Population pharmacokinetics and exposure-response of albinterferon alfa-2b

Albinterferon alfa-2b (albIFN) has been studied for treatment of chronic hepatitis C virus (HCV). A population pharmacokinetics model was developed using nonlinear mixed-effects modeling. Efficacy/safety exposure-response relationships were assessed for subcutaneous albIFN doses (900-1800 μg once every 2 or 4 weeks) administered for either 24 weeks (HCV genotypes 2/3) or 48 weeks (genotype 1), plus daily oral ribavirin. Sustained virologic response (SVR) exposure-response was modeled using logistic regression. Adverse event incidence was tabulated versus exposure quartiles. First-order absorption rate constant (0.0148 h(-1)), apparent clearance (38.9 mL/h), and apparent volume of distribution (11.6 L) had interindividual variances (coefficient of variation) of 21%, 34%, and 24%, respectively. Residual variance estimates were 27% (coefficient of variation) and 1.51 ng/mL (standard deviation). For the only explanatory covariate-body weight-exposure decreased as weight increased. Important SVR predictors included baseline HCV RNA, fibrosis score, and black race (genotype 1); SVR was minimally related to exposure. Most adverse events had similar incidence rates across exposure quartiles. Some adverse events had a higher incidence in the upper exposure quartile without evidence of exposure-response across the lower quartiles. Given the lack of consistent efficacy/safety exposure-response relationships, further investigation is necessary to optimize albIFN dosing.     

Albinterferon alfa-2b,a novel fusion protein of human albumin and human interferon alfa-2b,for chronic hepatitis C

ABSTRACT

Objective: New treatment options for chronic hepatitis C (CHC) that offer improved efficacy, tolerability, and convenience compared with weekly interferon alfa (IFNα)-based regimens are needed. Longer-acting IFNα formulations with reduced dosing requirements and improved tolerability have been a focus of drug development efforts. The objective of this report is to review the characteristics, pharmacokinetics, pharmacodynamics, and clinical and virologic outcomes reported in studies of albinterferon alfa-2b (alb-IFN), a novel fusion protein of human albumin and human IFNα-2b.

Methods: This review was based on all published data regarding alb-IFN to date. An unlimited PubMed database search was conducted using the keywords ‘albuferon,’ ‘albinterferon,’ and ‘albumin AND interferon.’

Results: Albinterferon alfa-2b has been developed for the treatment of CHC. This agent exhibits a prolonged half-life and duration of antiviral activity that indicate potential suitability for dosing intervals of 2–4 weeks. Phase 2 trials in prior IFN nonresponders and IFN-naïve patients with genotype 1 or 2/3 CHC have shown antiviral activity and acceptable safety/tolerability of alb-IFN 900–1500?µg every 2 weeks and 1200–1500?µg every 4 weeks. Based on the phase 2 data, alb-IFN 900?µg and 1200?µg every 2 weeks were selected for two ongoing phase 3 trials in IFN-naïve patients with genotype 1 and 2/3 CHC.

Conclusions: Albinterferon alfa-2b exhibits high antiviral activity, and appears to offer safety/tolerability comparable to the current standard of care, and health-related quality-of-life benefits in patients with CHC. Its ability to maintain drug concentrations above the 90% effective concentration over prolonged dosing intervals suggests that it may be an ideal partner for combination therapy with direct antiviral agents in CHC. The results of the phase 3 trials are eagerly anticipated as they should greatly clarify the future role of alb-IFN in the treatment of CHC.     

