty-eight healthy participants (19-54 years of age) received pregabalin. Peak plasma concentrations (C max) were lower for CR than the respective pregabalin IR doses, and time to C max occurred later. When pregabalin CR was administered with food at midday or in the evening, total exposures [area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC∞)] were equivalent for pregabalin CR and IR formulations regardless of fat or caloric content. When pregabalin CR was administered with an 800-1,000 calorie medium-fat breakfast, AUC∞ was equivalent for pregabalin CR and IR. Bioequivalence criteria for comparison of pregabalin CR after a low- or medium-calorie breakfast relative to pregabalin IR were not met; however, bioavailability of the pregabalin CR vs. IR formulation was relatively high (75-86 %). When pregabalin CR was administered fasted, the AUC∞ was 70-78 % of the AUC∞ of pregabalin CR administered with food and bioequivalence criteria were not met. Additionally, the AUC∞ of the pregabalin CR formulation administered fasted was 62-69 % of that of pregabalin IR administered fasted and bioequivalence criteria were not met. Single-dose pregabalin CR and IR were well tolerated in all studies, with no serious or severe adverse events reported. CONCLUSION: Time of day of administration and the fat and caloric content of the accompanying meal had minimal overall effect on the pharmacokinetic properties and bioavailability of the pregabalin CR formulation.

Pregabalin controlled-release pharmacokinetics in healthy volunteers: analysis of four multiple-dose randomized clinical pharmacology studies.

BACKGROUND: Pregabalin (Lyrica(®)) is approved as an immediate-release (IR) formulation for administration twice (BID) or three times (TID) a day depending on indication. Once daily (QD) dosing may be appropriate for ease of clinical use and patient convenience. OBJECTIVES: The objectives of this analysis were: (1) to evaluate the pharmacokinetics of pregabalin controlled-release (CR) administered with food relative to the pregabalin IR formulation administered fasted; (2) to evaluate the pharmacokinetics of a two-tablet dose of pregabalin CR compared with the equivalent one-tablet dose of pregabalin CR; and (3) to determine the safety and tolerability of multiple-dose administration of pregabalin CR and IR. METHODS: The pharmacokinetic properties of pregabalin CR were determined in four phase I, open-label, multiple-dose crossover studies (18-24 participants/study). Pregabalin CR (82.5, 165, 330 or 660 mg/day) administered QD was compared with pregabalin IR (75, 150, 300 or 600 mg/day, respectively) administered either BID or TID. Blood samples were collected up to 24 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. RESULTS: Eight-four healthy participants (19-55 years of age) received pregabalin. For all pregabalin CR doses, total exposure was equivalent to the corresponding pregabalin IR dose. Relative bioavailability of pregabalin CR was 93-97 % of pregabalin IR, and bioequivalence criteria with respect to the 24-h steady-state exposure (area under the plasma concentration-time curve from 0 to 24 h [AUC24]) were met. Administration of a two-tablet dose of pregabalin CR was bioequivalent to one-tablet pregabalin CR. The relative bioavailability of two-tablet pregabalin CR was 97-102 % of one-tablet pregabalin CR, and bioequivalence criteria with respect to AUC24 and peak plasma concentrations were met. Pregabalin CR pharmacokinetic parameters were dose proportional following administration of 82.5-660 mg/day pregabalin CR. Pregabalin was well tolerated across studies, with no serious or severe adverse events. CONCLUSION: Total daily exposure with multiple-dose pregabalin CR is equivalent to the corresponding pregabalin IR dose.

Bioequivalence assessment of a pregabalin capsule and oral solution in fasted healthy volunteers: a randomized, crossover study.

OBJECTIVE: To determine the oral bioavailability of a pregabalin capsule relative to a pregabalin solution. METHODS: This was an open-label, randomized, crossover study in 12 healthy volunteers. Pharmacokinetics were compared for a 100-mg capsule and a 100-mg capsule dissolved in water, administered fasted. RESULTS: Mean Cmax and AUC0-∞ for the capsule were within 2% of those for the solution (3.8 vs. 3.7 µg/ml and 26.7 vs. 27.0 µg×h/ml, respectively). The 90% confidence intervals for the ratios of Cmax and AUC0-∞ fell fully within 80 - 125%. CONCLUSIONS: A 100-mg pregabalin capsule is bioequivalent to a pregabalin solution (100-mg capsule dissolved in water).

Gabapentin to pregabalin therapy transition: a pharmacokinetic simulation.

