Asenapine pharmacokinetics in hepatic and renal impairment.

BACKGROUND AND OBJECTIVE: The effects of hepatic or renal impairment on the pharmacokinetics of atypical antipsychotics are not well understood. Drug exposure may increase in patients with hepatic disease, owing to a reduction of certain metabolic enzymes. The objective of the present study was to study the effects of hepatic or renal impairment on the pharmacokinetics of asenapine and its N-desmethyl and N⁺-glucuronide metabolites. METHODS: Two clinical studies were performed to assess exposure to asenapine, desmethylasenapine and asenapine N⁺-glucuronide in subjects with hepatic or renal impairment. Pharmacokinetic parameters were determined from plasma concentration-time data, using standard noncompartmental methods. The pharmacokinetic variables that were studied included the maximum plasma concentration (C(max)) and the time to reach the maximum plasma concentration (t(max)). Eligible subjects, from inpatient and outpatient clinics, were aged ≥18 years with a body mass index of ≥18 kg/m² and ≤32 kg/m². Sublingual asenapine (Saphris®) was administered as a single 5 mg dose. RESULTS: Thirty subjects participated in the hepatic impairment study (normal hepatic function, n = 8; mild hepatic impairment [Child-Pugh class A], n = 8; moderate hepatic impairment [Child-Pugh class B], n = 8; severe hepatic impairment [Child-Pugh class C], n = 6). Thirty-three subjects were enrolled in the renal impairment study (normal renal function, n = 9; mild renal impairment, n = 8; moderate renal impairment, n = 8; severe renal impairment, n = 8). Asenapine and N-desmethylasenapine exposures were unaltered in subjects with mild or moderate hepatic impairment, compared with healthy controls. Severe hepatic impairment was associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) values for total asenapine, N-desmethylasenapine and asenapine N⁺-glucuronide (5-, 3-, and 2-fold, respectively), with slight increases in the C(max) of asenapine but 3- and 2-fold decreases in the C(max) values for N-desmethylasenapine and asenapine N⁺-glucuronide, respectively, compared with healthy controls. The mean AUC(∞) of unbound asenapine was more than 7-fold higher in subjects with severe hepatic impairment than in healthy controls. Mild renal impairment was associated with slight elevations in the AUC(∞) of asenapine compared with healthy controls; alterations observed with moderate and severe renal impairment were marginal. N-desmethylasenapine exposure was only slightly altered by renal impairment. No correlations were observed between exposure and creatinine clearance. CONCLUSION: 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.

Effect of renal impairment on the pharmacokinetics of PD 0200390, a novel ligand for the voltage-gated calcium channel alpha-2-delta subunit.

AIMS: To 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). METHODS: In 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 < or =80 ml min(-1); n= 6); moderate RI (CLcr >30 to 50 ml min(-1); n= 6); and severe RI (CLcr < or =30 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. RESULTS: PD 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 (CL(R)) clearance rates decreased with deteriorating renal function, whereas area under the concentration-time curve (AUC(0-infinity)) 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 CL(R) 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. CONCLUSIONS: PD 0200390 pharmacokinetic parameters (CL/F, CL(R) and AUC(0-infinity)) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.

Transcriptional regulation of the PXR gene: identification and characterization of a functional peroxisome proliferator-activated receptor alpha binding site within the proximal promoter of PXR.

The pregnane X receptor (PXR, NR1I2) is widely regarded as a central factor in the body's response to changes in the fluxome, the overall metabolite profile in the body. PXR expression is regulated by a number of chemicals at the transcriptional level; the majority of these chemicals are ligands for PXR and substrates for PXR target genes. However, transcriptional activators of PXR, such as clofibrate, do not seem to be PXR ligands or substrates for its target genes. Understanding the molecular mechanisms underlying both these expected and, more importantly, unexpected transcriptional activations is central to fully understanding the roles of PXR in the human body. We have carried out an in silico analysis of the human PXR proximal promoter, identifying putative protein/DNA interaction sites within the 2 kilobases (kb) 5' to the putative transcription start site. These sites included several for liver-enriched transcription factors, such as the hepatic nuclear factors and CAAT-enhancer binding protein alpha, and chicken ovalbumin upstream promoter transcription factor, commensurate with the high expression of PXR in liver. Furthermore, we identified putative binding sites for a number of ligand-activated transcription factors, suggesting that these factors may regulate PXR gene expression. Further analysis of this regulatory region has shown that transcriptional activation of PXR by peroxisome proliferator-activated receptor alpha (PPARalpha) is via a binding site located approximately 1.3 kb upstream of the putative transcription start site, with ablation of this site preventing PPARalpha-mediated activation of PXR gene expression. We present a model of how regulation of PXR gene expression by ligand-activated transcription factors may play a central role in the body's response to xenobiotic exposure.