Biological activity of EDQM CRS for Interferon alfa-2a and Interferon alfa-2b - assessment in two in vitro bioassays

The European Directorate for the Quality of Medicines (EDQM) supplies Chemical Reference Substances (CRS) for Interferon (IFN) alfa-2a (CRS I0320300) and for IFN alfa-2b (CRS I0320301) for specified physicochemical tests. However, no information is provided as to their biological activity. In contrast, the World Health Organization (WHO) provides the 2nd International Standards (IS) for IFN alfa-2a (code 95/650) and for IFN alfa-2b (code 95/566), with activity defined in International Units (IU) for calibration of biological activity of preparations of IFN. We have compared the EDQM CRSs with the WHO ISs in two bioassay systems, one measuring the anti-proliferative activity in the Daudi cell line and the other measuring a reporter gene activation in an A549 cell line. In each of these assay systems, the CRSs gave dose - response relations, which were similar to those for the WHO ISs. Estimates of relative activity for each CRS, in terms of the respective IS, showed specific biological activity for the CRSs of the same order as the nominal specific activity for the ISs. However, the estimates of relative activity were not consistent between the two assays systems, emphasizing the need for calibration within each system, if the CRS were to be used as a working standard for bioassays. For structure-activity studies, both physicochemical and biological activity characterisation are required for the same biopharmaceutical preparation. CRS I0320300 and CRS I0320301 may prove useful as working standards for some bioassay systems.     

Multiple-dose pharmacokinetics of peginterferon alfa-2b in patients with renal insufficiency

What is already known about this subject?

• Current therapy for hepatitis C typically consists of pegylated interferon (PEG-IFN) alfa in combination with ribavirin.
• Pegylation of IFN alfa-2b confers a 10-fold increase in elimination half-life and a 30% reduction in volume of distribution compared with non-PEG-IFN alfa-2b.
• A single-dose pharmacokinetic study conducted in patients with chronic renal dysfunction has shown that renal elimination accounts for 30% of total PEG-IFN alfa-2b clearance and that PEG-IFN alfa-2b exposure increases with severity of renal insufficiency.

What this study adds

• Because the primary mechanism of IFN clearance is catabolism in the kidney, appropriate dosing of IFN-based therapies in patients with renal insufficiency is an important issue.
• This multiple-dose pharmacokinetic study shows that exposure to PEG-IFN alfa-2b is increased in patients with renal insufficiency, suggesting that doses of the drug should be reduced by 50% in patients with severe renal insufficiency and by 25% in those with moderate insufficiency.
• PEG-IFN alfa-2b was well tolerated in all patient groups during the 4-week treatment period, with similar adverse events occurring in patients with renal insufficiency and in those with normal renal function.

Aim

To evaluate the safety, tolerability and multiple-dose pharmacokinetics of pegylated interferon (PEG-IFN) alfa-2b in patients with moderate or severe renal insufficiency and in those with normal renal function.

Methods

In an open-label study, subjects with normal renal function (creatinine clearance >80 ml min⁻¹ per 1.73 m²) and patients with moderate (30–50 ml min⁻¹ per 1.73 m²) or severe (10–29 ml⁻¹ min⁻¹ per 1.73 m²) renal impairment received weekly injections of PEG-IFN alfa-2b (1.0 µg kg⁻¹) for 4 weeks. Safety assessments were made before each injection and blood samples were taken up to 168 h after the final dose.

Results

Renal insufficiency increased PEG-IFN alfa-2b exposure. Area under the curve for 0–τ (dosing interval of 168 h), AUC_τ, was increased 30% and 120% in patients with moderate or severe renal insufficiency, respectively. Mean maximum serum concentration was almost doubled in patients with severe insufficiency [1305.8 pg ml⁻¹; 95% confidence interval (CI) 825, 1786] compared with subjects with normal renal function (731.4 pg ml⁻¹; 95% CI 407, 1056), whereas the apparent volume of distribution was reduced (0.80 l kg⁻¹vs. 1.28 l kg⁻¹, respectively). Elimination half-life was extended in patients with moderate and severe renal insufficiency (65.6 h and 64.9 h, respectively) compared with subjects with normal renal function (51.5 h). Significant differences were observed in the AUC and C_max values of patients with severe renal dysfunction, compared with those who had normal renal function (P< 0.05; Kruskal–Wallis test). PEG-IFN alfa-2b was well tolerated and adverse events were similar in both treatment groups.

Conclusions

Exposure to PEG-IFN alfa-2b is increased in patients with renal insufficiency, suggesting that doses of the drug should be reduced by 50% in patients with severe renal insufficiency and by 25% in those with moderate insufficiency.     

