Degree Of Hepatic Impairment Research Articles

Phase I study of the pharmacokinetics and safety of rezafungin in subjects with moderate/severe hepatic impairment and matched control subjects.

Rezafungin is a second-generation, once-weekly echinocandin antifungal approved for the treatment of invasive candidiasis, including candidemia. In phase II/III studies of rezafungin versus caspofungin, patients with severe hepatic impairment were excluded due to lack of caspofungin data in this population. This open-label, single-dose, phase I study evaluated the pharmacokinetics (primary objective) and safety of rezafungin in subjects with moderate or severe hepatic impairment versus matched, healthy subjects with normal hepatic function. Eight subjects each with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment were matched 1:1 with healthy subjects for age, sex, and body mass index. Each subject received a single 400-mg, intravenous, 1-h infusion of rezafungin. Plasma pharmacokinetic sampling was performed at various time points through 336 h postdose. Pharmacokinetic parameters were derived by non-compartmental analysis. Safety was assessed throughout. All 32 subjects received study treatment and were included in all analyses. Despite overlapping distributions of total plasma concentrations, based on geometric least-squares (LS) mean ratios, the area under the plasma concentration-time curve from time zero (prior to the start of infusion) to infinity (AUC0-∞) was 32% lower in subjects with moderate (LS mean ratio, 67.55; 90% confidence interval [CI]: 53.91, 84.65) and severe (LS mean ratio, 67.84; 90% CI: 57.49, 80.05) hepatic impairment versus matched healthy subjects. The maximum plasma concentration (Cmax) was 12% lower in moderate hepatic impairment and 28% lower in severe hepatic impairment groups. Linear regression showed no significant trend in the degree of hepatic impairment (based on Child-Pugh score) on AUC0-∞ or Cmax (p > 0.05). Treatment-emergent adverse events were reported in seven subjects (21.9%; three subjects in each of the hepatic impairment groups, and one healthy subject), none of which were severe, serious, or resulted in withdrawal. Rezafungin is well tolerated and can be administered to patients with moderate or severe hepatic impairment without the need for dose adjustment. The modest reduction in exposures in subjects with hepatic impairment is not clinically meaningful and is unlikely to impact efficacy.

Is Halving Maintenance of Voriconazole Safe and Efficient in Patients Suffering from Invasive Fungal Infections with Serious Hepatic Dysfunction?

There is a wide debate about the efficacy and safety of voriconazole in patients with impaired hepatic function at Child-Pugh C level. The purpose of this study was to investigate the safety and efficacy between the two groups treated with different dosages of voriconazole (400mg/day vs 200mg/day) in the treatment of invasive fungal infections (IFIs) in patients with hepatic dysfunction. A retrospective study enrolling patients with hepatic dysfunction receiving intravenous voriconazole for IFIs from January 1st, 2017, to December 30th, 2021 was conducted. Patients were enrolled in the 400mg per day dose group and 200mg per day dose group. In patients with the same degree of hepatic impairment, factors affecting prognosis were screened and differences in steady-state blood trough concentrations (Cmin) of voriconazole, positive G/GM tests and adverse effects (AEs) were compared between the two groups described above. In total, 308 patients with IFIs were enrolled. For Child-Pugh C class, patients receiving the halved maintenance dose had a lower Cmin and AEs rate but higher recovered rate compared to those receiving maintenance dose, and significant predictors of recovery were dosage (OR, 5.131; 95% CI, 1.599-16.464; p = 0.006) and diabetes (OR, 0.111; 95% CI, 0.020-0.597; p = 0.010). For patients of Child-Pugh A & B class, chronic liver disease (OR, 0.334; 95% CI, 0.159-0.704; p = 0.004) was a prognosis-related factor. Halving maintenance dose ensure the efficacy and safety of voriconazole in patients suffering from invasive fungal infections with serious hepatic dysfunction.

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment

Background The primary objective of this study was to investigate if hepatic impairment alters the safety, pharmacokinetics, and pharmacodynamics of HSK3486. Research design and methods This was a clinical trial of HSK3486 in subjects with normal hepatic function (n = 8), and mild (Child-Pugh A; n = 8), or moderate (Child-Pugh B; n = 8) hepatic impairment. Each subject received an IV bolus dose of 0.4 mg/kg HSK3486 for 1 min, immediately followed by a maintenance infusion of 0.4 mg/kg/h HSK3486 for 30 min. Results In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS). Conclusions Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment. Trial registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596). Key Message HSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects. There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function. HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.

