Mild Liver Impairment Research Articles

Prolonged release pirfenidone pharmacokinetics is modified in cirrhosis GENESIS study

BackgroundIn both clinical and experimental trials, pirfenidone (PFD) showed anti-inflammatory and antifibrogenic effects. Considering the wide variation in hepatic functional reserve in patients with cirrhosis, we decided to learn more about the pharmacokinetics of a new formulation of prolonged release PFD in this population (PR-PFD), focusing on assessing changes on AUC0–∞, AUC0–t, and Cmax. MethodsIn this study, 24 subjects with cirrhosis were included: eight subjects with mild liver impairment (Child–Pugh A) and eight with moderate liver impairment (Child–Pugh B), and a third group of eight age-matched subjects without fibrosis. All participants were under fasting conditions before receiving orally two 600-mg tablets of a prolonged-release formulation of pirfenidone (PR-PFD) and remained in the clinical unit for 36 h after PR-PFD administration. Serial blood samples were collected after dosing (0.5-36 h). A validated high-performance liquid chromatography–mass spectrometry method was used to determine PFD plasma concentrations. ResultsThe exposure to PR-PFD was 3.6- and 4.4-fold greater in subjects with Child–Pugh A and Child–Pugh B than in subjects without cirrhosis, and Cmax was 1.6- and 1.8-fold greater in subjects with Child–Pugh B and Child–Pugh-A than in patients without cirrhosis, without significant differences between the two cirrhotic groups. PFD was well tolerated. ConclusionThe pharmacokinetic parameters of PR-PFD are significantly modified in patients with cirrhosis compared with those in controls, indicating that liver impairment should be considered in clinical practice.

S2688 COVID-19-Induced Acute Hepatitis Treated Successfully With N-Acetylcysteine: Case Report

INTRODUCTION: Mild liver impairment is widely reported in patients with COVID19. However, Acute hepatitis (AH) was reported in only one case found in a 99-case series published in China.N- acetylcysteine (NAC) is a known medication used in acetaminophen-induced hepatitis, works as a hepatoprotective agent via multiple mechanisms, including restoring hepatic glutathione as well as an antioxidant. It seems that its therapeutic use could be extended to manage cases of AH induced by other medical conditions like COVID 19 as in our case. CASE DESCRIPTION/METHODS: 64 years old male presented with progressive dyspnea, fever, and myalgia. He was diagnosed with COVID19 at a different facility two days prior to the current presentation and was sent home to self-quarantine. On presentation, the patient was mildly hypoxia that responded to nasal oxygen, but never hypotensive. Laboratory results were significant for elevated aspartate transaminase (AST) and alanine transaminase (ALT) at 1,264, 767 Units/L respectively. Alkaline phosphates showed a 1.5-fold increase from his baseline. Total bilirubin, Albumin, prothrombin time, partial thromboplastin time, international normalized ratio (INR) were all normal throughout hospitalization. Viral hepatitis panel and autoimmune hepatitis panel (including anti-mitochondrial antibody, anti-smooth muscle antibody, antinuclear antibody, and immunoglobulin G level were also negative. Serum salicylate and acetaminophen levels, urine toxicology screening test, and respiratory viral panel (novel Coronavirus not included) were all negative. Serum ferritin was elevated at 20,325 ng/mL, while serum iron was 40 mcg/dL and total iron-binding capacity was 282 mcg/dL. Upon admission, the patient was given a loading dose of NAC followed by maintenance doses. Two days later, AST and ALT started to trend down. Two days later, alkaline phosphatase followed suit. The patient was also placed on the COVID19 treatment regimen used in our facility, including Azithromycin, Hydroxychloroquine, and Zinc sulfate. Systemic corticosteroids were initiated on day 6 due to worsening hypoxia. Eventually, the patient’s inflammatory markers normalized on day 9. Hypoxia improved and he was successfully discharged home. DISCUSSION: We reported a rare case of COVID19 induced AH along with our observation of possible benefit from using NAC in treating this condition. NAC is known for its safety profile. Hence, we believe that more studies need to investigate the role of NAC in treating cases of AH.Figure 1.: Liver enzymes trending over time. ALT( alanine transaminase), AST Aspartate transferase, ALk Pho (alkaline phosphatase).Figure 2.: Patient vital signs during admission.

