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.

SUMMARYPurpose: Pregabalin, a high-affinity ligand for a2d 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.

Pregabalin add-on treatment demonstrates a dose-response relationship in 3 out of 4 patients with refractory partial seizures. A dose of 186 mg pregabalin daily is expected to decrease the seizure rate by 50% of maximum from baseline. Age, race, and menopausal status of women did not affect the dose-response relationship.

Every year, the pharmaceutical industry generates a large number of scientific reports related to drug research, development, and regulatory submissions. Many of these reports are created using text processing tools such as Microsoft Word. Given the large number of figures, tables, references, and other elements, this is often a tedious task involving hours of copying and pasting and substantial efforts in quality control (QC). In the present article, we present the LaTeX-based open-source reporting platform, PharmTeX, a community-based effort to make reporting simple, reproducible, and user-friendly. The PharmTeX creators put a substantial effort into simplifying the sometimes complex elements of LaTeX into user-friendly functions that rely on advanced LaTeX and Perl code running in the background. Using this setup makes LaTeX much more accessible for users with no prior LaTeX experience. A software collection was compiled for users not wanting to manually install the required software components. The PharmTeX templates allow for inclusion of tables directly from mathematical software output as well and figures from several formats. Code listings can be included directly from source. No previous experience and only a few hours of training are required to start writing reports using PharmTeX. PharmTeX significantly reduces the time required for creating a scientific report fully compliant with regulatory and industry expectations. QC is made much simpler, since there is a direct link between analysis output and report input. PharmTeX makes available to report authors the strengths of LaTeX document processing without the need for extensive training. Graphical Abstract ᅟ.

Data from 4 phase 2/3 studies were pooled to characterize the exposure response of daily pregabalin (150-600 mg) in patients with fibromyalgia using self-assessed daily pain scores (PAIN) and end-of-treatment patient global impression of change (PGIC). The exposure responses of both endpoints were characterized by an Emax model using nonlinear mixed-effects modeling (NONMEM). Drug effect on PAIN relative to placebo was significant with additional maximum effect of 1.51 points on the logit scale and EC50 of 1.54 ng/mL (dose of 174 mg) and a rapid onset (half-life of 11 hours), consistent with the half-life of the drug. The decrease in PAIN with placebo occurred more slowly, reaching maximum response (1.52 points on the logit scale) after 1 month. Drug response in fibromyalgia was dependent on age and sex, with greater PAIN reduction in older patients, in addition to the effect of creatinine clearance, and in females. For PGIC, administration of pregabalin resulted in an increase in the proportion of patients reporting improvement with an ED50 of 228 mg. The analyses support the recommended dose of pregabalin in patients with fibromyalgia of 300 to 450 mg/d.

SUMMARYBy reducing neuronal excitability through selective binding to the a 2 d 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 steadystate 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. KEY WORDS: Pregabalin, Antiepileptic drugs, Anticonvulsants, Coadministration, Population pharmacokinetics.Pregabalin is a selective, high-affinity ligand for a novel central nervous system binding site, the a 2 d subunit of voltage-dependent calcium channels (Gee et al., 1996). The ability of pregabalin to decrease neuronal excitability by selectively attenuating presynaptic calcium influx through these channels Fink et al., 2002) may underlie its efficacy in patients with partial seizures (French et al., 2003;Miller et al., 2003), chronic pain disorders (Iacobellis et al., 2000;Glessner et al., 2001;Crofford et al., 2002;Dworkin et al., 2003), and generalized anxiety disorder Pande et al., 2003). A population pharmacokinetic analysis (Bockbrader et al., 2010) was performed to characterize pregabalin pharmacokinetics in healthy volunteers (Corrigan et al., 2001), patients with various chronic pain disorders, and patients with epilepsy who participated in a series of phase 3 add-on trials. The analyses revealed that pregabalin pharmacokinetics were similar in the different populations (Randinitis et al., 2003). Furthermore, concomitant anticonvulsant medications, including carbamazepine, lamotrigine, phenobarbital, phenytoin, tiagabine, topiramate, and valproate, had no effect on the pharmacokinetics of pregabalin.The purpose of the present study was to determine the effect of pregabalin on the pharmacokinetics of commonly used antiepileptic drugs (AEDs) in patients with partial seizures. Plasma concentrations of carbamazepine, lamotrigine, phenobarbital, phenytoin, tiagabine, topiramate, and valproate were determined prior to and during pregabalin administration in the phase 3 add-on epilepsy trials, and were utilized to determine if pregabalin coadministration had ...

The weight of a typical 82-kg patient receiving placebo or pregabalin (300 mg/day) approaches an asymptotic fractional change from baseline weight of 0.7%, or 2.5%, respectively, with a half-life of 17 days. Substantial between-subject variability remains unexplained.

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