Clinical Characterisation and Management of the Main Treatment-Induced Toxicities in Patients with Hepatocellular Carcinoma and Cirrhosis.

Simple SummaryThe incidence of hepatocellular carcinoma continues to increase worldwide. In almost all cases, hepatocellular carcinoma develops in subjects with hepatic cirrhosis and patients can therefore present symptoms that are attributable to both conditions. There are several ablation techniques currently available for the treatment of unresectable HCC associated with early-stage cirrhosis. Moreover, novel therapies with biological agents and immunotherapy have come to be standard options in the approach to systemic treatment of hepatocellular carcinoma. However, in addition to being costly, these drugs are not devoid of adverse effects and their management cannot forgo the consideration of the underlying hepatic impairment. Therefore, these patients require a mandatory multidisciplinary management.The incidence of hepatocellular carcinoma (HCC) continues to increase worldwide, particularly in Western countries. In almost all cases, HCC develops in subjects with hepatic cirrhosis, often as the result of hepatitis B or C virus infection, alcohol abuse or metabolic forms secondary to non-alcoholic steatohepatitis. Patients with HCC and hepatic symptoms can therefore present symptoms that are attributable to both conditions. These patients require multidisciplinary management, calling for close interaction between the hepatologist and the oncologist. Indeed, the treatment of HCC requires, depending on the disease stage and the degree of hepatic impairment, locoregional therapies that can in turn be broken down into surgical and nonsurgical treatments and systemic treatments used in the event of progression after the administration of locoregional treatments. The past decade has seen the publication of countless papers of great interest that have radically changed the scenario of treatment for HCC. Novel therapies with biological agents and immunotherapy have come to be standard options in the approach to treatment of this cancer, obtaining very promising results where in the past chemotherapy was almost never able to have an impact on the course of the disease. However, in addition to being costly, these drugs are not devoid of adverse effects and their management cannot forgo the consideration of the underlying hepatic impairment. Patients with HCC and cirrhosis therefore require special attention, starting from the initial characterisation needed for an appropriate selection of those to be referred for treatment, as these patients are almost never fit. In this chapter, we will attempt to investigate and clarify the key points of the management of the main toxicities induced by locoregional and systemic treatments for HCC secondary to cirrhosis.

Avatrombopag in the treatment of thrombocytopenia in adults with chronic liver disease scheduled to undergo a procedure: a profile of its use in the USA

Avatrombopag (Doptelet®) is the first thrombopoietin receptor agonist approved in the USA to treat thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a procedure. It is an important new development to mitigate the risk of bleeding and improve post-procedure management in this patient population. Relative to placebo, oral avatrombopag significantly increased the proportion of patients who did not require a platelet transfusion or rescue procedure up to 7 days after the scheduled procedure. Its efficacy was not altered by the bleeding risk associated with the procedure, or by patient age, sex, race, or degree of hepatic impairment. Avatrombopag has a convenient 5-day oral administration regimen and is well tolerated.

Elevated cystatin C: is it a reflection for kidney or liver impairment in hepatic children?

Aim of the studyTo assess if elevated serum cystatin C (Cyst-C) is an indicator for renal or hepatic dysfunction in presence of liver fibrosis.Material and methodsData of 50 children with chronic liver diseases (CLDs), out of which 25 were without renal impairment, and 25 with renal impairment were analyzed. Twenty healthy children served as a healthy control group. Routine investigations, creatinine clearance, hepatitis viral markers, abdominal ultrasonography, and liver biopsy were performed for patients with CLDs. Measurement of serum Cyst-C concentration by particle induced immunonephelometry were completed for both patients and control group.ResultsResults showed that serum Cyst-C is not correlated with the degree of hepatic impairment (p > 0.05). Cyst-C levels were significantly higher in patients with renal impairment (3.66 ± 0.85) than those without (0.71 ± 0.12), and healthy control group (0.63 ± 0.85). Cystatin-C showed significant elevation in patients with severe fibrosis with renal impairment (3.66 ± 0.85) than those without (0.76 ± 0.04) (p < 0.0001). Cyst-C at cutoff levels of 1.65 mg/l showed 100% accuracy in discrimination between those with and those without renal impairment. Cyst-C > 2.34 mg/l predicting GFR < 40 ml/min with accuracy of 90%. Cyst-C > 2.73 mg/l predicting GFR < 20 ml/min with accuracy of 81.5%.ConclusionsSerum Cyst-C is a promising marker to estimate renal impairment in children with CLDs. Further studies are needed to estimate the accuracy of serum Cyst-C for early detection of renal impairment and close monitoring of the hepatic children.

Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C

Ledipasvir/sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A inhibitor ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved in the US, European Union, Canada, and other regions for the treatment of chronic hepatitis C virus infection in adults. Following absorption, ledipasvir reaches maximum plasma concentrations (T max) 4-4.5h post-dose and is eliminated with a terminal half-life (t 1/2) of 47h. Sofosbuvir undergoes intracellular activation to an active triphosphate GS-461203 (not detected in plasma) and ultimately to GS-331007, a predominant circulating metabolite, which is the primary analyte of interest in clinical pharmacology studies. Sofosbuvir is rapidly absorbed and eliminated from plasma (T max: 0.8-1h; t 1/2: 0.5h). The peak plasma concentrations for GS-331007 are achieved between 3.5 and 4h post-dose; the elimination t 1/2 for GS-331007 is 27h. Ledipasvir/sofosbuvir exhibits a favorable clinical pharmacology profile; it can be administered once daily without regard to food and does not require dose modification in hepatitis C virus-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. The pharmacokinetic profiles of ledipasvir, sofosbuvir, and GS-331007 (predominant circulating metabolite of sofosbuvir) are not significantly affected by demographic variables; pharmacokinetic/pharmacodynamic analyses reveal no exposure-response relationships for efficacy or safety. The review summarizes the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic analyses for ledipasvir/sofosbuvir.

Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir.

Sofosbuvir (SOVALDI(®)), a potent, once-daily, orally administered nucleotide analog prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase is approved in the USA, EU, Canada, and other regions for the treatment of HCV infection as a component of an antiviral treatment regimen. Sofosbuvir undergoes intracellular activation to form GS-461203 (active triphosphate, not detected in plasma), and ultimately the inactive, renally eliminated metabolite GS-331007. GS-331007 was identified as the primary analyte of interest for clinical pharmacology studies as it accounted for >90 % of systemic drug-related material exposure, and provided comparable exposure-response relationships for viral kinetics as observed for sofosbuvir. GS-331007 and sofosbuvir exhibit linear pharmacokinetics with minimal accumulation upon multiple dosing. Compared to healthy subjects, HCV-infected patients had modestly lower (39 %) GS-331007 area under the plasma concentration-time curve (AUC) and higher sofosbuvir AUC (60 %). Sofosbuvir can be administered without dose modification in HCV-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. Sofosbuvir has a low propensity for clinically significant drug interactions with common concomitant medications used by HCV-infected patients. Clinically significant alterations in GS-331007 or sofosbuvir exposures are limited to potent inducers of intestinal P-glycoprotein that may lower exposure. In HCV-infected patients, demographic variables do not significantly influence GS-331007 and sofosbuvir exposures and no consistent exposure-response relationships were observed for efficacy or safety. This review focuses on the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic-pharmacodynamic relationships of sofosbuvir, and summarizes a number of drug interaction studies with important concomitant medications commonly used by HCV-infected patients.

Sofosbuvir in the treatment of chronic hepatitis C: new dog, new tricks.

The existing standard of care for chronic hepatitis C virus (HCV) infection includes the use of pegylated interferon and ribavirin as primary components of treatment, with the addition of a direct-acting antiviral for genotype 1 infection. Sofosbuvir, an oral nucleotide inhibitor of the HCV nonstructural protein 5B RNA-dependent RNA polymerase enzyme, was recently approved for use in combination with ribavirin and/or pegylated interferon for chronic HCV infection, depending on the genotype. Sofosbuvir is orally administered, and peak plasma concentrations are not affected by food. The drug is renally eliminated and does not require adjustment in mild to moderate renal insufficiency or in any degree of hepatic impairment. Sofosbuvir is not metabolized by cytochrome P450 isoenzymes, nor does it induce or inhibit the metabolism of agents that are substrates of these enzymes. Sofosbuvir demonstrates a high barrier to resistance and was well tolerated by patients in clinical trials. Overall efficacy rates vary between 70% and 90%.

Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment

Macitentan is under development for the treatment of pulmonary arterial hypertension (PAH). Patients with PAH may suffer from comorbidities such as renal or hepatic impairment. Two prospective, single-center, open-label studies evaluated the pharmacokinetics of macitentan and its metabolites (pharmacologically active ACT-132577 and inactive ACT-373898) in healthy subjects and in subjects with mild, moderate, and severe hepatic impairment or severe renal function impairment (SRFI). After administering a single oral dose of 10 mg macitentan the pharmacokinetic parameters including area under the curve from zero to infinity (AUC∞) were derived from plasma concentration-time profiles. Exposure to macitentan and ACT-132577 was lower in hepatically impaired versus healthy subjects, with no correlation with the degree of hepatic impairment. Exposure to ACT-373898 was lower in subjects with moderate hepatic impairment only. Plasma concentration-time profiles for macitentan and ACT-132577 (active) were similar in healthy subjects and subjects with SRFI. AUC∞ of ACT-373898 (inactive) was 7.3-fold higher in subjects with SRFI versus healthy subjects. No safety concerns were raised in either study. Based on these observations, pharmacokinetic alterations of macitentan due to hepatic or renal function impairment are not considered clinically relevant and no dose adjustment is necessary in these patients.

Pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in renal and hepatic impairment patients.

Hepatic and renal impairment studies were conducted with ruxolitinib, a JAK1&2 inhibitor that is cleared predominantly by metabolism. Both studies were open label, single-dose studies. Ruxolitinib area under the curve (AUC) was increased by 87%, 28%, and 65%, respectively, in subjects with mild, moderate, and severe hepatic impairment compared to healthy subjects with no correlation between exposure of ruxolitinib and the degree of hepatic impairment. The pharmacodynamics (PD) data were consistent with ruxolitinib pharmacokinetics (PK). The renal impairment study showed a surprising finding. While there was no change in ruxolitinib PK with varying degrees of renal impairment, the PD showed increasing pharmacological activity with increased severity of renal impairment. Analysis of the metabolite exposures revealed that active metabolites contributed to the observed incremental increase in PD activity. The recovery of ruxolitinib in dialysate was negligible. The starting dose of ruxolitinib in subjects with any hepatic impairment or moderate or severe renal impairment should be decreased to 10 mg twice daily (BID) if their platelet counts are between 100 × 10(9) /L and 150 × 10(9) /L. Subjects on dialysis should initiate dosing with a single dose of 15 or 20 mg, based on platelet counts, with dosing only on the days of dialysis.

A correlative analysis of biochemical and radiologic hepatic disease in metastatic pancreatic adenocarcinoma (PA).

e15163 Background: The liver is the most common site of distant metastases (mets) in patients with PA. We aimed to study radiomorphology of PA-related liver mets and its correlation with the degree of biochemical hepatic dysfunction. The impact of liver failure on patient mortality was also assessed. Methods: Using National Cancer Institute-Organ Dysfunction Working Group guidelines, patients were stratified into 4 groups A (Normal), B (Mild), C (Moderate), D (severe) based on serum bilirubin and aspartate transaminase levels. Two sets of results were recorded for each patient - at diagnosis (baseline) and the the last available prior to death. CT scan at diagnosis were used to measure both the number and diameter of two largest lesions for each patients’ liver mets. Results: 58 patients with metastatic PA were identified. 5 of these patients were excluded from this study as their imaging was not available. 34 (59%) had hepatic mets. Of 34 patients, 47.1% (n=16) had diffuse mets. 23.5% (n=8) had 6-10 liver mets. 20.6% (n=7) had 2-5 liver mets. 8.8% (n=3) had a solitary metastasis. Four of these patients were excluded as they were still alive at the time of the biochemical analysis. Of 31 patients at baseline: 25.8% (n=8), 35.5% (n=7), 22.6% (n=7), 16.1% (n=5) of patients had group A, B, C and D hepatic dysfunction respectively. The median time between last liver function testing and death was 10 days (range 0-114 days). Prior to death, 16.1% (n=5), 35.5% (n=11), 6.5% (n=2), 41.9% (n=13) of patients had group A, B, C and D dysfunction respectively. Of the 13 patients with severe hepatic dysfunction prior to death, 7 had no radiographic evidence of extrinsic obstruction. No difference in number of liver mets were seen between groups A and B when compared to C and D. However, groups C+D had higher mean size, 2.8 x 2.3 vs. 2.4 x 1.8 cm (p=0.047). No survival difference was noted (4.6 vs 2.5 months, p=0.425). Conclusions: The majority of patients had diffuse liver mets at diagnosis. There was no significant correlation between the radiological burden of hepatic disease and the degree of hepatic impairment at diagnosis. PA-related liver mets was the likeliest cause of death in up to 22.6% of patients.