A pharmacokinetic evaluation of ropeginterferon alfa-2b in the treatment of polycythemia vera

ABSTRACT

Introduction

Polycythemia vera (PV) is a Philadelphia chromosome-negative chronic myeloproliferative neoplasm (MPN). A newly developed PV treatment option, ropeginterferon alfa-2b, contains recombinant human alfa monoisomer as an active ingredient, resulting in a novel pharmacologic profile and improved tolerability. Efficacy studies conclude remarkable long-term hematological response and sustained JAK2V617F allele burden reduction. Ropeginterferon alfa-2b compound has been approved for the treatment of polycythemia vera without symptomatic splenomegaly.     

Peginterferon alfa-2a/ribavirin in hepatitis C virus patients nontolerant or nonresponsive to peginterferon alfa-2b/ribavirin

Background  Peginterferon alfa-2a/ribavirin treatment resulted in fewer incidences of depression and flu-like symptoms than that of standard interferon/ribavirin, whereas peginterferon alfa-2b/ribavirin and standard interferon/ribavirin treatment resulted in similar incidences of these adverse events (AEs).
Aim  To assess the efficacy and safety of peginterferon alfa-2a/ribavirin in genotype 1-infected patients treated for up to 12 weeks with peginterferon alfa-2b/ribavirin but not achieving early virologic response (EVR) (non-EVR) or nontolerant (NT) because of depression, fatigue, flu-like symptoms, or injection-site reactions.
Methods  Nontolerants were treated for an additional 36 weeks and non-EVRs for an additional 60 weeks with peginterferon alfa-2a (180 μg/week)/ribavirin (1000/1200 mg/day). Patients with detectable HCV RNA after 12 weeks were discontinued.
Results  Of 25 NTs, 23 (92%) were HCV-RNA negative after 12 weeks on peginterferon alfa-2a/ribavirin and 14 (56%) achieved sustained virologic response. Of 32 non-EVRs to peginterferon alfa-2b/ribavirin, four (13%) achieved EVR with peginterferon alfa-2a/ribavirin and one (3%) achieved sustained virologic response. Four non-EVRs and 0 NTs were withdrawn for AEs; 26 (81%) and 24 (96%), respectively, completed peginterferon alfa-2a/ribavirin treatment or were withdrawn for insufficient response at week 12. In NTs, depression, fatigue, flu-like symptoms, and injection-site reactions declined during treatment.
Conclusion  Most patients who did not tolerate peginterferon alfa-2b/ribavirin because of AEs, and who completed the full 36-week course of peginterferon alfa-2a/ribavirin treatment, achieved sustained virologic response.     

Cost-efficacy analysis of peginterferon alfa-2b plus ribavirin compared with peginterferon alfa-2a plus ribavirin for the treatment of chronic hepatitis C