Asymptomatic Coronavirus Disease 2019 (COVID-19) Carriers: Are They Infectious?

Coronavirus disease 2019 (COVID-19) is highly contagious in symptomatic patients as it is thought to be transmitted through respiratory droplets. However, it is debatable whether asymptomatic COVID-19 patients are contagious due to lack of data. From 1st March to 15th April 2020, a total of 247 COVID-19 cases were admitted to Tengku Ampuan Afzan Hospital and 1010 close contacts were identified. We studied the epidemiological and clinical outcomes in asymptomatic subjects, as well as estimated the metrics of disease transmission between asymptomatic, symptomatic, and pneumonia subjects. From a total of 125 asymptomatic subjects, majority (n=116, 92.8%) remained asymptomatic upon discharge. Only 9 (7.2%) subjects developed mild symptoms after admission. Seven subjects had abnormal chest radiograph suggestive of pneumonia, and 22 subjects (17.6%) were found to have mild liver impairment. None of the asymptomatic subjects required oxygen support, inotropic support or ICU care during admission. Fifteen second generation COVID-19 cases were found transmitted from the asymptomatic group, with an attack rate of 3.9%, which was statistically significantly lower compared to the symptomatic (7.6%) or pneumonia groups (25.7%, p<0.001). In conclusion, asymptomatic COVID-19 patients show excellent clinical outcome. They are infectious but had a lower transmission risk compared with symptomatic or pneumonia patients.

Clinical effect of voriconazole in the treatment of invasive fungal infections in lung cancer patients with radiotherapy and chemotherapy

Objective To investigate the clinical effect of voriconazole in the treatment of invasive fungal infections in lung cancer patients with radiotherapy and chemotherapy, to provide a reference for clinical treatment. Methods The clinical data of 64 lung cancer patients with radiotherapy and chemotherapy with invasive fungal infections were retrospectively analyzed.According to the treatment methods, they were divided into control group and observation group, 32 cases in each group.Fluconazole treatment was used in the control group, and the observation group used voriconazole therapy.The overall response rate, time to return to normal white blood cells and other indicators of liver and kidney function were compared between the two groups. Results The effective rate of the observation group was 81.25%, which was significantly higher than 68.75% of the control group, the difference was statistically significant(χ2=5.876, P=0.008). The temperature recovery, cough disappeared, leukocyte recovery time of the observation group were (3.61±0.61)d, (6.11±0.81)d, (7.85±0.92)d, which were significantly shorter than those of the control group, the differences were statistically significant(t=4.145, P=0.025; t=4.045, P=0.027; t=4.385, P=0.021). The treatment of the two groups had mild liver and kidney damage, and there was no significant difference between the two groups(all P>0.05). Conclusion Voriconazole treatment has good clinical effect for lung cancer patients after radiotherapy and chemotherapy with invasive fungal infections, the treatment period is short, but with mild liver and kidney function impairment, the treatment should strengthen the monitoring. Key words: Voriconazole; Lung diseases, fungal

Abstract B20: Pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment: Results from an open-label, multicenter study.