Effects of Hepatic Impairment on the Pharmacokinetics of Everolimus: A Single-Dose, Open-Label, Parallel-Group Study

BackgroundAlthough the pharmacokinetics of everolimus, an oral mammalian target of rapamycin inhibitor, have been characterized in patients with moderate hepatic impairment, they have not been assessed in those with mild or severe hepatic impairment. ObjectiveThe goal of this study was to assess the pharmacokinetics and safety of everolimus in healthy volunteers with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment in otherwise good health to inform dosing in the clinical setting. MethodsA multicenter, open-label, Phase I study in which all enrollees received a single, 10-mg, oral everolimus dose was conducted. Blood samples for pharmacokinetic assessment were collected at predetermined time points up to 168 hours postdosing. Safety was also assessed. Proposed dose recommendations based on Child-Pugh status at baseline and day 8 were calculated based on AUC0–∞ geometric mean ratios and their associated 90% CIs. Post hoc analysis of the relationship between pharmacokinetic parameters and markers of hepatic function was also performed to identify thresholds for dose adjustment. ResultsThirteen subjects with normal hepatic function and 7 patients with mild, 8 patients with moderate, and 6 patients with severe hepatic impairment were enrolled. Compared with normal subjects, everolimus AUC0–∞ for patients with mild, moderate, and severe hepatic impairment increased by 1.60-, 3.26-, and 3.64-fold, respectively. Based on Child-Pugh classification at day 8, the everolimus doses required to adjust the exposure of patients with mild, moderate, and severe hepatic impairment to that of normal subjects were 6.25, 3.07, and 2.75 mg, respectively. Thresholds for 2-fold everolimus dose reduction were 15.0 μmol/L for bilirubin, 43.1 g/L for albumin, and 1.1 for the international normalized ratio; using these thresholds could lead to underdosing or overdosing in some patients. Most adverse events were of grade 1 severity, ≤1 day in duration, and not everolimus related. ConclusionsEverolimus exposure after a single 10-mg dose was influenced by the degree of hepatic impairment. Child-Pugh classification was found to be the most conservative means of guiding dose adjustment in patients with hepatic impairment. Based on these data, as well as previously reported data for patients with moderate hepatic impairment, everolimus once-daily dosing should be 7.5 mg and 5 mg in patients with mild and moderate impairment, respectively. Everolimus is not recommended in patients with severe hepatic impairment unless benefits outweigh risks; in that case, 2.5 mg once daily should not be exceeded. ClinicalTrials.gov identifier: NCT00968591.

Influence of Hepatic Impairment on the Pharmacokinetics and Safety Profile of Dapagliflozin: An Open-Label, Parallel-Group, Single-Dose Study

Background Dapagliflozin, a selective inhibitor of renal sodium glucose co-transporter 2, is under development for the treatment of type 2 diabetes mellitus. Dapagliflozin elimination is primarily via glucuronidation to an inactive metabolite, dapagliflozin 3-O-glucuronide. Pharmacokinetic studies are recommended in subjects with impaired hepatic function if hepatic metabolism accounts for a substantial portion of the absorbed drug. Objective The purpose of our study was to compare the pharmacokinetics of dapagliflozin in patients with mild, moderate, or severe hepatic impairment (HI) with healthy subjects. Methods This was an open-label, parallel-group study in male or female patients with mild, moderate, or severe HI (6 per group according to Child-Pugh classification) and in 6 healthy control subjects. The control subjects were matched to the combined HI group for age (±10 years), weight (±20%), sex, and smoking status, with no deviations from normal in medical history, physical examination, ECG, or laboratory determinations. All participants received a single 10-mg oral dose of dapagliflozin, and the pharmacokinetics of dapagliflozin and dapagliflozin 3-O-glucuronide were characterized. Dapagliflozin tolerability was also assessed throughout the study. Results Demographic characteristics and baseline physical measurements (weight, height, and body mass index) were similar among the 18 patients in the HI groups (58–126 kg; 151.2–190.0 cm, and 31.5–37.7 kg/m 2, respectively) and the healthy subject group (65.0–102.6 kg; 166.0–184.0 cm, and 23.3–34.3 kg/m 2, respectively). In those with mild, moderate, or severe HI, dapagliflozin mean C max values were 12% lower and 12% and 40% higher than healthy subjects, respectively. Mean dapagliflozin AUC 0–∞ values were 3%, 36%, and 67% higher compared with healthy subjects, respectively. Dapagliflozin 3-O-glucuronide mean C max values were 4% and 58% higher and 14% lower in those with mild, moderate, or severe HI compared with healthy subjects, respectively, and mean dapagliflozin 3-O-glucuronide AUC 0–∞ values were 6%, 100%, and 30% higher compared with healthy subjects, respectively. These values were highly dependent on the calculated creatinine clearance of each group. All adverse events were mild or moderate, with no imbalance in frequency between groups. Conclusions Compared with healthy subjects, systemic exposure to dapagliflozin in subjects with HI was correlated with the degree of HI. Single 10-mg doses of dapagliflozin were generally well tolerated by participants in this study. Due to the higher dapagliflozin exposures in patients with severe HI, the benefit:risk ratio should be individually assessed because the long-term safety profile and efficacy of dapagliflozin have not been specifically studied in this population.

Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Saxagliptin

Patients with type 2 diabetes mellitus often have impaired renal function or may have impaired hepatic function, which can pose significant safety and tolerability issues for antihyperglycaemic pharmacotherapies. Therefore, the pharmacokinetics and tolerability of saxagliptin and its pharmacologically active metabolite, 5-hydroxy saxagliptin, in nondiabetic subjects with mild, moderate or severe renal or hepatic impairment, or end-stage renal disease (ESRD) were compared with saxagliptin and metabolite pharmacokinetics and tolerability in healthy adult subjects. Two open-label, parallel-group, single-dose studies were conducted. Subjects received a single oral dose of saxagliptin 10 mg (Onglyza™). Compared with healthy subjects, the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) for saxagliptin was 16%, 41% and 108% (2.1-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. AUC∞ values for 5-hydroxy saxagliptin were 67%, 192% (2.9-fold) and 347% (4.5-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. As creatinine clearance (CLCR) values decreased, saxagliptin and 5-hydroxy saxagliptin AUC∞ generally increased or became more variable. Twenty-three percent of the saxagliptin dose (measured as the sum of saxagliptin and 5-hydroxy saxagliptin) was cleared by haemodialysis in a 4-hour dialysis session. In the hepatic impairment study, the differences in exposure to saxagliptin and 5-hydroxy saxagliptin were less than 2-fold across all groups. As compared with healthy subjects matched for age, bodyweight, sex and smoking status, the AUC∞ values for saxagliptin were 10%, 38% and 77% higher in subjects with mild, moderate or severe hepatic impairment, respectively. These values were 22%, 7% and 33% lower, respectively, for 5-hydroxy saxagliptin compared with matched healthy subjects. One-half the usual dose of saxagliptin 5 mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate (CLCR 30-50 mL/min) or severe (CLCR<30 mL/min not on dialysis) renal impairment or ESRD, but no dose adjustment is recommended for those with mild renal impairment or any degree of hepatic impairment.

A fourth dimension in decision making in hepatology

Today, the assessment of liver function in patients suffering from acute or chronic liver disease is based on liver biopsy and blood tests including synthetic function, liver enzymes and viral load, most of which provide only circumstantial evidence as to the degree of hepatic impairment. Most of these tests lack the degree of sensitivity to be useful for follow-up of these patients at the frequency that is needed for decision making in clinical hepatology. Accurate assessment of liver function is essential to determine both short- and long-term prognosis, and for making decisions about liver and non-liver surgery, TIPS, chemoembolization or radiofrequency ablation in patients with chronic liver disease. Liver function tests can serve as the basis for accurate decision-making regarding the need for liver transplantation in the setting of acute failure or in patients with chronic liver disease. The liver metabolic breath test relies on measuring exhaled (13) C tagged methacetin, which is metabolized only by the liver. Measuring this liver-specific substrate by means of molecular correlation spectroscopy is a rapid, non-invasive method for assessing liver function at the point-of-care. The (13) C methacetin breath test (MBT) is a powerful tool to aid clinical hepatologists in bedside decision-making. Our recent findings regarding the ability of point-of-care (13) C MBT to assess the hepatic functional reserve in patients with acute and chronic liver disease are reviewed along with suggested treatment algorithms for common liver disorders.