OBJECTIVE: Combination therapy with pegylated interferon (Peg) and ribavirin (RBV) is the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. This analysis compares the cost efficacy of treatment with pegylated interferon alfa-2b plus ribavirin (Peg-2b plus RBV) with pegylated interferon alfa-2a plus ribavirin (Peg-2a plus RBV) in hypothetical cohorts of 100 chronic HCV patients comprised 75% of genotype 1. METHODS: A decision analysis model was constructed from the viewpoint of a managed care organization to compare Peg-2b plus RBV (1.5 mcg per kilogram per week plus RBV 800 mg per day) and Peg-2a plus RBV (180 mcg per week plus RBV 1,000-1,200 mg per day) pursuant to the label dosing approved by the U.S. Food and Drug Administration. The model also included the so-called weight-based dosing regimen with Peg-2b plus RBV (1.5 mcg per kilogram per week plus RBV 10.6 mg/kg per day). Patient weight was assumed to be 80 kg. For purposes of this analysis, early virologic response (EVR), defined as viral negative or 2-log drop in viral load, was assessed at 12 weeks for only genotype 1 patients, and nonresponders were assumed to discontinue therapy. The positive predictive value (PPV) was calculated for each treatment group for genotype 1 patients, which is determined from the values for EVR and sustained viral response (SVR). Genotype 2 and genotype 3 patients were assumed to be treated for 24 weeks. Treatment duration and efficacy data were obtained from the published literature. Product pricing was based on average wholesale price, October 2004, and sensitivity analysis was performed using prices from the Federal Supply Schedule. Economic outcomes were determined from hypothetical 100-patient cohorts assumed to be comprised 75% of genotype 1 HCV. RESULTS: Taking into account both EVR and SVR, the PPV for genotype 1 patients was 0.63 and 0.57 for Peg-2b plus RBV and Peg-2a plus RBV, respectively. The proportion of treated patients achieving SVR would be nearly identical, (53.6%) and (53.8%) for Peg-2a plus RBV and Peg-2b plus flat RBV, respectively. For Peg- 2b plus weight-based RBV, the proportion of patients achieving SVR was higher (61.4%). Consequently, this leads to fewer overall treatment weeks for the Peg- 2b plus RBV cohorts. Therefore, the cost per successful treatment (defined as SVR) was 19.4% less (37,638 US dollars) for Peg-2b plus flat dosing of RBV as compared with Peg-2a plus RBV (46,717 US dollars). When Peg-2b plus RBV was dosed 1.5 mcg per kilogram per week plus RBV 10.6 mg/kg/day, then the cost per SVR was 39,045 US dollars. The cost for the 100-patient cohort was 2,024,846 US dollars for Peg-2b plus RBV, 2,397,529 US dollars for Peg-2b plus weight-based RBV, and 2,505,317 US dollars for Peg-2a plus RBV. This difference is due to a lower PPV in the Peg-2a plus RBV groups and hence more patients treated in spite of a low probability of achieving SVR. CONCLUSION: The results of this cost-efficacy analysis suggest that treating HCV genotype 1 patients with Peg-2b plus RBV may result in savings to a health care system because fewer of these patients are treated beyond 12 weeks when achieving sustained viral clearance is unlikely.     

Protein adsorption and excipient effects on kinetic stability of silicone oil emulsions

The effect of silicone oil on the stability of therapeutic protein formulations is of concern in the biopharmaceutical industry as more proteins are stored and delivered in prefilled syringes. Prefilled syringes provide convenience for medical professionals and patients, but prolonged exposure of proteins to silicone oil within prefilled syringes may be problematic. In this study, we characterize systems of silicone oil‐in‐aqueous buffer emulsions and model proteins in formulations containing surfactant, sodium chloride, or sucrose. For each of the formulations studied, silicone oil‐induced loss of soluble protein, likely through protein adsorption onto the silicone oil droplet surface. Excipient addition affected both protein adsorption and emulsion stability. Addition of surfactant stabilized emulsions but decreased protein adsorption to silicone oil microdroplets. In contrast, addition of sodium chloride increased protein adsorption and decreased emulsion stability. Silicone oil droplets with adsorbed lysozyme rapidly agglomerated and creamed out of suspension. This decrease in the kinetic stability of the emulsion is ascribed to surface charge neutralization and a bridging flocculation phenomenon and illustrates the need to investigate not only the effects of silicone oil on protein stability, but also the effects of protein formulation variables on emulsion stability. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1721–1733, 2010     

α—2b干扰素治疗慢性丙型肝炎的经济学评价

目的：对上海、北京和三石家庄三城市应用α－２ｂ干扰素治疗慢性丙型肝炎做经济学评价。方法：根据对三城市的部分慢性丙肝、代偿性肝硬化、失代偿性肝硬化病人调查所得的门诊费用、住院费用,并根据慢性丙型肝炎的自然史和α－２ｂ干扰素治疗组和常规治疗组的慢性丙肝病人在３０ａ内的有关费用和预后,并进行成本－效益和成本－效果分析。结果：治疗后３０ａ内,α－２ｂ干扰素治疗组比常规治疗组增加８５２个存活人年和１４８７个     

Population pharmacokinetics of peginterferon alfa-2b in pediatric patients with chronic hepatitis C

Purpose

The aim of this study was to characterize the population pharmacokinetics of peginterferon (PEG-IFN) alfa-2b in pediatric patients with chronic hepatitis C and to identify covariates influencing PEG-IFN alfa-2b disposition.