Abstract Background: Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of Bruton's tyrosine kinase, and is extensively metabolized by CYP3A. No subjects with clinically significant hepatic impairment have been enrolled in the clinical efficacy and safety studies performed to date and more data are needed to understand the safety of ibrutinib in this patient population. Methods: This was an open-label, multi-center, single-dose study in 30 subjects with pharmacokinetic (PK) sampling up to 96 h postdose. Ibrutinib was administered orally at 140 mg following an overnight fast to non-cancer subjects with mild (n=6), moderate (n=10), and severe (n=8) hepatic impairment according to Child-Pugh, and to age- and weight-matched control subjects (n=6). Results: Subjects with mild, moderate, and severe hepatic impairment, but who were otherwise healthy, showed a significant increase in ibrutinib plasma exposures, as well as fraction unbound ibrutinib, with increasing impairment. Regardless of the severity of hepatic impairment, ibrutinib plasma concentration versus time profiles showed an elimination profile with an initial rapid decline which became gradual towards the terminal phase. Compared to control subjects, mean unbound exposure (AUClast,unbound) in the mild, moderate, and severe cohorts was 4.4-, 9.6-, and 13-fold higher. Compared with normal hepatic function, Cmax of unbound ibrutinib increased 5.7- to 9.9- fold with increasing hepatic impairment. Terminal half-life trended slightly higher in moderately and severely impaired subjects, but the risk for accumulation on repeated dosing appears negligible as half-life did not exceed 10 hours. Urinary excretion of unchanged ibrutinib, although increasing with severity of hepatic impairment, remained negligible at &amp;lt;&amp;lt; 1% of the dose. A single dose of 140 mg was well tolerated in this study. Conclusion: Based on the observed effect on plasma exposure, the recommended doses for patients with mild and moderate liver impairment are 280 mg/day and 140 mg/day (Child-Pugh Class A and B), respectively. Since no lower capsule strengths are currently available, it is not recommended to administer ibrutinib to patients with severe liver impairment (Child-Pugh Class C). Citation Format: Donna Skee, Jan De Jong, Peter Hellemans, Dominique Swerts, Deborah Conover, Christopher Jones, Eric Lawitz, Thomas Marbury, William Smith, Vijay Chauhan, Juhui James Jiao, Juthamas Sukbuntherng, Erik Mannaert. Pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment: Results from an open-label, multicenter study. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B20.

Differential management of mild-to-severe psoriasis with biologic drugs: An Italian Delphi consensus expert panel

Background: In the management of moderate-to-severe psoriasis, increasingly complex clinical scenarios necessitate practical tools for appropriate biologic therapy selection in individual patients. An Italian Delphi consensus panel provided guidance on biologic use in selected clinical scenarios.Methods: Ten experts defined statements under consideration, which were distributed as an online survey to a dermatologist panel. Plenary discussions of contentious statements were held to achieve consensus.Results: The survey was sent to 30 clinicians. After plenary discussions, consensus was reached on all 20 statements on the following topics: special populations; infections; comorbidities; immunogenicity; extra-cutaneous involvement; pregnancy; and adherence. Three statements required further discussion in order to gain consensus: use of subcutaneous biologics in mild liver impairment (final 94% agreement), use of any biologic in discoid lupus erythematosus (final 100% disagreement), and use of etanercept in patients with history of hypersensitivity reactions to drugs and/or food (final 75% disagreement).Conclusions: This Delphi expert consensus on the use of biologics in psoriasis provides practical recommendations for dermatologists to use when choosing an appropriate biologic in challenging but common clinical scenarios. More data are required to clarify clinical differences of biologic drugs used to treat psoriasis.

Pharmacokinetics and Safety of Boosted Elvitegravir in Subjects with Hepatic Impairment

Elvitegravir (EVG), an HIV strand transfer integrase inhibitor, is metabolized primarily via cytochrome P450 3A4 (CYP3A) and secondarily via glucuronidation. The pharmacokinetics (PK) and safety of cobicistat (COBI)-boosted EVG (EVG/co) were evaluated in subjects with impaired liver function. The enrolled subjects had stable moderate liver impairment (n = 10; Child-Pugh-Turcotte [CPT] class B) or were healthy controls (n = 10) matched for age (±5 years), gender, and body mass index (±15%). EVG/co (150/150 mg) was administered once daily for 10 days, followed by pharmacokinetic (PK) sampling. Safety was assessed throughout the study. EVG and COBI exposures were compared between the impairment and control groups, with a ≥100% increase considered clinically relevant. EVG and COBI protein binding was also measured. All enrolled subjects completed the study. The treatment-emergent adverse event (AE) incidences were comparable between the groups; all study drug-related AEs were mild. The geometric mean ratio (90% confidence interval [CI]) for EVG area under the concentration-time curve over the dosing interval (AUCtau) and maximum observed plasma concentration (Cmax) were 135% (103%, 177%) and 141% (109%, 183%), respectively. The corresponding values for COBI were 99.8% (76.0%, 131%) and 86.1% (65.4%, 113%), respectively, indicating no clinically relevant change in exposure. No correlations were observed between the EVG and COBI exposures versus CPT score. The EVG- and COBI-free fractions were similar between groups. EVG and COBI do not require dose adjustment in moderate or mild liver impairment, as no clinically relevant PK changes were observed for EVG or COBI in this special population. No PK or safety data are available for EVG or COBI in subjects with severe hepatic impairment.

