pyrimidinones and Liver-Diseases

Trametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).. Advanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on "3 + 3" design within each HD group. PK samples were collected at cycle 1 days 15-16.. Forty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).. RP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients - 1.5 mg QD in Mod group, and 1 mg QD in Sev group.. This study was registered in the ClinicalTrials.gov website ( NCT02070549 ) on February 25, 2014. .

Topics: Adult; Aged; Female; Humans; Liver Diseases; Male; Middle Aged; Neoplasms; Pyridones; Pyrimidinones

The effect of hepatic impairment on lopinavir/ritonavir pharmacokinetics was investigated. Twenty-four HIV-1-infected subjects received lopinavir 400 mg/ritonavir 100 mg twice daily prior to and during the study: 6 each with mild or moderate hepatic impairment (and hepatitis C virus coinfected) and 12 with normal hepatic function. Mild and moderate hepatic impairment showed similar effects on lopinavir pharmacokinetics. When the 2 hepatic impairment groups were combined, lopinavir Cmax and AUC12 were increased 20% to 30% compared to the controls. Hepatic impairment increased unbound lopinavir AUC12 by 68% and Cmax by 56%. The effect of hepatic impairment on low-dose ritonavir pharmacokinetics was more pronounced in the moderate impairment group (181% and 221% increase in AUC12 and Cmax, respectively) than in the mild impairment group (39% and 61% increase in AUC12 and Cmax, respectively). While lopinavir/ritonavir dose reduction is not recommended in subjects with mild or moderate hepatic impairment, caution should be exercised in this population.

Topics: Adult; Area Under Curve; Biological Availability; Drug Combinations; Drug Monitoring; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Lopinavir; Male; Middle Aged; Pyrimidinones; Radioligand Assay; Ritonavir

This study evaluated the effect of hepatic impairment on the pharmacokinetics of telbivudine, an investigational nucleoside antiviral for the treatment of chronic hepatitis B virus infection. Twenty-four subjects were assigned to four hepatic function groups (normal function and mild, moderate, and severe impairment, with six subjects in each group) on the basis of Child-Pugh scores. The subjects were administered a single oral dose of 600 mg telbivudine, and blood samples were collected over a 48-h interval for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. Telbivudine plasma concentration-time profiles were similar across the four hepatic function groups. The principal pharmacokinetic parameters of drug exposure, i.e., the maximum plasma concentration and area under the drug concentration-time curve, were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. Results from this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in hepatitis B virus-infected patients with decompensated liver diseases.

Topics: Administration, Oral; Antiviral Agents; Area Under Curve; Case-Control Studies; Chromatography, High Pressure Liquid; Female; Humans; Liver Diseases; Male; Mass Spectrometry; Middle Aged; Nucleosides; Pyrimidinones; Severity of Illness Index; Telbivudine; Thymidine

To investigate the effects of age and renal and hepatic impairment on the pharmacokinetics, tolerability and safety of sildenafil (single 50-mg oral dose) and its major circulating N-desmethyl metabolite, UK-103,320.. Three open-label, parallel-group studies were conducted. The first study compared sildenafil pharmacokinetics, safety and toleration in 15 healthy young male subjects (mean age 30 years; range 19--45 years) to 15 healthy elderly male subjects (mean age 70 years; range 65--81 years). The second study included eight male volunteers with normal renal function and 16 male volunteers with varying degrees of renal impairment as assessed by measurement of creatinine clearance (CLcr). The third study included 12 male volunteers with normal hepatic function and 12 male volunteers with chronic stable hepatic cirrhosis (Child-Pugh A and B). For all three studies, blood and urine samples were collected predose and at specified intervals up to 48 h postdose for assays of sildenafil and UK-103,320, and measurements of protein binding.. Significant differences in Cmax and AUC were observed between the young and the elderly subjects for both the parent drug and the metabolite. In the elderly, AUC values were approximately twice as high and Cmax values 60--70% higher than those for young men, while t1/2 values were approximately 1 h longer for sildenafil and 2 h longer for UK-103,320. Due to a significantly smaller unbound fraction of drug in the elderly, free drug concentrations were only approximately 40% higher in the elderly group compared to the young group. In the renal impairment study, significant correlations with CLcr were demonstrated for sildenafil oral clearance (CL/F) and Cmax and UK-103,320 Cmax and AUC. Pairwise comparisons between subjects with normal renal function and those with severe renal impairment (CLcr<30 ml min-1) supported these findings, showing significant increases in Cmax and AUC for both the parent drug and the metabolite in the severely impaired subjects. The hepatic impairment study demonstrated that the pharmacokinetics of sildenafil were altered in subjects with chronic stable cirrhosis, as shown by a 46% reduction in CL/F and a 47% increase in Cmax compared with subjects with normal hepatic function, suggesting a reduction in first-pass metabolism as well as systemic clearance. The increase in systemic exposure for UK-103,320 was approximately twice that seen for the parent drug. In all three studies, sildenafil was well tolerated, most adverse events were mild and no subjects discontinued treatment.. Sildenafil pharmacokinetics were affected by age and by renal and hepatic impairment, suggesting that a lower starting dose of 25 mg should be considered for patients with severely compromised renal or hepatic function.