Methods

Pharmacokinetic data from a multicenter open-label study of subcutaneously administered peginterferon alfa-2b (60 μg/m²/wk) plus oral ribavirin (15 mg/kg/day) in patients with chronic hepatitis C aged 3–17 years old was used to develop a population pharmacokinetic nonlinear mixed-effects model.

Results

The final population pharmacokinetic analysis was conducted with the pooled data from 107 pediatric patients. A one-compartment model with first-order absorption, first-order elimination, exponential inter-individual variability on clearance, and a combination additive and proportional residual error model adequately described the PEG-IFN alfa-2b pharmacokinetic profile. Age (apparent clearance and apparent volume of distribution) and sex (apparent clearance) were significant covariates. The mean body surface area normalized apparent clearance of PEG-IFN alfa-2b was 0.56 L/h/m², and was similar when evaluated across the pediatric age groups.

Conclusion

The final population model suggests age-dependent increases in clearance and volume of distribution of PEG-IFN alfa-2b in pediatric patients with chronic hepatitis C. The apparent clearance normalized to body surface area was similar across pediatric age groups, supporting the use of body size–adjusted dosing in pediatric subjects.     

聚乙二醇干扰素α-2b联合病毒唑治疗慢性丙型肝炎的临床观察

目的评价聚乙二醇干扰素α-2b联合病毒唑治疗慢性丙型病毒性肝炎的临床效果及用药安全性,探讨临床慢性丙型肝炎的抗病毒方法。方法选择68例慢性丙型肝炎患者随机分成联合治疗组与对照组,联合治疗组38例,给予聚乙二醇干扰素α-2b80μg,1次/周皮下注射,加上病毒唑450mg,3次/d,疗程为6个月;对照组30例,用甘乐能干扰素α-2b3Mu隔日肌内注射1次,加上病毒唑450mg,3次/d,疗程6个月。两组停药后随访6个月。分别观察两组慢性丙肝患者治疗前后的临床症状、体征改善状况,生化应答率、病毒应答率和临床不良反应。结果治疗结束时联合治疗组显效率、有效率和总有效率分别是71.05%、18.42%和89.47%;对照组分别是66.67%、16.67%和83.34%;两组比较差异无统计学意义（P〉0.05）。随访6个月联合治疗组的持续应答率为47.37%,而对照组为16.67%,两组有统计学意义（P〈0.01）。两组副作用均有发热、乏力、胃肠道症状、白细胞下降、肌肉酸痛等（P〉0.05）。结论聚乙二醇干扰素α-2b联合病毒唑治疗慢性丙型肝炎,可迅速缓解患者的症状体征,促进HCV-RNA的阴转,临床用安全,停药6个月后的持续完全应答显著优于甘乐能干扰素。     

硅油二次注入术治疗带硅油眼的复发性视网膜脱离

目的 分析带硅油眼复发性视网膜脱离的原因,总结硅油二次注入术治疗带硅油眼复光、复杂性视网膜脱离的效果。方法 对150例带硅油眼的复发性视网膜脱离,其中40例复杂性视网膜脱离接受硅油二次注入术进行了回顾性分析。结果 带硅油眼的视网膜脱离以下方为主,其主要原因为硅油上浮,原裂孔封闭不好或裂好,新裂孔形成,增殖性玻璃体视网膜病变（PVR）的牵引。对40例带硅油眼的视网膜脱离进行了硅油再次注入术,平均随访8个月。视网膜解剖复位34例（85％）。硅油二次取出术12例,视网膜解剖复位9例（75％）。结论 带硅油眼的复发性视网膜脱离的主要原因是玻璃体牵引,对于复杂性病例,行硅油再次注入术成功率较高。     

Structural stability of β-lactoglobulin in the presence of kosmotropic salts A kinetic and thermodynamic study

