Moderate Hepatic Insufficiency Research Articles

Advances in contezolid: novel oxazolidinone antibacterial in Gram-positive treatment.

The principal objective of this project was to review and thoroughly examine the chemical characteristics, pharmacological activity, and quantification methods associated with contezolid. The article was based on published and ongoing preclinical and clinical studies on the application of contezolid. These studies included experiments on the physicochemical properties of contezolid, in vitro antimicrobial research, in vivo antimicrobial research, and clinical trials in various phases. There were no date restrictions on these studies. In June 2021, contezolid was approved for treating complicated skin and soft tissue infections. The structural modification of contezolid has resulted in better efficacy compared to linezolid. It inhibits bacterial growth by preventing the production of the functional 70S initiation complex required to translate bacterial proteins. The current evidence has indicated a substantial decline in myelosuppression and monoamine oxidase inhibition without impairing its antibacterial properties. Contezolid was found to have a more significant safety profile and to be metabolised by flavin monooxygenase 5, reducing the risk of harmful effects due to drug-drug interactions. Adjusting doses is unnecessary for patients with mild to moderate renal or hepatic insufficiency. As an oral oxazolidinone antimicrobial agent, contezolid is effective against multi-drug resistant Gram-positive bacteria. The introduction of contezolid provided a new clinical option.

A Phase I Clinical Study of the Pharmacokinetics and Safety of Prusogliptin Tablets in Subjects with Mild to Moderate Hepatic Insufficiency and Normal Liver Function.

Prusogliptin is a potent and selective DPP-4 inhibitor. In different animal models, Prusogliptin showed potential efficacy in the treatment of type 2 diabetes. However, the knowledge of its pharmacokinetics and safety in patients with liver dysfunction is limited. The present study evaluated the pharmacokinetics and safety of Prusogliptin in subjects with mild or moderate hepatic impairment compared with healthy subjects. According to the liver function of the subjects, we divided them into a mild liver dysfunction group, a moderate liver dysfunction group and a normal liver function group. All subjects in three groups received a single oral dose of Prusogliptin 100-mg tablets. Pharmacokinetics and safety index collection was carried out before and after taking the drug. Plasma pharmacokinetics of Prusogliptin were evaluated, and geometric least- -squares mean (GLSM) and associated 90% confidence intervals for insufficient groups versus the control group were calculated for plasma exposures. After a single oral administration of 100 mg of Prusogliptin tablets, the exposure level of Prusogliptin in subjects with mild liver dysfunction was slightly higher than that in healthy subjects. The exposure level of Prusogliptin was significantly increased in subjects with moderate liver dysfunction. There were no adverse events in this study. The exposure level of Prusogliptin in subjects with liver dysfunction was higher than that in healthy subjects. No participant was observed of adverse events. Prusogliptin tablets were safe and well tolerated in Chinese subjects with mild to moderate liver dysfunction and normal liver function.

Physiologically based pharmacokinetic model combined with reverse dose method to study the nephrotoxic tolerance dose of tacrolimus.

Nephrotoxicity is the most common side effect that severely limits the clinical application of tacrolimus (TAC), an immunosuppressive agent used in kidney transplant patients. This study aimed to explore the tolerated dose of nephrotoxicity of TAC in individuals with different CYP3A5 genotypes and liver conditions. We established a human whole-body physiological pharmacokinetic (WB-PBPK) model and validated it using data from previous clinical studies. Following the injection of 1mg/kg TAC into the tail veins of male rats, we developed a rat PBPK model utilizing the drug concentration-time curve obtained by LC-MS/MS. Next, we converted the established rat PBPK model into the human kidney PBPK model. To establish renal concentrations, the BMCL5 of the in vitro CCK-8 toxicity response curve (drug concentration range: 2-80mol/L) was extrapolated. To further investigate the acceptable levels of nephrotoxicity for several distinct CYP3A5 genotypes and varied hepatic function populations, oral dosing regimens were extrapolated utilizing in vitro-in vivo extrapolation (IVIVE). The PBPK model indicated the tolerated doses of nephrotoxicity were 0.14-0.185mg/kg (CYP3A5 expressors) and 0.13-0.155mg/kg (CYP3A5 non-expressors) in normal healthy subjects and 0.07-0.09mg/kg (CYP3A5 expressors) and 0.06-0.08mg/kg (CYP3A5 non-expressors) in patients with mild hepatic insufficiency. Further, patients with moderate hepatic insufficiency tolerated doses of 0.045-0.06mg/kg (CYP3A5 expressors) and 0.04-0.05mg/kg (CYP3A5 non-expressors), while in patients with moderate hepatic insufficiency, doses of 0.028-0.04mg/kg (CYP3A5 expressors) and 0.022-0.03mg/kg (CYP3A5 non-expressors) were tolerated. Overall, our study highlights the combined usage of the PBPK model and the IVIVE approach as a valuable tool for predicting toxicity tolerated doses of a drug in a specific group.

