Summary:Purpose: Pregabalin (PGB) is an α 2 -δ 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, multipledose 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.

Twelve patients chronically maintained on warfarin were administered 80 mg atorvastatin for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of the two-week treatment period. Thus atorvastatin had no consistent effect on the anticoagulant activity of warfarin and adjustment in warfarin dosing should not be necessary.

The effect of rosuvastatin on warfarin pharmacodynamics and pharmacokinetics was assessed in 2 trials. In trial A (a randomized, double‐blind, 2‐period crossover study), 18 healthy volunteers were given rosuvastatin 40 mg or placebo on demand (o.d.) for 10 days with 1 dose of warfarin 25 mg on day 7. In trial B (an open‐label, 2‐period study), 7 patients receiving warfarin therapy with stable international normalized ratio values between 2 and 3 were coadministered rosuvastatin 10 mg o.d. for up to 14 days, which increased to rosuvastatin 80 mg if the international normalized ratio values were <3 at the end of this period. The results indicated that rosuvastatin can enhance the anticoagulant effect of warfarin. The mechanism of this drug‐drug interaction is unknown. Rosuvastatin had no effect on the total plasma concentrations of the warfarin enantiomers, but the free plasma fractions of the enantiomers were not measured. Appropriate monitoring of the international normalized ratio is indicated when this drug combination is coadministered.

Severe hepatic impairment (Child-Pugh class C) was associated with pronounced increases in asenapine exposure, but significant increases were not seen with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, or with any degree of renal impairment. Asenapine is not recommended in patients with severe hepatic impairment; no dose adjustment is needed in patients with mild or moderate hepatic impairment, or in patients with renal impairment.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• PD 0200390 is a ligand for the alpha-2-delta protein, an auxiliary subunit of voltage-gated calcium channels, which is the first in a new class being investigated for the treatment of insomnia.• Preclinical studies showed that PD 0200390 increases slow-wave sleep in rats; in humans, data in healthy volunteers showed that PD 0200390 is safe and well tolerated, and that renal excretion of unchanged drug is the primary route of elimination of PD 0200390. • This study investigated the effect of renal impairment on the single-dose pharmacokinetics and tolerability of PD 0200390, to determine whether dose adjustments may be required in individuals with renal dysfunction. WHAT THIS STUDY ADDS• PD 0200390 was well tolerated in subjects with mild, moderate or no renal impairment, whereas the group of patients with severe renal impairment experienced an increased frequency of treatment-associated adverse events.• The degree of renal impairment had a predictable effect on the clearance of PD 0200390; correlation between key pharmacokinetic parameters (renal and oral clearance, and drug exposure) and changes in renal function were confirmed by regression analysis.• Dose adjustment may be required when PD 0200390 is administered to patients with impaired renal function, to compensate for increased exposure. AIMSTo investigate the pharmacokinetics and safety of PD 0200390 in healthy subjects and subjects with renal impairment (RI) and to examine the relationship between oral and renal PD 0200390 clearance and estimated creatinine clearance (CLcr). METHODSIn this open-label study, 26 subjects were categorized into four groups based on renal function: no RI (CLcr >80 ml min -1 ; n = 6); mild RI (CLcr 51 to Յ80 ml min -1 ; n = 6); moderate RI (CLcr >30 to 50 ml min -1 ; n = 6); and severe RI (CLcr Յ30 ml min -1 ; n = 8). Subjects received a single, oral dose of PD 0200390 25 mg. Noncompartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data. RESULTSPD 0200390 was rapidly absorbed; mean time to maximum plasma concentration was 1.66-3.24 h. Mean half-life in subjects with normal renal function was 5.36 h, and increased with worsening RI. Oral (CL/F) and renal (CLR) clearance rates decreased with deteriorating renal function, whereas area under the concentration-time curve (AUC0-•) values increased by 56, 117 and 436% in subjects with mild, moderate and severe RI, respectively, indicating increased PD 0200390 exposure. Regression analysis demonstrated that CL/F and CLR correlated with CLcr (r = 0.953 and 0.961, respectively). PD 0200390 was well tolerated in subjects with mild, moderate or no RI. The most common adverse events were somnolence, dizziness and headache; these occurred with greatest intensity in the severe RI group. CONCLUSIONSPD 0200390 pharmacokinetic parameters (CL/F, CLR and AUC0-•) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.