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Area Under Curve; Humans; Kidney; Kidney Diseases; Liver; Liver Diseases; Male; Metabolic Clearance Rate; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidinones; Sildenafil Citrate; Sulfones

Chronic liver disease is often found in HIV infected patients. LPV as first choice drug is often used over long time periods. TDM as a tool in patients care is important but the knowledge of LPV-plasma-levels in patients with chronic liver disease remain uncertain. With this retrosepective analysis we want to show if there are differences in LPV-plasma-levels between patients with and without chronic liver diseases over a long-time period. LPV-plasma-levels were analysed with an HPLC-based methode. The LPV-plasma-levels over the time course in patients with chronic liver disease (n = 30) and patients without liver disease (n = 38) was evaluated. Liver function tests, CD4-cell count and HI-viral load was also correlated with liver disease. The LPV plasma-levels of n = 450 samples from 30 patients with liver disease (Hepatitis B: n = 17, Hepatitis C: n = 16, Alcoholic liver disease: n = 7) were determined over 18.7 +/- 16,3 months (1 - 48.5 months). A median of 10 samples per patient was eligible (2 - 50 samples). There are no significant differences according to liver disease in LPV-plasma levels (mean Ctrough without: 5917 +/- 4811 ng/ml, mean Ctrough with liver-disease: 6564 +/- 4517 ng/ml, p > 0.05). The intraindividual and interindividual variation of LPV-plasma levels, CD-4 increase, HI-virus suppression and liver tests in patients with and without liver disease is comparable. In this clinical setting no differences in LPV-plasma levels between patients with and without chronic liver disease could be demonstrated. LPV-therapy in patients with chronic liver disease is therefore safe. In patients with impaired liver function TDM is a helpful tool for dose adjustment.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Chronic Disease; Drug Monitoring; Female; Humans; Liver Diseases; Lopinavir; Male; Middle Aged; Pyrimidinones; Retrospective Studies

In RESIST, enfuvirtide co-administered with ritonavir-boosted tipranavir was associated with higher plasma tipranavir concentrations, which seldom rose above those associated with an increased risk of grade 3/4 transaminase elevations. Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group. Observed increases in plasma tipranavir concentrations thus had no apparent effect on the risk of hepatotoxicity.

Topics: Alanine Transaminase; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Lopinavir; Peptide Fragments; Pyridines; Pyrimidinones; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Saquinavir; Sulfonamides; Treatment Outcome; Viral Load

We describe the hepatotoxicity encountered in a cohort of HIV-positive patients treated with lopinavir/ritonavir. We used the database from the SCOLTA project, an on-line pharmacovigilance programme involving 25 Italian infectious disease centres. A total of 755 patients were followed, over a mean observation period of 16 months. The incidence of severe events was low despite the high prevalence of patients co-infected with hepatitis virus at enrollment.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Italy; Liver Diseases; Lopinavir; Male; Middle Aged; Product Surveillance, Postmarketing; Pyrimidinones; Ritonavir