Effect of rosuvastatin on warfarin pharmacodynamics and pharmacokinetics.

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.

Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo.

Avasimibe, an acyl-CoA:cholesterol acyltransferase inhibitor, has been previously shown to be a potent inducer of CYP3A4 and multiple drug resistance protein 1. We have further characterized the drug interaction potential of avasimibe by studying the inductive and inhibitory effect of this compound on major drug-metabolizing enzymes. Enzymes known to be involved in the metabolism of drugs likely to be coadministered with avasimibe, such as CYP1A1/2, CYP2C, and CYP2B6, were evaluated further by microarray analysis, Western immunoblotting, and activity assays, using rifampicin and beta-naphthoflavone as positive controls. No change was observed in CYP1A1/2 mRNA or activity levels after avasimibe treatment. Differential induction of CYP2C9- and CYP2B6-immunoreactive protein and activity was observed depending on drug concentration and donor. Microarray analysis showed a similar increase in CYP2C and CYP2B6 mRNA levels. The inhibition potential of avasimibe on the major drug-metabolizing enzymes was assessed using pooled human liver microsomes. Avasimibe inhibited CYP2C9 (IC50 2.9 microM), CYP1A2 (IC50 13.9 microM), and CYP2C19 (IC50 26.5 microM). A clinical drug interaction study was conducted to determine whether avasimibe might interact with the CYP2C9 substrate warfarin. Volunteers received 750 mg of avasimibe and showed a 54.2% reduction in trough concentrations of S-warfarin and decreased prothrombin times by 12, 15, 19, and 21% on days 6 through 9, respectively. These results demonstrate that avasimibe's inductive spectrum resembles that of rifampin.

Gene expression changes in rat liver following exposure to liver growth agents: role of Kupffer cells in xenobiotic-mediated liver growth.

Many xenobiotics are known to cause liver enlargement and hepatocarcinogenesis in rats, although the molecular mechanisms that underlie this effect remain largely undefined. Human exposure to several of these compounds, including glucocorticoids and peroxisome proliferators may be significant, due to their use in both pharmaceutical and industrial processes. It is therefore important to elucidate the molecular mechanisms underlying this abnormal liver enlargement in rats, as this will enable more accurate extrapolation of the possible outcomes of human exposure. Male Sprague-Dawley rats were dosed with the peroxisome proliferator Wy-14,643 and changes in liver gene expression examined using subtractive suppression hybridisation examined either 12 of 24hr later. Twenty-five transcripts were identified which showed differential gene expression in liver following exposure to Wy-14,643. Biochemical indices of liver growth (DNA synthesis, apoptosis) showed that these changes correlated with the initiation of liver enlargement. Rats were next treated with either Wy-14,643, cyproterone acetate and dexamethasone, chemically and mechanistically-distinct hepatomegalic compounds. Carboxylesterase and Kupffer cell receptor mRNA levels were seen to alter in a qualitatively similar fashion for all three compounds, and in a liver specific fashion. In addition, these changes correlated with a decrease in the density of Kupffer cells within the liver, which are known to release mitogenic cytokines, and have been linked to Wy-14,643-induced cell proliferation. We therefore propose that Kupffer cells play a role in a general mechanism of xenobiotic-mediated liver enlargement.

Efficacy of levetiracetam in developmentally disabled patients: a review of the literature and six case reports.

Objective. Seizures in developmentally disabled are often refractory to treatment. This study aimed to expand the clinical experience with levetiracetam as an antiepileptic drug (AED) for this population.Methods. Four males and two females (aged 25-51) with mental retardation requiring institutionalization and uncontrolled seizures (1.7-12.2/month) received levetiracetam (0.5-2.5g/day) in addition to their standard AEDs. Clinical response was closely followed for 4-10 months (mean, 6 months) with respect to seizure control and adverse effects.Results. Two of the patients became seizure-free, while the other four had seizure reductions ranging from 71 to 92%. None of the patients experienced adverse effects, and three had improvements in behavior.Conclusions. Levetiracetam may be extremely effective in patients with developmental disability. Behavioral abnormalities improved in 50% of the patients.