The objective of this modeling study was to assess different dosage regimens that might be used to guide clinicians in transitioning patients from gabapentin to pregabalin therapy when such a transition is clinically warranted. Two different gabapentin to pregabalin transition designs were simulated based on their respective population pharmacokinetic profiles. The first design involved immediate discontinuation of gabapentin therapy with initiation of pregabalin therapy at the next scheduled dose period. The second design featured a gradual transition involving coadministration of 50% of the gabapentin dosage and 50% of the desired pregabalin dosage for 4 days, followed by discontinuation of gabapentin and fully targeted dosages of pregabalin. Both transition designs were studied at 3 dosage levels: gabapentin 900 mg/d to pregabalin 150 mg/d, gabapentin 1800 mg/d to pregabalin 300 mg/d, and gabapentin 3600 mg/d to pregabalin 600 mg/d. Overall drug exposure achieved during the 2 transition designs was the sum of the gabapentin and pregabalin concentrations, expressed as pregabalin-equivalent concentrations. The pharmacokinetic simulations show that during the transition period in both designs, predicted pregabalin-equivalent concentrations did not depart from those calculated during periods of steady-state gabapentin or pregabalin monotherapy. Transition from gabapentin to pregabalin was seamless and rapid, with predicted pregabalin-equivalent concentrations highly comparable with plasma pregabalin concentrations within 1 day of pregabalin initiation in the immediate discontinuation model and within 1 day of gabapentin cessation in the gradual discontinuation model. These data suggest that transitioning patients from gabapentin to pregabalin could theoretically be achieved by either of the 2 approaches assessed.

Population pharmacokinetics of pregabalin in healthy subjects and patients with post-herpetic neuralgia or diabetic peripheral neuropathy.

AIM: Pregabalin, a chemical analogue of the mammalian neurotransmitter γ-aminobutyric acid, has been approved in many countries for partial-onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters. METHODS: This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post-herpetic neuralgia or diabetic peripheral neuropathy (n= 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM. RESULTS: A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/F) was proportional to estimated creatinine clearance (CL(cr) ). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post-herpetic neuralgia and diabetic peripheral neuropathy. CONCLUSION: The developed model identified CL(cr) and ideal body weight as clinically influential covariates on CL/F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug.

Pregabalin effect on steady-state pharmacokinetics of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, and tiagabine.

By reducing neuronal excitability through selective binding to the α(2)δ subunit of voltage-dependent calcium channels, pregabalin effectively treats epilepsy, chronic pain, and anxiety disorders. To evaluate if pregabalin coadministration affects pharmacokinetics of other antiepileptic drugs, population pharmacokinetic analyses using NONMEM software were performed on data from three epilepsy trials involving seven antiepileptic drugs with pregabalin as add-on therapy. Results demonstrated that pregabalin did not alter the steady-state plasma concentrations of carbamazepine, lamotrigine, phenobarbital, phenytoin, tiagabine, topiramate, and valproate. Furthermore, the small percent change in the population estimate of antiepileptic drug plasma clearance values (-2% to +7%) suggests that pregabalin coadministration exerted no significant effect on the pharmacokinetics of these antiepileptic drugs, with the possible exception of tiagabine (+34.9%). These findings are in agreement with those of previously published reports. A further clarification study is necessary for tiagabine. In conclusion, it appears that pregabalin can be coadministered with other antiepileptic drugs without concern for significantly altering their pharmacokinetic profiles.

Population pharmacokinetics of pregabalin in healthy subjects and patients with chronic pain or partial seizures.

PURPOSE: Pregabalin, a high-affinity ligand for α2δ subunits of voltage-gated calcium channels, is a novel pharmacotherapy for chronic pain, partial seizures, and other disorders. The present study investigated the population pharmacokinetics of pregabalin following single and multiple doses in healthy volunteers and patient populations. METHODS: Using nonlinear mixed-effect modeling, 5,583 plasma pregabalin concentration-time samples from 1,723 subjects were analyzed: 2,868 samples from healthy volunteers or subjects with renal impairment (n = 123), 1,513 from patients with partial seizures (n = 626), and 1,202 from patients with chronic pain (n = 974). A one-compartment model with first-order elimination and absorption processes and absorption lag time was used. KEY FINDINGS: This pharmacostatistical model showed that: (1) pregabalin oral clearance (CL/F) was directly proportional to creatinine clearance (CLcr), but was independent of gender, race, age, female hormonal status, daily dose, and dosing regimen; (2) apparent volume of distribution was dependent on body weight and gender; (3) absorption rate was decreased when given with food; and (4) coadministration with marketed antiepileptic drugs (AEDs) had no significant effect on pregabalin CL/F. SIGNIFICANCE: Pregabalin CL/F is related to CLcr, and this relationship is similar among healthy volunteers and patients with either partial seizures or chronic pain disorders. The only factor having a clinically significant influence on steady-state plasma pregabalin concentrations is renal function.

A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin.