Voriconazole Induced Severe Liver Toxicity Post Keratitis

The case involved a 72-year old Saudi female patient who was treated for fungal keratitis. Aspergillus species was confirmed. The patient showed mild liver impairment upon admission. Antimicrobial eye drop solutions which comprise the medicines for the treatment regimen included antibiotics (gentamicin, cefazoline, ceftazidine, and moxifloxacin) and antifungal (amphotericin B and, voriconazole) that were started on day one, as well as, voriconazole systemic. On day 9 of the hospitalization, the liver function tests (LFTs) revealed significantly higher values compared to day zero. All medicines were continued at their usual doses and no adverse drug reaction was reported. On Day 13, the patient experienced abdominal pain, hallucination, nausea, tachycardia, and vomiting, in addition to elevated LFTs. At this time, oral voriconazole was discontinued. Patient was discharged with no further reports. An analysis of adverse drug event (ADE) report was performed and results showed that systemic voriconazole is the possible cause of the significant increase in LFTs and the manifested symptoms of liver toxicity.

Influence of mild and moderate liver impairment on the pharmacokinetics and metabolism of almorexant, a dual orexin receptor antagonist

This single-dose study aimed at investigating the effect of different degrees of hepatic impairment on the pharmacokinetics (PK), metabolism, and tolerability of almorexant, a first-in-class dual orexin receptor antagonist. Subjects with mild (Child-Pugh A, Group A, n=8) and moderate (Child-Pugh B, Group B, n=9) liver impairment and subjects with normal liver function (Group DA and DB, both n=9) received a dose of 100mg almorexant. PK parameters of almorexant and its four primary metabolites were determined. Almorexant exposure increased with severity of hepatic impairment. Geometric mean ratios (90% confidence interval) of AUC0−∞ were 2.8 (1.5–5.4), 7.2 (3.7–14.1), and 3.3 (1.7–6.4) comparing A vs. DA, B vs. DB, and B vs. A, respectively. The four metabolic pathways involved in the formation of the primary metabolites were affected in a different fashion. Geometric mean AUC0−∞ ratios comparing A vs. DA were 6.9, 1.1, 1.4, and 3.6 for M3, M5, M6, and M8, respectively. Comparing B vs. DB the corresponding figures were 7.3, 2.0, 5.4, and 1.3, respectively. Significant effects of hepatic impairment on the PK of almorexant suggested the need for dose adjustment in subjects with mild hepatic impairment and did not support its use in subjects with moderate or severe hepatic impairment.

Brivaracetam Disposition in Mild to Severe Hepatic Impairment

Brivaracetam is a high-affinity synaptic vesicle protein 2A (SV2A) ligand in clinical development for epilepsy. This open-label, single-dose study evaluated brivaracetam disposition in participants with different degrees of hepatic impairment versus matched healthy controls. Twenty-six participants (38-72 years; 19 males and 7 females) with hepatic impairment classified by Child-Pugh score (mild, n = 6; moderate, n = 7; severe, n = 7) or normal hepatic function (n = 6) received a single oral dose of 100 mg brivaracetam. The pharmacokinetics of brivaracetam and its three main metabolites (acid, hydroxy, hydroxyacid) were determined and correlated with impairment severity. Dynamic liver function tests correlated with hepatic impairment severity. The plasma half-life of brivaracetam was 9.8, 14.2, 16.4, and 17.4 hours and the area under the plasma concentration-time curve was 29.7, 44.6, 46.7, and 47.1 µg h/mL in healthy controls and participants with mild, moderate, and severe liver impairment, respectively. Production of the acid metabolite was increased and the hydroxylated metabolites were decreased in participants with hepatic impairment versus healthy controls. Exposure to brivaracetam increased by 50-60% in patients with hepatic impairment, irrespective of severity. The relative importance of biotransformation pathways was altered; cytochrome P450 (CYP)-dependent hydroxylation decreased; CYP-independent acid metabolite formation increased concomitantly.