Safety and Tolerability of Fesoterodine in Older Adult Patients with Overactive Bladder

BackgroundOlder patients (> 65 yr) suffering from overactive bladder (OAB) are more likely to have functional impairment and comorbidity than those without OAB. This article reviews available published studies and discusses how fesoterodine might meet the specific needs of the older OAB patient.MethodsA comprehensive literature search was undertaken in order to evaluate fesoterodine safety in older OAB patients.ResultsFesoterodine offers flexible dosing, allowing the clinician to balance risk and benefits according to the symptoms and preferences of the patient. Its balanced affinity for M2 and M3 muscarinic receptors may lead to its benefit on OAB symptoms. Its active metabolite is a P-gp substrate that is actively transported from the central nervous system (CNS), potentially avoiding adverse CNS effects. Fesoterodine can be used in mild or moderate hepatic or renal insufficiency and no dose adjustment is routinely required. Fesoterodine’s benefit has been demonstrated in multiple clinical trials in older and medically vulnerable patients. Fesoterodine was rated as “beneficial” in the LUTS-FORTA classification due to its efficiency and tolerability in older patients.ConclusionHere, the use of fesoterodine in older and vulnerable patients is summarized given the need to approach pharmacotherapy for OAB differently in older adults.

Study of the Safety and Tolerability of AXA1665 in Subjects With Mild and Moderate Hepatic Insufficiency

Study of the Safety and Tolerability of AXA1665 in Subjects With Mild and Moderate Hepatic Insufficiency

PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice.

PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice.

Influence of hepatic impairment on the pharmacokinetics of the dopamine agonist rotigotine

The transdermally applied dopamine receptor agonist rotigotine is extensively metabolized in the liver. An open-label, parallel-group study was conducted to evaluate the effects of moderate hepatic impairment on the pharmacokinetics, safety and tolerability of rotigotine. Eight subjects with normal hepatic function and nine with moderate hepatic impairment (Child-Pugh class B) received one rotigotine transdermal patch (providing a dose of 2 mg/24 h) daily for 3 days with a 24-h patch-on period. Blood and urine samples were collected to evaluate pharmacokinetic parameters characterizing drug bioavailability and elimination. Primary variables included plasma and urine concentrations of unconjugated rotigotine (active parent compound) and total rotigotine (unconjugated rotigotine plus sulfate and glucuronide conjugates) under steady-state (SS) conditions. For unconjugated rotigotine, point estimates for the ratios of AUC(0-24)SS and C max,SS between the two groups (normal vs. impaired hepatic function) were near 1: AUC(0-24)SS, 0.90 (90 % CI 0.59, 1.38) and C max,SS, 0.94 (90 % CI 0.66, 1.35); t max,SS and t 1/2 were lower in subjects with hepatic impairment, while renal clearance was unaffected and overall clearance was higher. For total rotigotine, C max,SS was higher in subjects with hepatic impairment compared with those with normal hepatic function (P = 0.0239, ANOVA). A tendency to reduced non-renal clearance was observed in subjects with hepatic impairment, consistent with their higher plasma concentrations of total rotigotine. Thus, moderate hepatic impairment did not influence the pharmacokinetics of unconjugated rotigotine under steady-state conditions suggesting that dose adjustment will not be required for patients with mild or moderate hepatic insufficiency. In addition, the rotigotine patch was well tolerated in subjects with moderate hepatic impairment.