Pregabalin and gabapentin share a similar mechanism of action, inhibiting calcium influx and subsequent release of excitatory neurotransmitters; however, the compounds differ in their pharmacokinetic and pharmacodynamic characteristics. Gabapentin is absorbed slowly after oral administration, with maximum plasma concentrations attained within 3-4 hours. Orally administered gabapentin exhibits saturable absorption--a nonlinear (zero-order) process--making its pharmacokinetics less predictable. Plasma concentrations of gabapentin do not increase proportionally with increasing dose. In contrast, orally administered pregabalin is absorbed more rapidly, with maximum plasma concentrations attained within 1 hour. Absorption is linear (first order), with plasma concentrations increasing proportionately with increasing dose. The absolute bioavailability of gabapentin drops from 60% to 33% as the dosage increases from 900 to 3600 mg/day, while the absolute bioavailability of pregabalin remains at > or = 90% irrespective of the dosage. Both drugs can be given without regard to meals. Neither drug binds to plasma proteins. Neither drug is metabolized by nor inhibits hepatic enzymes that are responsible for the metabolism of other drugs. Both drugs are excreted renally, with elimination half-lives of approximately 6 hours. Pregabalin and gabapentin both show dose-response relationships in the treatment of postherpetic neuralgia and partial seizures. For neuropathic pain, a pregabalin dosage of 450 mg/day appears to reduce pain comparably to the predicted maximum effect of gabapentin. As an antiepileptic, pregabalin may be more effective than gabapentin, on the basis of the magnitude of the reduction in the seizure frequency. In conclusion, pregabalin appears to have some distinct pharmacokinetic advantages over gabapentin that may translate into an improved pharmacodynamic effect.

Clinical pharmacokinetics of pregabalin in healthy volunteers.

Pregabalin has shown clinical efficacy for treatment of neuropathic pain syndromes, partial seizures, and anxiety disorders. Five studies in healthy volunteers are performed to investigate single- and multiple-dose pharmacokinetics of pregabalin. Pregabalin is rapidly absorbed following oral administration, with peak plasma concentrations occurring between 0.7 and 1.3 hours. Pregabalin oral bioavailability is approximately 90% and is independent of dose and frequency of administration. Food reduces the rate of pregabalin absorption, resulting in lower and delayed maximum plasma concentrations, yet the extent of drug absorption is unaffected, suggesting that pregabalin may be administered without regard to meals. Pregabalin elimination half-life is approximately 6 hours and steady state is achieved within 1 to 2 days of repeated administration. Corrected for oral bioavailability, pregabalin plasma clearance is essentially equivalent to renal clearance, indicating that pregabalin undergoes negligible nonrenal elimination. Pregabalin demonstrates desirable, predictable pharmacokinetic properties that suggest ease of use. Because pregabalin is eliminated renally, renal function affects its pharmacokinetics.

Pregabalin drug interaction studies: lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine, and valproate in patients with partial epilepsy.

PURPOSE: Pregabalin (PGB) is an alpha2-delta ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures. METHODS: Given its efficacy as adjunctive therapy, the potential for interaction of PGB with other antiepileptic drugs (AEDs) was assessed in patients with partial epilepsy in open-label, multiple-dose studies. Patients received PGB, 600 mg/day (200 mg q8h) for 7 days, in combination with their individualized maintenance monotherapy with valproate (VPA), phenytoin (PHT), lamotrigine (LTG), or carbamazepine (CBZ). RESULTS: Trough steady-state concentrations of CBZ (and its epoxide metabolite), PHT, LTG, and VPA were unaffected by concomitant PGB administration. Likewise, PGB steady-state pharmacokinetic parameter values were similar among patients receiving CBZ, PHT, LTG, or VPA and, in general, were similar to those observed historically in healthy subjects receiving PGB alone. The PGB-AED combinations were generally well tolerated. PGB may be added to VPA, LTG, PHT, or CBZ therapy without concern for pharmacokinetic drug-drug interactions.

Pharmacokinetics of pregabalin in subjects with various degrees of renal function.

The objectives of this study were to determine the single-dose pharmacokinetics of pregabalin in subjects with various degrees of renal function, determine the relationship between pregabalin clearance and estimated creatinine clearance (CLcr), and measure the effect of hemodialysis on plasma levels of pregabalin. Results form the basis of recommended pregabalin dosing regimens in patients with decreased renal function. Thirty-eight subjects were enrolled to ensure a wide range of renal function (CLcr < 30 mL/min, n = 8; 30-50, n = 5; 50-80, n = 7; and > 80, n = 6). Also enrolled were 12 subjects with renal impairment requiring hemodialysis. Each subject received 50 mg of pregabalin as two 25-mg capsules in this open-label, parallel-group study. Pregabalin concentrations were measured using previously validated liquid chromatographic methods. Pregabalin pharmacokinetic parameters were evaluated by established noncompartmental methods. Pregabalin was rapidly absorbed in all subjects. Total and renal pregabalin clearance were proportional (56% and 58%, respectively) to CLcr. As a result, area under the plasma concentration-time profile (AUC) and terminal elimination half-life (t1/2) values increased with decreasing renal function. Pregabalin dosage adjustment should be considered for patients with CLcr < 60 mL/min. A 50% reduction in pregabalin daily dose is recommended for patients with CLcr between 30 and 60 mL/min compared to those with CLcr > 60 mL/min. Daily doses should be further reduced by approximately 50% for each additional 50% decrease in CLcr. Pregabalin was highly cleared by hemodialysis. Supplemental pregabalin doses may be required for patients on chronic hemodialysis treatment after each hemodialysis treatment to maintain steady-state plasma pregabalin concentrations within desired ranges.