Telaprevir: Pharmacokinetics and Drug Interactions

Telaprevir is an inhibitor of the HCV NS3/4A protease. When used in combination with pegylated interferon and ribavirin, telaprevir has demonstrated a substantial increase in sustained virological response compared with pegylated interferon and ribavirin used alone. Telaprevir has good oral bioavailability, which is enhanced when administered with food. Telaprevir is extensively metabolized and primarily eliminated via faeces. No dose adjustment of telaprevir is needed in patients with mild to severe renal impairment or mild liver impairment. Telaprevir is a substrate and inhibitor of cytochrome P450 3A and P-glycoprotein and, thus, might interact with coadministered drugs that affect or are affected by these metabolic/transport pathways. This article reviews the pharmacokinetic and drug interaction profile of telaprevir.

Acute copper sulphate poisoning: a forgotten cause of severe intravascular haemolysis

Acute copper sulphate poisoning is a rare mode of attempted suicide. A 25-year-old male was admitted to our hospital with severe gastrointestinal symptoms after voluntary ingestion of an unknown amount of copper sulphate solution 18 h before admission. Laboratory tests showed leucocytosis with a left shift (leucocyte count 55 · 10/l), haematocrit 0AE44, haemoglobin concentration 149 g/l and platelet count 206 · 10/l. On day 3, severe intravascular haemolysis occurred with haematocrit 0AE25, haemoglobin 93 g/l and increased reticulocytes (9AE4%). The patient also developed rhabdomyolysis and mild renal and liver impairment. Blood film examination showed anisocytosis, poikilocytosis, marked echinocytosis, pyknocytosis including many blister and bite erythrocytes with precipitation of haemoglobin, microspherocytosis and basophilic stippling (left). His serum samples were initially dark brownish-red, due to haemoglobinaemia and methaemoglobinaemia, which resolved gradually after successful treatment (right). Serum and urine copper levels were elevated. The course was favourable after symptomatic treatment and copper chelation therapy with dimercaprol. Intravascular haemolysis is largely due to copper sulphate being a potent oxidant that overwhelms the capacity of the pentose shunt to protect against oxidation. Copper inhibits glucose-6-phosphate dehydrogenase and glutathione reductase and increases cell permeability because of inhibition of the Na/K ATPase pump.

Influence of different degrees of liver impairment on the pharmacokinetics of clazosentan

Clazosentan is a selective endothelin A receptor antagonist, formulated for parenteral use, which is in clinical development for the treatment of aneurysmal subarachnoid haemorrhage. The human ADME study showed that most of clazosentan is excreted via the biliary route. The pharmacokinetics (PK) of clazosentan are similar in healthy subjects and those with severe renal impairment. The results of the present study showed that there was an increase in the exposure to clazosentan with increasing severity of liver impairment. Changes in PK in subjects with mild liver impairment compared with healthy subjects are unlikely to be clinically relevant. There are significant differences in the PK parameters of clazosentan in subjects with moderate and severe liver impairment compared with healthy subjects. The results of this study will allow confident dosing of clazosentan in individuals with moderate and severe liver impairment. AIM To investigate the effect of mild, moderate and severe liver impairment on the pharmacokinetics (PK), tolerability and safety of clazosentan, an intravenous endothelin receptor antagonist. Healthy subjects with normal liver function (n= 8), subjects with mild (Child Pugh A, n= 8), and with moderate (Child-Pugh B, n= 8) liver impairment received a continuous intravenous infusion of 1 mg h(-1) and subjects with severe liver impairment (Child Pugh C, n= 8) received a continuous intravenous infusion of 0.5 mg h(-1) clazosentan for a duration of 6 h. The pharmacokinetic (PK) parameters of clazosentan were determined by both model-independent and model-dependent methods. Mean plasma concentrations of clazosentan increased with increasing severity of liver impairment. Geometric means of area under the plasma concentration-time curve from 0 to infinity (AUC((0,∞)) ) were 1.41- (90% CI 1.04, 1.90), 2.37- (90% CI 1.75, 3.19), and 3.79- (90% CI 2.81, 5.11) fold higher in subjects with mild, moderate and severe liver impairment, respectively, compared with healthy subjects. Similar results were obtained by non-compartmental and two-compartmental analysis. A significant positive correlation between clazosentan AUC((0,∞)) and Child-Pugh score (r= 0.83), bilirubin (r= 0.78) and prothrombin time (r= 0.62), and a significant negative correlation with albumin concentrationl (r= 0.71) was observed. Administration of clazosentan was well tolerated in all groups. The increase in exposure to clazosentan in Child-Pugh A patients is not expected to be clinically relevant and no dose adjustment for these patients is proposed. It is recommended to reduce the dose of clazosentan to half in Child-Pugh B and to one fourth in Child-Pugh C patients.