Simultaneous determination of morinidazole, its N-oxide, sulfate, and diastereoisomeric N+-glucuronides in human plasma by liquid chromatography–tandem mass spectrometry

Morinidazole is a new third-generation 5-nitroimidazole antimicrobial drug. To investigate the pharmacokinetic profiles of morinidazole and its major metabolites in humans, a liquid chromatography–tandem mass spectrometry method was developed and validated for simultaneous determination of morinidazole, its N-oxide metabolite (M4-1), a sulfate conjugate (M7), and two diastereoisomeric N+-glucuronides (M8-1 and M8-2) in human plasma. A simple acetonitrile-induced protein precipitation was employed to extract five analytes and internal standard metronidazole from 50μL human plasma. To avoid the interference from the in-source dissociation of the sulfate and achieve the baseline-separation of diastereoisomeric N+-glucuronides, all the analytes were separated from each other with the mobile phase consisting of 10mM ammonium formate and acetonitrile using gradient elution on a Hydro-RP C18 column (50mm×2mm, 4μm) with a total run time of 5min. The API 4000 triple quadrupole mass spectrometer was operated under the multiple reaction-monitoring mode using the electrospray ionization technique. The developed method was linear in the concentration ranges of 10.0–12,000ng/mL for morinidazole, 1.00–200ng/mL for M4-1, 2.50–500ng/mL for M7, 3.00–600ng/mL for M8-1, and 10.0–3000ng/mL for M8-2. The intra- and inter-day precisions for each analyte met the accepted value. Results of the stability of morinidazole and its metabolites in human plasma were also presented. The method was successfully applied to the clinical pharmacokinetic studies of morinidazole injection in healthy subjects, patients with moderate hepatic insufficiency, and patients with severe renal insufficiency, respectively.

The effect of hepatic insufficiency on the pharmacokinetics of ridaforolimus.

e13001 Background: Ridaforolimus (RIDA) (AP23573; MK-8669), a unique rapamycin analog and a potent inhibitor of mTOR signaling, is being developed for the treatment of solid tumors. The study aims were to assess the safety and whole blood pharmacokinetics following single 10 mg doses of RIDA in patients with moderate hepatic insufficiency (Child-Pugh [CP] score of 7-9). Methods: This was an open-label study comparing the pharmacokinetics after administration of a 10 mg single dose of RIDA to patients with moderate hepatic insufficiency (assessed by the CP scale) with healthy matched controls. Nineteen (19) males and females of non-childbearing potential were enrolled: ten (10) patients with moderate hepatic insufficiency (CP score of 7-9) and 9 healthy matched control subjects (race, age [±5 years], gender, BMI [±3.3 units]). Results: A summary of the blood pharmacokinetic parameters of RIDA administered to patients with moderate hepatic insufficiency and to healthy matched control subjects is presented below. RIDA was generally well tolerated and no patients were discontinued due to drug-related AEs. Conclusions: RIDA exposure in patients with moderate hepatic insufficiency was approximately 2-fold higher than in healthy matched controls. Since RIDA is being studied in phase III at the maximally tolerated dose of 40 mg, this finding is likely to be clinically meaningful and caution should be exercised when dosing patients with moderate hepatic insufficiency. Moderate hepatic insufficiency Healthy matched control Moderate hepatic insufficiency/ healthy matched control Pharmacokinetic parameter N# GM 95% CI N GM 95% CI GMR 90% CI AUC0-∞ † (ng/ml·hr) 10 1168 (669, 2,039) 9 589 (315, 1,100) 1.98 (1.06, 3.71) Cmax † (ng/ml) 10 53.9 (25.5, 114.2) 9 41.4 (17.8, 96.0) 1.30 (0.56, 3.03) Tmax ‡ (hr) 10 6.0 (3.0, 8.0) 9 4.0 (4.0, 8.0) Apparent t1/2 § (hr) 10 111.4 28.0 9 75.0 41.0 Abbreviations: GM, geometric mean; GMR, geometric mean ratio; CI, confidence interval. † Geometric mean computed from least squares estimate from an ANCOVA performed on the natural-log transformed values. ‡ Median [Min, Max] reported for Tmax. § Harmonic mean, jack-knife standard deviation (SD) reported for t1/2. # AN 0003 who discontinued had sufficient PK to be included in the primary analysis.