Abstract 2770: An open-label comparative study of the pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with mild, moderate, or severe hepatic impairment, or normal hepatic function

Abstract Zibotentan (ZD4054) is a small-molecule, specific endothelin A (ETA) receptor antagonist being investigated for the treatment of hormone-resistant prostate cancer. Zibotentan is eliminated by both renal (58%) and metabolic clearance. The current study investigated whether hepatic impairment has a clinically relevant effect on exposure to zibotentan. This open-label, two-centre study investigated the PK and tolerability of zibotentan in subjects with hepatic impairment, compared with subjects with normal hepatic function. Subjects were divided into four categories using the Child-Pugh (CP) classification: mild hepatic impairment (CP A), moderate hepatic impairment (CP B), severe hepatic impairment (CP C) and normal hepatic function. Each subject received a single oral dose of zibotentan 10 mg. AUC and Cmax are expressed as the ratio (R) of geometric means and 90% confidence intervals (CI) for each hepatic impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure of zibotentan was considered if the upper 90% CI for the ratio exceeded two. Thirty-seven subjects were enrolled and 32 subjects (eight per group) received zibotentan and completed the study. Compared with the normal function group, zibotentan Cmax was 7% (R 0.93; 90% CI 0.75-1.15), 11% (R 0.89; 90% CI 0.72-1.1) and 5% (R 0.95; 90% CI 0.77-1.17) lower in subjects with CP A, CP B and CP C hepatic impairment, respectively. Zibotentan AUC was 40% (R 1.40; 90% CI 0.91-2.17), 45% (R 1.45; 90% CI 0.94-2.24) and 190% (R 2.90; 90% CI 1.88-4.49) higher in subjects with CP A, CP B and CP C hepatic impairment, respectively, compared with those with normal function. Mean t½ was 9.28 h, 13.0 h, 14.6 h and 24.8 h for the normal function, CP A, CP B and CP C hepatic impairment groups, respectively. Compared with the normal function group, CL/F was approximately 25%, 29% and 64% lower, respectively, in the CP A, CP B and CP C hepatic impairment groups. Zibotentan was well tolerated by all subjects, with headache (CTC Grade 1-2) being the most common adverse event in each group. Despite increased exposure to zibotentan with increased hepatic impairment, there were no differences in the type or severity of adverse events. In conclusion, following a single oral dose of zibotentan 10 mg, there was no significant difference in Cmax with degree of hepatic impairment, indicating that hepatic impairment did not affect the absorption of zibotentan. AUC was higher and t½ longer in subjects with hepatic impairment than in those with normal function due to the slower clearance of zibotentan, with the extent of the difference being related to the degree of impairment. Trial sponsored by AstraZeneca (NCT00672581; AZ code D4320C00025). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2770.

Proactive Management of Adverse Events Maintains the Clinical Benefit of Ixabepilone

Ixabepilone is a novel microtubule-stabilizing agent with clinical efficacy in advanced breast cancer, including patients whose disease has progressed on prior anthracyclines and taxanes. The safety profile of single-agent ixabepilone and combination ixabepilone plus capecitabine therapy is reviewed, outlining the steps to effectively manage and prevent common adverse events. Ixabepilone is generally well tolerated, and importantly, its toxicity profile does not overlap with that of capecitabine. Peripheral sensory neuropathy and neutropenia are the most common toxicities associated with ixabepilone; both can be effectively managed by monitoring patients and then, depending on severity, instituting a treatment delay until recovery and reducing the ixabepilone dose for subsequent treatment cycles. Ixabepilone dose reductions are recommended for most grade 3 events, excluding transient fatigue, arthralgia, and myalgia, whereas treatment discontinuation is recommended for persistent grade 3 neuropathy or any grade 4 nonhematological toxicity. Because ixabepilone exposure is greater in patients with hepatic impairment and those receiving concomitant strong cytochrome P-450 CYP3A4 inhibitors, dose adjustments and restrictions are recommended according to the degree of hepatic impairment, whether ixabepilone is administered alone or in combination with capecitabine, and whether a strong CYP3A4 inhibitor is being coadministered. Patients should be premedicated with oral H(1) and H(2) antihistamines to prevent hypersensitivity reactions. Unlike taxanes, corticosteroid premedication is not required unless a hypersensitivity reaction occurred during a previous cycle or during treatment with another Cremophor-containing agent. By effectively managing adverse events and taking steps to minimize them, clinicians can ensure that patients derive the maximum benefit from ixabepilone therapy.