Bendamustine pharmacokinetic profile and exposure–response relationships in patients with indolent non-Hodgkin’s lymphoma

The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin's lymphoma, and supported understanding of exposure-response relationships for efficacy and safety. Bendamustine was administered as a 60-min 120 mg/m(2) intravenous infusion on days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined. Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t (1/2) (40 min) was considered the pharmacologically relevant (beta elimination) t (1/2) since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m(2) administration, except bendamustine C (max) was a significant (P value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics. The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t (1/2) and low concentrations of bendamustine observed by 12 h after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine C (max) increases.

Effect of Mild and Moderate Liver Disease on the Pharmacokinetics of Isavuconazole after Intravenous and Oral Administration of a Single Dose of the Prodrug BAL8557

Isavuconazole is a promising new antifungal drug with favorable pharmacokinetic properties and excellent activity against a number of fungi. It is administered as a water-soluble prodrug (BAL8557) that is cleaved by plasma esterases to isavuconazole, which is eliminated primarily by hepatic metabolism. The objective of this investigation was to assess the effect of alcohol-related liver disease on the pharmacokinetics of isavuconazole. Subjects were 16 healthy individuals, 16 with mild liver impairment, and 16 with moderate liver impairment who were randomized to receive a single oral or intravenous dose of BAL8557 equivalent to 100 mg isavuconazole. Blood samples were collected for 21 days following drug administration, and plasma concentrations of isavuconazole, BAL8557, and the cleavage product BAL8728 were measured using high-pressure liquid chromatography coupled with tandem mass spectrometry. Following intravenous administration, the half-life of isavuconazole increased from 123 h for healthy volunteers to 224 h and 302 h for subjects with mild and moderate liver impairment, respectively. The systemic clearance of isavuconazole following intravenous administration decreased from 2.73 liters/h for healthy subjects to 1.43 liters/h for subjects with moderate liver impairment (47.6% decrease [P < 0.05]). A similar decrease (23.5%) was observed after oral administration. These results suggest that a dose adjustment may be needed when isavuconazole is used to treat fungal infections in patients with liver disease.

Current Therapeutic Drugs for Type 2 Diabetes, Still Useful After 50 Years?

Current Therapeutic Drugs for Type 2 Diabetes, Still Useful After 50 Years?

Severe Acute Copper Sulphate Poisoning: A Case Report

As copper sulphate pentahydrate (CSP) is a common compound used in agriculture and industry, chronic occupational exposures to CSP are well known, but acute poisoning is rare in the Western world. This case report describes acute poisoning of a 33-year-old woman who attempted suicide by ingesting an unknown amount of CSP. On admission to the hospital, she had symptoms and signs of severe hemorrhagic gastroenteritis, dehydration, renal dysfunction and methaemoglobinaemia with normal serum copper level. Therapy included early gastric lavage, fluid replacement, vasoactive drugs, furosemide, antiemetic drugs, ranitidine, and antidotes methylene blue and 2,3-dimercaptopropane-1-sulphonate (DMPS). However, the patient developed severe intravascular haemolysis, acute severe hepatic and renal failure, as well as adrenal insufficiency. After prolonged, but successful hospital treatment, including haemodialysis and IV hydrocortisone, the patient was discharged with signs of mild renal and liver impairment. Our conclusion is that in severe cases of copper poisoning early supportive measures are essential. In addition, antidotes such as methylene blue for methaemoglobinaemia and chelating agent such as DMPS improve morbidity and survival of severely poisoned victims.