Pharmacokinetics of Laropiprant, a Selective Prostaglandin D2Receptor 1 Antagonist, in Patients With Moderate Hepatic Impairment

This open-label study evaluated the influence of hepatic insufficiency on the pharmacokinetics of laropiprant (LRPT), a prostaglandin D(2) receptor-1 antagonist, to guide clinicians in the event of inadvertent dosing in patients with hepatic insufficiency. A single oral 40-mg dose of LRPT was administered to 8 patients with moderate hepatic insufficiency and 8 healthy control participants matched for important baseline characteristics. Blood samples were collected predose and up to 96 hours postdose to assess LRPT pharmacokinetics. No clinically significant effect of hepatic insufficiency would be declared if the 90% confidence interval (CI) for the estimated geometric mean ratio (GMR; hepatic insufficiency patients/healthy participants) of AUC(0-∞) was contained within the prespecified bounds of (0.50-3.00). Estimated GMRs of AUC(0-∞) and C(max) (90% CIs) were 2.78 (1.71, 4.50) and 2.17 (1.33, 3.53), respectively. The median time to C(max) and apparent terminal t(1/2) of LRPT were comparable between the 2 populations (P > .100). Single-dose LPRT 40 mg was generally well tolerated in all patients. The plasma pharmacokinetics of a single 40-mg oral dose of LRPT is not similar between patients with moderate hepatic insufficiency and matched healthy participants. The GMR (90% CI) of AUC(0-∞) for patients with moderate hepatic insufficiency versus matched controls was 2.78 (1.71, 4.50).

Randomized Placebo-Controlled Crossover Trial of Tadalafil in Raynaud's Phenomenon Secondary to Systemic Sclerosis

Conclusion: Tadalafil is well tolerated and safe in patients with systemic sclerosis but lacks efficacy in comparison with placebo. Summary: The endothelial injury of systemic sclerosis is associated with decreased nitric oxide production (Kahaleh et al, Rheum Diseases Clin N Am 2008;34:57-71). Type V cyclic GMP phosphodiesterase (PDE-5) affects the tone of smooth muscle. An intracellular regulator of smooth muscle tone is cyclic nucleotide monophosphate, cGMP. Nitric oxide synthase produces nitric oxide. Through a complex pathway, nitric oxide facilitates conversion of GTP into cGMP. PDE-5 breaks down intracellular cGMP. Therefore, inhibition of PDE-5 results in increased availability of intracellular cGMP and results in vasodilatation. Tadalafil is a PDE-5 inhibitor effective in the use of male erectile dysfunction. However, PDE-5 inhibitors have also been suggested as beneficial in patients with severe Raynaud's syndrome (Fries R et al, Circulation 2005;119:2980-5). Tadalafil is an intriguing PDE-5 inhibitor in that it has a half-life of 17.5 hours and efficacy up to 36 hours. The pharmacokinetics of tadalafil are not affected by food or alcohol, age, diabetes, or moderate hepatic insufficiency. It therefore would seem an ideal drug for facilitating vasodilatation in patients with Raynaud's syndrome. This was a randomized, prospective, double-blind, placebo-controlled, crossover study comparing oral tadalafil with a fixed daily dose of 20 mg for 4 weeks vs placebo. The study was conducted in patients with Raynaud's syndrome secondary to systemic sclerosis. Thirty-nine completed the study. All patients fulfilled American College of Rheumatology classification criteria for systemic sclerosis. All were at least 18 years of age and had evidence of at least six Raynaud's attacks during the 2-week pretreatment period. Patients with unstable angina, congestive heart failure, or use of nitrites for angina pectoris or any other condition as well as those with significant central nervous system disease were excluded. Before enrollment, all patients discontinued any other type of vasodilator. Patients were evaluated for duration and frequency of Raynaud's attacks and Raynaud condition scores (RCS). At the end of the evaluation period, there were no significant statistical differences in RCS scores, frequency of Raynaud's attacks, or duration of Raynaud's attacks between the treatment and placebo groups. Comment: The results of the study are disappointing but not conclusive. The participants in this trial had a longer duration of Raynaud's syndrome than those in other trials. Severity of Raynaud's syndrome secondary to systemic sclerosis often increases over time. Patients here may have had greater endothelial cumulative damage than those in other studies. Other studies have primarily evaluated the effect of PDE-5 inhibitors on ulcer healing. Only two patients in this study had active digital ulcers. However, overall, the current results do not support the use of tadalafil as treatment for Raynaud's syndrome secondary to systemic sclerosis at the dosage of 20 mg/d. The study was also burdened by a large placebo effect.