Pharmacokinetics of Dalbavancin in Patients With Renal or Hepatic Impairment

Three open-label studies assessed the safety, tolerability, and pharmacokinetics of intravenous dalbavancin in patients with hepatic or renal impairment, including patients with end-stage renal disease (ESRD) receiving dialysis. In each study, 4 to 10 patients with mild, moderate, or severe impairment and age-, sex-, and weight-matched controls were administered either a single dose (500 or 1000 mg) or 2 doses (1000 mg followed by 500 mg 1 week apart) of dalbavancin. Dalbavancin exposures were not increased due to mild renal impairment. The mean area under the concentration-time curve from time 0 to infinity (AUC0-infinity) values were approximately 50% higher in patients with moderate renal impairment or ESRD and 100% higher in patients with severe renal impairment. Dose adjustment is not considered necessary in patients with mild or moderate renal impairment or for patients with ESRD receiving hemodialysis; however, a lower dose of dalbavancin (750 mg followed 1 week later by 375 mg) may be considered for patients with severe renal impairment (creatinine clearance<30 mL/min). AUC0-infinity values were similar in patients with mild hepatic impairment and were about 27% to 36% lower in patients with moderate to severe hepatic impairment compared with controls. No dosage adjustment is recommended in patients with any degree of hepatic impairment. Dalbavancin was well tolerated in all impairment groups.

Effects of hepatic impairment on the pharmacokinetics of nilotinib: An open-label, single-dose, parallel-group study

Background: Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor approved for the treatment of patients who have imatinib-resistant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic or accelerated phase or who are unable to tolerate imatinib. Nilotinib is metabolized in the liver via oxidation and hydroxylation pathways, mediated primarily by the cytochrome P450 3A4 isozyme. Interpatient variability in systemic exposure to nilotinib has been reported to range from 32% to 64%. Objective: This study compared the pharmacokinetics of nilotinib in subjects with hepatic impairment and subjects with normal hepatic function. Methods: Hepatic impairment was classified as mild (Child-Pugh grade A), moderate (Child-Pugh grade B), or severe (Child-Pugh grade C). Healthy control subjects were matched with hepatically impaired subjects by age (±10 years) and body weight (±20%). All subjects received a single oral dose of nilotinib 200 mg under fasted conditions, and serial blood samples were collected at specific times up to 120 hours after dosing. Serum nilotinib concentrations were measured using a validated LC-MS/MS assay with a lower limit of quantification of 2.5 ng/mL. The pharmacokinetic parameters analyzed were C max, T max, AUC 0−last, AUC 0−∞, t ½, CL/F, and Vz/F. Tolerability assessments included adverse events (AEs), regular monitoring of clinical laboratory measures (eg, hematology, blood chemistry, urinalysis), physical examinations, vital signs, and ECGs. Each AE was evaluated in terms of its clinical significance, severity, duration, relation to study drug, and action taken. Results: The study enrolled 18 subjects with hepatic impairment (all male; age range, 47–67 years; weight range, 73.9–103.9 kg) and 9 healthy controls (all male; age range, 36–62 years; weight range, 73.3–109.5 kg). Among subjects with hepatic impairment, 6 had mild impairment, 6 moderate impairment, and 6 severe impairment. The nilotinib AUC 0−∞ was a mean of 35%, 35%, and 19% higher in subjects with mild, moderate, and severe impairment, respectively, compared with healthy controls. The nilotinib CL/F was lower in all hepatic-impairment groups compared with healthy controls. The mean (SD) t ½ was 15.1 (4.97) and 16.0 (9.13) hours in the mild-impairment and control groups, respectively, but was 21.6 (7.77) and 32.4 (10.7) hours in the moderate- and severe-impairment groups, respectively, reflecting the decrease in CL/F and/or increase in Vz/F in the latter 2 groups. All AEs were mild or moderate, and the frequency of AEs was not associated with the degree of hepatic impairment. AEs included abdominal pain (1 subject with mild impairment), dyspepsia (2 with mild impairment), flatulence (1 with severe impairment), nausea (1 with mild impairment), urinary tract infection (1 with mild impairment), back pain (1 each with mild impairment and severe impairment, 1 control subject), and headache (1 each with mild impairment and severe impairment). Conclusions: After a single 200-mg dose, nilotinib pharmacokinetics were modestly affected by hepatic impairment. The extent of change in nilotinib exposure in subjects with hepatic impairment was generally within the range of variability that has been observed clinically. The results of this study suggest that dose adjustment may not be necessary in patients with hepatic impairment. Nilotinib should be used with caution, and careful clinical monitoring is recommended in this population. ClinicalTrials.gov identifier: NCT00418626.