Phase I study of the effects of hepatic impairment on the pharmacokinetic (PK) and safety of satraplatin in patients with refractory non-hematologic cancer

2045 Background: Satraplatin (S) is a third-generation oral platinum analog that has demonstrated activity in the treatment of patients with platinum-sensitive malignancies. A worldwide double-blind, placebo controlled randomized phase III trial evaluating S as 2nd line therapy for HRPC has recently completed enrollment. The current study was designed to determine the effect of hepatic impairment on S pharmacokinetics in patients with refractory cancer, as well as treatment efficacy and toxicity. Methods: S was administered orally at a dose of 80mg/m2/day (d) on d1–5 every 35 days. Study groups (cohorts) were defined at 4 levels of hepatic impairment - Group 1 (G1) = control; G2 = Child-Pugh Class A; G3 = Child-Pugh Class B; and Group 4 = Child-Pugh Class C. Results: 19 pts have been enrolled to date (11 M/ 8 F); median age is 57 (range 44–80). Pts with prostate (2), pancreas (4), colorectal (3), adenocystic (2), and 1 each neuroendocrine, hepatocellular, melanoma, breast, ovarian, SCLC, and anal cancers were enrolled. 8 pts were in G1, 3 pts in G2, 4 pts in G3, and 5 pts in G4. Accrual is ongoing in this study with a total of 8 pts planned for each group. The median number of prior regimens was 5 (range 2–8). A total of 35 cycles of S have been given: median 2/pt (range 1–4). 9 pts have completed 2 cycles of S. Hematologic toxicities during the first 2 cycles included grade (G) 3/4 thrombocytopenia in 15 %. There were no cases of G 3/4 neutropenia or anemia. One case of G3 hypokalemia, was reported. Two patients developed acute renal failure; one of which was due to uncontrolled nausea (N) and vomiting (V) and the other was associated with rapid disease progression in the liver. Both were G4 patients. Otherwise, N, V, and diarrhea were mild to moderate, and controlled with oral therapy. Conclusions: S is, in general, well tolerated in patients with mild or moderate liver impairment. Severe thrombocytopenia is the most common side-effect. Of the patients enrolled to date 15% did not have progression of disease. PK data will also be presented. [Table: see text]

A phase I pharmacokinetic (PK) study of the Epothilone B analogue, ixabepilone (BMS-247550) in patients (pts) with advanced malignancies and varying degrees of hepatic impairment. A SWOG Early Therapeutics Committee and NCI Organ Dysfunction Working Group Trial

2004 Background: Ixabepilone (Ix) is a semisynthetic Epothilone B derivative with antitumor activity in breast cancer pts previously treated with taxanes and in chemotherapy naïve prostate cancer pts. Because Ix is hepatically metabolized, the following study was performed to define dosing recommendations for pts with varying degrees of hepatic impairment. Methods: Pts were classified into hepatic dysfunction cohorts defined by a modified NCI Organ Dysfunction Working Group (NCI) schema. Starting doses were escalated in new pts independently in each cohort using a standard phase I design. Results: Overall, 71 pts were registered and 66 pts are evaluable for cycle 1 dose limiting toxicities (DLTs). Ix was administered at 10–40 mg/m2 as 10 minute infusions q3wks. Dose levels reached 40, 40, 30, and 20 mg/m2 for pts in Groups A, B, C and D, respectively. In group B, DLTs were observed in 2/12 pts treated at 30 mg/m2 (febrile neutropenia, grade (gr)3 mucositis, and gr3 diarrhea) and 3/8 pts at 40 mg/m2 (febrile neutropenia, gr3 nausea/vomiting, gr3 hyponatremia). In group C, DLTs were observed in 2/10 pts at 20 mg/m2 (gr3 dehydration, gr3 muscle weakness) and 2/3 pts at 30 mg/m2 (febrile neutropenia, gr 4 neutropenia). In group D, DLTs were observed in 2/9 pts at 10 mg/m2 (gr3 infection and gr3 renal failure) and 1/5 pts treated at 20 mg/m2 (gr3 infection). Otherwise, Ix was generally well tolerated. Pharmacokinetic parameters are currently being analyzed. No objective responses have been documented. Conclusions: Ix dose reduction is required in pts with moderate to severe liver dysfunction. The recommended Ix dose for group C patients is 30 mg/m2. To define the impact of mild liver impairment, Group B has been stratified further into B1 (Bili ≤ ULN and AST &gt; ULN) and B2 (ULN &lt; Bili ≤ 1.5 × ULN, AST any). Accrual continues to groups B1 and B2 at 40 mg/m2 and group D at 20 mg/m2. [Table: see text] [Table: see text]