Combined indocyanine green test and standard remnant liver volume to predict post-hepatectomy hepatic insufficiency for the patients with hepatocellular carcinoma

To discuss the safety line to avoid the post-hepatectomy hepatic insufficiency by combining indocyanine green test by pulse dye-densitometry (PDD-ICG) and standard remnant liver volume (SRLV). Seventy-five hepatic cancer patients undergone hepatectomy from March 2007 to February 2008 were included. According to the liver function decompensatory grades after operation, the relationship between ICG retention rate at 15 min (ICGR15) and standard remnant liver volume by linear regression were analyzed. There were 60 cases with slight hepatic insufficiency, 12 cases with moderate hepatic insufficiency, and 3 cases with severe hepatic insufficiency. There were no difference in age [(50 +/- 13) years old and (53 +/- 9) years old], prothrombin time [(13.6 +/- 1.0) s and (13.5 +/- 1.0) s], international normalized ratio (1.09 +/- 0.10 and 1.06 +/- 0.10) between slight hepatic insufficiency group and moderate and severe hepatic insufficiency group (P > 0.05). And there were difference in K value (0.20 +/- 0.04 and 0.17 +/- 0.03), ICGR15 (6 +/- 4 and 9 +/- 4), SRLV [(545 +/- 93) ml and (398 +/- 82) ml] between two groups (P < 0.05). Compared ICG test and standard remnant liver volume of the patients with moderate hepatic insufficiency after operation, the liner relationship was found (R = 0.640, P = 0.025), and the regression equation was: standard remnant liver volume (ml/m(2)) = 1594.6 x ICGR15 + 265. PDD-ICG test and standard remnant liver volume are effective to estimate hepatic function reserve of patient undergone hepatectomy.

Lack of a Clinically Important Effect of Moderate Hepatic Insufficiency and Severe Renal Insufficiency on Raltegravir Pharmacokinetics

Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor with potent activity in vitro and in vivo. Raltegravir is primarily cleared by hepatic metabolism via glucuronidation (via UDP glucuronosyltransferase 1A1), with a minor component of elimination occurring via the renal pathway. Since the potential exists for raltegravir to be administered to patients with hepatic or renal insufficiency, two studies were conducted to evaluate the influence of moderate hepatic insufficiency (assessed by using the Child-Pugh criteria) and severe renal insufficiency (creatinine clearance, <30 ml/min/1.73 m(2)) on the pharmacokinetics of raltegravir. Study I evaluated the pharmacokinetics of 400 mg raltegravir in eight patients with moderate hepatic insufficiency and eight healthy, matched control subjects. Study II evaluated the pharmacokinetics of 400 mg raltegravir in 10 patients with severe renal insufficiency and 10 healthy, matched control subjects. All participants received a single 400-mg dose of raltegravir in the fasted state. In study I, the geometric mean ratios (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% confidence intervals (CIs) for the area under the concentration-time curve from time zero to infinity (AUC(0-infinity)), the maximum concentration of drug in plasma (C(max)), and the concentration at 12 h (C(12)) were 0.86 (90% CI, 0.41, 1.77), 0.63 (90% CI, 0.23, 1.70), and 1.26 (90% CI, 0.65, 2.43), respectively. In study II, the GMRs (mean value for the group with renal insufficiency/mean value for the healthy controls) and 90% CIs for AUC(0-infinity), C(max), and C(12) were 0.85 (90% CI, 0.49, 1.49), 0.68 (90% CI, 0.35, 1.32), and 1.28 (90% CI, 0.79, 2.06), respectively. Raltegravir was generally well tolerated by patients with moderate hepatic or severe renal insufficiency, and there was no clinically important effect of moderate hepatic or severe renal insufficiency on the pharmacokinetics of raltegravir. No adjustment in the dose of raltegravir is required for patients with mild or moderate hepatic or renal insufficiency.