A new class of highly fluorescent (phi(F) 0.3-0.8) low molecular weight water-soluble cholephilic compounds has been synthesized in two steps from dipyrrinones. The dipyrrinone nitrogens are first bridged by reaction with 1,1'-carbonyldiimidazole to form an N,N'-carbonyldipyrrinone (3H,5H-dipyrrolo[1,2-c:2',1'-f]pyrimidine-3,5-dione) nucleus, and a sulfonic acid group is then introduced at C(8) by reaction with concd H(2)SO(4). The resulting sulfonated N,N'-carbonyl-bridged dipyrrinones ("sulfoglows") are isolated as their sodium salts. When the alkyl substituents of the lactam ring are lengthened from ethyl to decyl, sulfoglows become increasingly lipophilic while maintaining water solubility. Low molecular weight sulfoglows were rapidly excreted intact in both bile and urine after intravenous infusion into rats, but higher molecular weight sulfoglows were excreted more selectively in bile. Hepatobiliary excretion of sulfoglows was partially, but not completely, blocked in mutant rats deficient in the multidrug-resistance associated transport protein Mrp2 (ABCC2). These observations point to the feasibility of developing simple sulfoglows with clinical diagnostic potential that are normally excreted in bile but appear in urine when hepatic elimination is impaired by cholestatic liver disease.

Topics: Animals; Bile; Bilirubin; Colchicine; Drug Evaluation, Preclinical; Feasibility Studies; Fluorescent Dyes; Liver; Liver Diseases; Male; Mitochondrial Proteins; Pyrimidinones; Pyrroles; Rats; Rats, Gunn; Rats, Sprague-Dawley; Ribosomal Proteins; Saccharomyces cerevisiae Proteins; Spectrometry, Fluorescence; Sulfonic Acids; Urine

With the advent of highly active antiretroviral therapy (HAART), HIV positivity is no longer a contraindication for liver transplantation. Some of the antiretroviral agents, particularly protease inhibitors (e.g., ritonavir, indinavir, and nelfinavir) have been described as potent inhibitors of the metabolism of certain immunosuppressive drugs. In this article we describe a profound interaction between tacrolimus and Kaletra (Abbott Laboratories, Chicago, IL) (a combination of lopinavir and ritonavir) in 3 liver transplantation patients. Patient 1, who was maintained on a 5 mg twice daily dose of tacrolimus with a trough blood concentration around 10.6 ng/mL, required only 0.5 mg of tacrolimus per week after addition of Kaletra to achieve similar tacrolimus blood concentrations, with a half-life of 10.6 days. In patient 2, the area under the blood concentration versus time curve for tacrolimus increased from 31 ng/mL/h to 301 ng/mL/h after addition of Kaletra, with a corresponding half-life of 20 days. When the patient was subsequently switched to nelfinavir, the half-life decreased to 10.3 days. Patient 3, who was maintained with 4 to 8 mg/d of tacrolimus and a corresponding blood concentration of 10 ng/mL before Kaletra, required a tacrolimus dose of 1 mg/wk and tacrolimus concentrations of 5 ng/mL with Kaletra. In conclusion, a combination of lopinavir and ritonavir led to a much more profound increase in tacrolimus blood concentrations than use of single protease inhibitor, nelfinavir. A tacrolimus dose of less than 1 mg/wk may be sufficient to maintain adequate blood tacrolimus concentrations in patients on Kaletra. Patients may not need a further dose of tacrolimus for 3 to 5 weeks depending on liver function when therapy with Kaletra is initiated. Great caution is required in the management of tacrolimus dosage when Kaletra is introduced or withdrawn in HIV-positive patients after liver transplantation, particularly in the presence of hepatic dysfunction.

Topics: Adult; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Tacrolimus

A novel one-pot synthesis of imidazo[1,2-c]pyrimido[5,4-e]pyrimidinones (2), tetraazaacenaphthene-3,6-diones (4), tetarazaphenalene-1,7-dione (4d) is delineated from the reaction of cyclic ketene aminal (1) and alkyl or aryl isothiocyanate through tandem addition-cyclization reactions. However, reaction of ketene aminal (1a) with alkyl isothiocyanate only yielded angularly cyclized product 5 which did not react further to yield 6. The structure of 2c and 4d was ascertained by single crystal X-ray diffraction analysis which demonstrated a network of various inter- and intramolecular interactions, responsible for the stability and packing of the molecules in the crystalline state. Some of the compounds (2a--h) were screened for hepatoprotective activity but only 2a was found most effective.

Topics: Acenaphthenes; Animals; Antioxidants; Aza Compounds; Crystallography, X-Ray; Cyclization; Humans; Ketones; Liver Diseases; Molecular Structure; Protective Agents; Pyrimidinones