Pharmacokinetic Profile of Dexloxiglumide

Dexloxiglumide is a potent and selective cholecystokinin type 1 (CCK1) receptor antagonist currently under development in a variety of diseases affecting the gastrointestinal tract such as gastro-oesophageal reflux disease, irritable bowel syndrome (IBS), functional dyspepsia, constipation and gastric emptying disorders. In female patients with constipation-predominant IBS, clinical efficacy has been demonstrated following administration of dexloxiglumide 200 mg three times daily. Dexloxiglumide is rapidly and extensively absorbed after single oral administration in humans with an absolute bioavailability of 48%. The incomplete bioavailability is due to both incomplete absorption and hepatic first-pass effect. Following multiple-dose administration of 200 mg three times daily, the accumulation is predictable, indicating time-independent pharmacokinetics. In addition, dexloxiglumide pharmacokinetics are dose-independent after both single and repeated oral three-times-daily doses in the dose range 100-400 mg. Dexloxiglumide absorption window extends from the jejunum to the colon and the drug is a substrate and a weak inhibitor of P-glycoprotein and multidrug resistance protein 1. Plasma protein binding of dexloxiglumide is 94-98% and the drug has a moderate to low volume of distribution in humans. Systemic clearance of dexloxiglumide is moderate and cytochrome P450 (CYP) 3A4/5 and CYP2C9 have been implicated in the metabolism of dexloxiglumide to produce O-demethyl dexloxi-glumide. This metabolite is further oxidised to dexloxiglumide carboxylic acid. These two major metabolites (accounting for up to 50% of dexloxiglumide elimination) have been identified. However, in human plasma the unchanged drug represents the major (up to 91%) component of the metabolic profile. The parent drug is believed to be the major contributor to the efficacy of the compound, since its major metabolites are pharmacologically inactive. In addition, the drug is a single isomer chiral drug (eutomer) that does not undergo chiral inversion into its pharmacologically inactive enantiomer (distomer). After oral administration of (14)C-dexloxiglumide, radioactivity is mainly excreted in bile and in faeces (74% of dose) with much lower excretion in urine (20% of dose). Renal excretion of unchanged dexloxiglumide is low (7% of dose in urine and faeces, 1% of dose in urine) and is dose-independent in the dose range 100-400 mg. As the kidney is a minor contributor to the elimination of dexloxiglumide and/or its metabolites in humans, the pharmacokinetics of the drug should not be affected in patients with renal insufficiency. The pharmacokinetics of dexloxiglumide are also not affected by age, sex and administration with a high-fat breakfast. Mild and moderate liver impairment do not affect the pharmacokinetics of dexloxiglumide but severe liver impairment causes increases in systemic exposure to dexloxiglumide and O-demethyl dexloxiglumide. Thus, the drug should be prescribed with caution in patients with severe hepatic impairment even though no dose adjustment is warranted. The results of different drug interaction studies have indicated that no clinically relevant metabolic and concomitant drug-drug interactions are expected during the clinical use of dexloxiglumide.