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.

The discovery of (2R,4R)-N-(4-chlorophenyl)-N- (2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor.

Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.

Structure-based drug design of pyrrolidine-1, 2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors.

A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.

Formulation modifications of PD 0313052, a direct Factor Xa Inhibitor, alter pharmacokinetics and pharma-codynamics following subcutaneous administration to rabbits.

PURPOSE: PD 0313052 is a potent, direct factor Xa (FXa) inhibitor (Ki = 0.33 nM) and its antithrombotic effect has been previously demonstrated in several animal models, via intravenous (IV) administration. In the present study, we evaluated four different subcutaneous (SC) formulations to test the feasibility of developing PD 0313052 as a subcutaneous agent. METHODS: PD 0313052 was formulated in saline, methylcellulose (MC, 0.5% methylcellulose solution containing 1% Tween-80), sesame oil, and F127 (25% aqueous solution). Each formulation was injected subcutaneously into rabbits and the relative plasma exposure and the duration of action of PD 0313052 were assessed. Plasma concentration, FXa activity, and coagulation parameters were used to monitor the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of PD 0313052. RESULTS: Regardless of formulation, there was a significant (p < 0.05) correlation between PD 0313052 plasma concentration and FXa activity (R2 = 0.90), prothrombin time (PT) (R2 = 0.86), and Heptest (R2 = 0.93). The saline and MC formulations had similar effects on FXa activity, coagulation parameters, and Heptest, peaking at 30 to 120 minutes after administration and decreasing rapidly thereafter. In contrast, formulations of F127 and sesame oil yielded lower maximal effects on PD markers but produced sustained PD effects over time. CONCLUSION: The data indicate that PD 0313052 is bioavailable after SC administration to rabbits and that there is a strong correlation between the PD parameters and plasma concentrations of PD 0313052. Modifications in the formulation of PD 0313052 produce marked differences in the PK and PD profiles of this agent after SC administration to rabbits. These results suggest that SC formulations can be optimized to improve the PK and PD profiles of PD 0313052, and that PD 0313052 is a viable candidate for development as a SC antithrombotic agent.

The discovery of glycine and related amino acid-based factor Xa inhibitors.

Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.

In vitro and in vivo antithrombotic activity of PD-198961, a novel synthetic factor Xa inhibitor.

PD-198961, 3-(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-4-hydroxybenzenecarboximidamide, is a novel, synthetic factor Xa inhibitor with a Ki of 2.7 nM against human factor Xa. The aim of the present study was to evaluate the pharmacokinetic profile and antithrombotic efficacy of PD-198961 in rabbits. When tested in vitro, PD-198961 doubled prothrombin time (PT) and activated partial thromboplastin time (aPTT) at concentrations of 0.13 and 0.32 microM in human plasma, 0.2 and 0.09 microM in rabbit plasma, 0.3 and 0.4 microM in dog plasma, respectively. Intravenous administration of PD-198961 at 1 mg/kg over 30 minutes resulted in a maximal prolongation in PT and aPTT of 4.9 +/- 0.4 and 4.1 +/- 0.9-fold of baseline, respectively. The peak plasma concentration of PD-198961 was 977 +/- 96 ng/ml. The anticoagulant effect of PD-198961 was readily reversible; coagulation parameters and plasma concentration returned to near baseline 15 minutes after cessation of infusion. There was a good correlation between PT prolongation and plasma concentration of PD-198961 (r = 0.93). In an FeCl3-induced model of arterial thrombosis in rabbits, the antithrombotic effects of PD-198961 were compared with that of LB-30057, a direct thrombin inhibitor, and enoxaparin, a low molecular weight heparin (LMWH). PD-198961 dose dependently increased the time to occlusion (TTO), reduced thrombus weight (TW), and decreased the incidence of occlusion. When administered at 3.0 microg/kg/min IV, PD-198961 prolonged TTO from 28 +/- 5 minutes (control) to 120 +/- 0 minutes (P < 0.001) and reduced TW from 9.9 +/- 1.5 mg (control) to 2.8 +/- 0.9 mg (P < 0.01). PD-198961 also dose dependently inhibited ex vivo plasma FXa activity. At the highest dose tested, PD-198961 increased aPTT to 1.4 +/- 0.1-fold of baseline (compared with 1.5 +/- 0.1 and 2.8 +/- 0.3-fold of baseline for LB-30057 [CI-1028] and enoxaparin, respectively), and had modest effects on bleeding time (< or = 2-fold). These results indicate that PD-198961 is a potent FXa inhibitor and an effective antithrombotic agent at doses that produce only modest changes in normal hemostasis.

Assessment of ex vivo pharmacodynamic markers during inhibition of thrombosis by CI-1031 (ZK-807834), a novel direct factor Xa inhibitor.

CI-1031 (ZK-807834) is a novel, synthetic factor Xa (FXa) inhibitor with a Ki of 0.11 nM against human FXa. In human plasma in vitro, CI-1031 doubled PT and aPTT at 0.23 and 0.49 microM, respectively. The in vivo antithrombotic effect of CI-1031 was evaluated in a veno-venous shunt model of thrombosis in anesthetized rabbits. After thrombus formation was verified in the first shunts, rabbits received either vehicle or CI-1031 intravenously (bolus injection of 60, 240, or 480 microg/kg followed by an infusion of 2, 8, or 16 microg/kg/min for 140 min, respectively). The second shunts were inserted after 20 min of infusion of CI-1031 or vehicle. CI-1031 dose-dependently prolonged time to occlusion (TTO) in the second shunts (35 +/- 21, 62 +/- 24, and 120 +/- 0 min for the three dose groups, respectively, vs. 10 +/- 1 min for vehicle). Thrombus mass (TM) was reduced in a dose-dependent manner by CI-1031 (42 +/- 7, 27 +/- 6, and 18 +/- 4 mg vs. 50 +/- 4 mg for vehicle). Maximal TM reduction was 70% with an IC(50) of 0.6 microg/ml. Among all the coagulation parameters tested, PT had the best correlation with plasma CI- 1031 concentration (r = 0.97). Ex vivo plasma anti-FXa activity was also well correlated with plasma concentration of CI-1031 and with PT (r = 0.96 and 0.98, respectively). These results indicate that CI-1031, which is currently undergoing clinical evaluation, is an effective antithrombotic compound with a favorable efficacy-to-bleeding ratio. In addition, CI-1031 concentration in plasma can be monitored using PT or anti-Xa assays, thereby providing reliable methods to ensure safe and accurate dose titration of CI-1031.