Raltegravir: The first HIV integrase inhibitor

Background: The availability of new classes of antiretroviral drugs has made it possible for HIV-infected individuals who are highly treatment experienced to achieve the goals of immunologic recovery and virologic suppression. Raltegravir is the first integrase inhibitor to be approved by the US Food and Drug Administration for use in antiretroviral treatment- experienced adult patients with viral resistance.Objective: This article reviews the pharmacology, pharmacokinetics, pharmacodynamics, efficacy, tolerability, resistance profile, drug interactions, and dosing and administration of raltegravir.Methods: Searches of MEDLINE and International Pharmaceutical Abstracts from 1964 to July 2008 were conducted using the terms integrase, raltegravir, and MK-0518. Relevant information was extracted from the identified clinical trials and review articles. Abstracts from the Conference on Retroviruses and Opportunistic Infections (1998-2008); Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2007); International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (2001-2007); and European AIDS Conference (2001-2007) were also searched.Results: Raltegravir blocks HIV replication by inhibiting essential strand-transfer activities of integrase. Raltegravir is rapidly absorbed, with a median Tmax of ~4 hours in the fasting state. No dose adjustment is recommended in patients with moderate renal or hepatic insufficiency, and raltegravir may be taken without regard to meals. In Phase II studies in treatment-naive patients, raltegravir had efficacy similar to that of standard initial therapies. In 2 interrelated Phase III clinical studies in treatment-experienced patients with drug-resistant disease, the addition of raltegravir to an optimized background regimen significantly lowered HIV RNA compared with optimized background treatment alone (62.1% vs 32.9%, respectively; P < 0.001). Raltegravir was generally well tolerated. The most common adverse effects reported in Phase II/III trials in treatment-experienced patients were diarrhea (16.6%), nausea (9.9%), and headache (9.7%). Cytochrome P450–related drug interactions are not expected, as raltegravir is not a CYP substrate, inducer, or inhibitor. However, to prevent failure of raltegravir, the drug should not be coadministered with rifampin.Conclusion: Raltegravir is a potent and generally well tolerated antiretroviral agent that may play an important role in the treatment of patients harboring resistance to other antiretrovirals.

Single‐ and Multiple‐Dose Administration of Caspofungin in Patients With Hepatic Insufficiency: Implications for Safety and Dosing Recommendations

This report investigated safety and dosing recommendations of intravenous caspofungin in hepatic insufficiency. In the single-dose study, 8 patients each with mild and moderate hepatic insufficiency received 70 mg of caspofungin. In the multiple-dose study, 8 patients with mild hepatic insufficiency and 13 healthy matched controls received 70 mg on day 1 and 50 mg daily on days 2 through 14. Eight patients with moderate hepatic insufficiency received 70 mg on day 1 and 35 mg daily on days 2 through 14. Caspofungin was generally well tolerated with no discontinuations due to serious or nonserious adverse experiences. The area under the concentration-time profile over the interval of last quantifiable point to infinity (AUC(0-infinity)) geometric mean ratio (GMR) (90% confidence interval [CI]) for mild hepatic insufficiency/historical controls was 1.55 (1.32-1.86) in the single-dose study and for mild hepatic insufficiency/concurrent controls was 1.21 (1.04-1.39) for day 14 area under the concentration-time profile calculated over the interval 0 to 24 hours (AUC(0-24h)) following multidose. The AUC(0-infinity) GMR (90% CI) for moderate hepatic insufficiency/historical controls was 1.76 (1.51-2.06) following 70 mg; AUC(0-24h) GMR (90% CI) for moderate hepatic insufficiency/concurrent controls was 1.07 (0.90-1.28) on day 14 after 35 mg daily. No dosage adjustment is recommended for patients with mild hepatic insufficiency. A dosage reduction to 35 mg daily following the 70-mg loading dose is recommended for patients with moderate hepatic insufficiency.