The thiol group of β-lactoglobulin reacted very sluggishly with dithio-bis-nitro-benzoic acid as compared to that of glutathione at pH 6.85. The pK_app value of the thiol group of the protein was 9.35. In the presence of 3 M urea, the thiol group reacted completely with dithio-bis-nitrobenzoic acid at pH 6.85. Heating (from 50° to 80°) increased the exposure of the thiol by dissociating the dimer unit. From the pseudo-first order rate constants of heat-exposure of thiol, thermodynamic activation parameters, ΔG⁺₊, ΔH⁺₊, and ΔS⁺₊, for the heat-dissociation of β-lactoglobulin dimer were estimated to be 23 290 cal/mol, 31 160cal/mol, and 22.9 e.u. (at 70°), respectively. Addition of kosmotropic salts, chloride, tartrate, sulfate, phosphate, and citrate (0.2 m ) decreased the heat-induced exposure of the thiol group (at 70°), probably by decreasing the dissociation of the dimer at pH 6.85. The relative change in free energy of activation for the dissociation of the dimer, Δ(ΔG⁺_+dimer), in the presence of the salts was positive, suggesting that these additives increase the stability of the dimer against heat. These salts also increased the conformational stability of β-lactoglobulin as revealed by an increase in - Δ(ΔG⁰_conf) values in their presence. Both Δ(ΔG⁺_+dimer) and - Δ(ΔG⁰_conf) values followed the order, chloride < tartrate < sulfate < phosphate < citrate. These salts seem to manifest their structure-stabilizing effect by increasing both inter- and intramolecular hydrophobic interactions via changes in structure of water.     

聚乙二醇干扰素α-2b致慢性丙型肝炎患者严重精神障碍

1例35岁男性患者,因慢性丙型肝炎给予聚乙二醇干扰素α-2b 200万U肌内注射,1次/周。4个月后患者出现幻听、妄想,性格有轻微改变。随后症状逐渐加重,1周后出现被害妄想、思维散漫、情感不协调、易激惹和自知力障碍。遂停用该药,并给予奥氮平对症治疗。治疗1周症状明显好转,治疗2周出院。出院后继续应用奥氮平治疗1周,随后自行停药,随访半年未再出现上述精神症状。     

Peginterferon alfa-2a versus peginterferon alfa-2b as initial treatment of hepatitis C virus infection: a cost-utility analysis from the perspective of the Veterans Affairs Health Care System

Study Objective . To assess the cost-utility of peginterferon alfa-2a plus ribavirin, peginterferon alfa-2b plus ribavirin, and no therapy for treatment-naïve patients with chronic hepatitis C virus (HCV) infection from the perspective of the Veterans Affairs (VA) health care system by using patient-reported utility scores. Design . Cost-utility analysis using a Markov model. Setting . Veterans Affairs health care system. Data Source . Data for the model were obtained from clinical trials and published literature. Data from the VA health care system were used to define the patient cohorts. Measurements and Main Results . A Markov model incorporating transition probabilities between disease health states that depend only on the current health state was developed to simulate the progression of HCV disease. The patient cohorts were a 45-year-old male cohort and a 55-year-old male cohort, each with liver fibrosis but no cirrhosis. The lifetime expected costs, quality-adjusted life-years (QALYs) gained, and incremental net monetary benefit (INMB) with HCV treatments were determined for each cohort by genotype (genotype 1, and genotypes 2 and 3). Both peginterferon regimens were significantly more cost-effective than no treatment, although no significant differences in costs or QALYs were noted between peginterferon regimens. For the 45-year-old cohort with a genotype 1 infection, the INMB was $128,583 (95% confidence interval [CI] $79,279–$177,308) and $128,025 (95% CI $80,425–$173,448) versus no treatment for peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin, respectively. Treatment with either peginterferon regimen produced significantly lower lifetime HCV-related medical costs for genotype 2 or 3 infections, but not genotype 1. Conclusions . Peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin were found to be cost-effective treatments for patients with HCV infections, particularly with genotypes 2 and 3. However, no significant differences in costs or efficacy were observed between these peginterferon treatment regimens.