Altered Pharmacokinetics of Voriconazole in a Patient with Liver Cirrhosis

Voriconazole (VRC; Vfend [Pfizer, United Kingdom]) is a broad-spectrum triazole with activity against fungi including non-albicans Candida, Aspergillus, Fusarium, and Scedosporium species. Favorable therapeutic responses in patients with plasma VRC levels above 2.05 μg/ml were found previously (9). The main adverse effects of VRC are hepatotoxicity and blurred vision (1, 2, 4, 6, 11). Prolonged exposure to high plasma VRC concentrations (trough blood VRC levels of >5.5 μg/ml for more than 7 days) was found to be associated with an enhanced risk of serious neurological adverse events (5). A 45-year-old male (body weight, 100 kg) with fatty-liver cirrhosis (Child-Pugh class C; model of end-stage liver disease score, 20) who was listed for liver transplantation and showed signs of portal hypertension (esophageal varices and ascites) and cholestasis (plasma bilirubin level, 20.26 mg/dl, or 346 μmol/liter) received 2 mg of VRC/kg of body weight orally twice a day because of suspected pulmonary aspergillosis. At day 30 of clinical treatment with VRC, he was transferred to the intensive care unit because of unconsciousness (Glasgow Coma Scale score, 5 of 15) and hyperventilation. Plasma VRC concentrations were determined by high-performance liquid chromatography and UV detection (3). Pharmacokinetic parameters were calculated using a noncompartmental model. Upon admission to the intensive care unit (15 h after the last intake of VRC), the plasma VRC level amounted to 13.9 μg/ml (Fig. ​(Fig.1).1). Therefore, VRC therapy was discontinued. The patient's condition, particularly the central nervous system symptoms, gradually improved as VRC levels slowly declined, and he could be transferred to the ward after 2 days (VRC concentration, 10.0 μg/ml). A half-life of 53.1 h (half-life in healthy volunteers, 4.7 h [7]), an apparent volume of distribution at steady state of 0.13 liters/kg (volume of distribution in healthy volunteers, 2.04 liters/kg [7]), and a VRC clearance rate as low as 1.4 ml/h/kg (clearance rate in healthy volunteers, 253.9 ml/h/kg [7]) were calculated. Even after 11 days, VRC was detectable in the plasma (0.66 μg/ml). Since diagnostic reevaluation did not reveal any signs of fungal infection, there was no need to continue antimycotic treatment at that time. The patient underwent a successful liver transplantation 1 month later. FIG. 1. Voriconazole elimination after discontinuation of voriconazole. The dashed line indicates the concentration limit for favorable responses (9). The elimination of VRC appears to be markedly prolonged in patients with decompensated liver cirrhosis, and this delay leads to potentially toxic levels of VRC in the plasma. After cytochrome P450 (2C9, 2C19, and 3A4)-dependent hepatic metabolism, about 80% of VRC is eliminated via the kidneys. Biliary elimination accounts for 20%. VRC displays nonlinear pharmacokinetics, with a prolonged half-life at higher concentrations (8). In patients with moderate liver cirrhosis (Child-Pugh class B), the VRC clearance rate is approximately half that in patients with normal hepatic function after oral intake. A reduction of the maintenance dose by 50% is recommended for patients with mild to moderate hepatic insufficiency (10). For patients with severely impaired liver function, a dose reduction of more than 50% appears to be required, and therapeutic drug monitoring will greatly improve therapeutic safety. Pharmacokinetic studies in patients with severe hepatic impairment should be performed in order to establish reliable dose recommendations for this group of patients, who are at high risk of developing invasive fungal infections.

Anidulafungin Does Not Require Dosage Adjustment in Subjects With Varying Degrees of Hepatic or Renal Impairment

Two open-label studies assessed the effects of hepatic and renal impairment on anidulafungin pharmacokinetics. A single 50-mg dose was administered intravenously to subjects with varying degrees of hepatic or renal insufficiency or with end-stage renal disease; all were matched to normal healthy controls. Anidulafungin was well tolerated. AUC, CL, C(max), t(max), t(1/2), and V(ss) between renally impaired subjects and controls were not significantly different (P>.05), and no measurable amounts of drug were found in dialysate. The same pharmacokinetic parameters were also not affected (P>.05) by mild or moderate hepatic insufficiency, with respective mean AUCs of 50.6 +/- 11.7 microg x h/mL and 68.6 +/- 14.5 microg x h/mL, compared to 70.0 +/- 13.4 microg x h/mL in controls. Statistically significant decreases (P<05) of AUC (33% change) and C(max) (36% change) in severely hepatically impaired subjects compared to controls--most likely secondary to ascites and edema--were not clinically relevant. Anidulafungin can be safely administered to patients with any degree of hepatic or renal impairment without dosage adjustment and without regard to hemodialysis schedules.

Febuxostat: A Novel Non-Purine Selective Inhibitor of Xanthine Oxidase for the Treatment of Hyperuricemia in Gout

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase being developed for the management of hyperuricaemia in patients with gout. To critically review the clinical trial data, safety profile, pharmacology, and role of febuxostat for the treatment of hyperuricemia and gout. A review of the literatures on febuxostat was performed. All available human studies describing the pharmacology of febuxostat were included; including pharmacodynamics, efficacy, and safety of febuxostat. Available studies, patents and abstracts were identified through PubMed (1990-December 2006), Delphion, Cochrane Databases, and the American College of Rheumatology and European League Against Rheumatism Web sites. Key search terms were febuxostat, TMX-67, and TEI-6720. Febuxostat has been used at a dose of 80 to 120 mg for the management of hyperuricemia in gout. The drug is mainly metabolized by the liver and therefore mild-moderate renal impairment does not appear to impede its effect. However, given the limited long-term liver function safety data, failure of a large percentage of patients taking febuxostat to achieve the primary end point of serum urate levels less than 6.0 mg/dL, and higher drop out rate in the Febuxostat group in the clinical trials, the exact role of febuxostat as a urate-lowering therapy remains uncertain. Febuxostat is a promising alternative to allopurinol for the treatment of gout and hyperuricemia. The optimal length of colchicines prophylactic therapy for chronic gout, clinical significance of abnormal liver function tests results during therapy, and safety in patients with moderate or severe hepatic and renal insufficiency warrant further investigation. A post-market surveillance is also needed to address the safety issue of long-term febuxostat treatment.

The LTC View on Rasagiline and Sitagliptin

The LTC View on Rasagiline and Sitagliptin

The Effect of Hepatic Insufficiency on the Safety and Pharmacokinetics of Paricalcitol (Zemplar®)

Background/Aims: Paricalcitol is highly protein bound, extensively metabolized and eliminated primarily by hepatobiliary excretion. This study was designed to determine if hepatic disease alters the pharmacokinetics or affects the safety of paricalcitol. Methods: Subjects with mild (n = 5) or moderate (n = 5) hepatic impairment, and subjects with normal hepatic function (n = 10) enrolled in and completed the study. Each subject was administered a single 0.24 µg/kg intravenous dose of paricalcitol, injected within 1 min. Results: For both total and unbound paricalcitol, there were no statistically significant differences in the pairwise comparisons between hepatic function groups in paricalcitol concentration at 5 min postdose (C₅) or area under the plasma concentration-time curve from time zero to infinity (AUC_0–∞), except C₅ of total paricalcitol between mild and moderate impairment groups (p = 0.02). Paricalcitol binding to plasma proteins was extensive in all hepatic function groups (mean values >99.7%); unbound fraction was greater in subjects with moderate impairment than either healthy subjects or subjects with mild impairment (p < 0.01). Paricalcitol appeared to be well tolerated both by healthy subjects and subjects with mild to moderate hepatic insufficiency. Conclusion: No adjustment of paricalcitol dose is required for subjects with mild to moderate hepatic impairment. However, caution should be exercised in extrapolating the results from this study to subjects with severe hepatic impairment.