Population pharmacokinetic analysis of weekly and biweekly IgPro20 (Hizentra®) dosing in patients with primary immunodeficiency

BackgroundIgPro20 (Hizentra®), a 20% subcutaneous immunoglobulin G (IgG), is an effective treatment for patients with primary immunodeficiencies with impaired IgG production. Flexible dosing regimens of IgPro20 have been supported by pharmacokinetic (PK) modeling and simulation. This study further describes the PK characteristics of serum IgG concentrations after weekly and biweekly administration of IgPro20 and compares predicted and actual serum IgG data using a previously-developed population PK (popPK) model.MethodsA popPK model was developed by combining data from a previously-published model with data from a Phase 4 study (IgPro20_4005). An external validation of the original model using dosing, demographics, and historic endogenous serum IgG concentrations from patients enrolled in study IgPro20_4005 was performed. This dataset was then simulated 300 times and predicted serum IgG PK characteristics compared with the observed data.ResultsA total of 173 patients (156 unique patients from original model and 17 patients from study IgPro20_4005) provided 4078 observations of serum IgG concentrations. The popPK estimates obtained demonstrated a clearance (% inter-individual variability) of 0.138 L/day (35%), volume of central compartment of 3.95 L (78.6%), inter-compartmental clearance of 0.260 L/day (56%), and volume of peripheral compartment of 4.44 L. Validation results indicated that observed serum IgG concentration vs time data fell within the 90% prediction intervals for median, 25th, and 75th percentiles of the simulated IgG concentration time courses.ConclusionsThe present analysis validated the ability of the previously published popPK model to predict serum IgG concentration time profiles after biweekly subcutaneous IgPro20 administration.     

Anemia treatment with Q2W darbepoetin alfa in patients with chronic kidney disease naïve to erythropoiesis-stimulating agents*

ABSTRACT

Objective: To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy.

Research design and methods: This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb)?<?11.0?g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75?µg/kg and titrated to achieve and maintain Hb levels at 11.0–13.0?g/dL. Treatment was administered from week 1 to week 19.

Main outcome measures: The primary endpoint was the proportion of subjects who achieved Hb?≥?11?g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed.

Results: Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hb?≥?11?g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hb?≥?11?g/dL were 60 and 80?µg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects.

Conclusions: This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results.

Trial registration: ClinicalTrials.gov identifier: NCT00112008.     

Evaluation of the US Oncology Network's recommended guidelines for therapeutic substitution with darbepoetin alfa 200 microg every 2 weeks in both naïve patients and patients switched from epoetin alfa

STUDY OBJECTIVE: To evaluate the efficacy of darbepoetin alfa 200 microg subcutaneously every 2 weeks after therapeutic substitution for epoetin alfa. DESIGN: Retrospective multicenter chart review. SETTING: Three US Oncology-affiliated outpatient sites. PATIENTS: Three hundred thirty anemic patients with nonmyeloid malignancies, of whom 174 had been treated previously with epoetin alfa (switched group) and 156 had not been treated recently with epoetin alfa (naive group). INTERVENTIONS: Therapeutic substitution with darbepoetin alfa was started according to the US Oncology Pharmacy and Therapeutics Committee's recommended dosing guidelines: anemic patients with cancer received a starting dosage of darbepoetin alfa 200 microg every 2 weeks regardless of whether or not they had previously received epoetin alfa. Hematologic and darbepoetin alfa usage data were abstracted from consecutive medical records dated from May 2002-March 2003. MEASUREMENTS AND MAIN RESULTS: Median exposure to darbepoetin alfa was 10 weeks (25th quartile 6 wks, 75th quartile 17 wks) and 10 weeks (25th quartile 5 wks, 75th quartile 18 wks) for the naive and switched groups, respectively. The week before the switch to darbepoetin alfa, the 174 patients receiving epoetin alfa were administered the following weekly doses: less than 40,000 U (9%), 40,000 U (50%), or 45,000-90,000 U (41%). Mean hemoglobin level increased from baseline (wk 0) in both the naive and switched groups. The proportion of patients receiving a red blood cell transfusion in the darbepoetin alfa treatment phase was low (15% in each group). No variation in transfusion rates was observed across weight categories in patients who received a fixed dosage of darbepoetin alfa. Darbepoetin alfa was well tolerated. A detailed usage algorithm was validated by these results and is being used in these three US Oncology-affiliated practices. CONCLUSION: A darbepoetin alfa starting dosage of 200 microg subcutaneously every 2 weeks administered according to US Oncology-recommended dosing guidelines is effective in treating chemotherapy-induced anemia in both epoetin alfa-naive patients and those switched from epoetin alfa.     

A comparison of sodium picosulphate (Laxoberal) with standardised senna (‘Senokot’) in geriatric patients

Summary

A comparison was made between the effectiveness of sodium picosulphate and that of standardised senna in a group of 50 long-stay geriatric patients. Both were found to be equally effective as laxatives, but there were wide variations in the responses of individual patients to these agents. Side-effects were uncommon. They may well have been reduced further if a small starting dose of sodium picosulphate had been used.     

Granisetron in the treatment of chemotherapy-induced nausea and vomiting (CINV) – is there still a role after comparison with palonosetron?

Introduction: Chemotherapy-induced nausea and vomiting (CINV) has a negative impact on the lives of subjects receiving chemotherapy. In 2009, the second generation 5-HT₃-receptor antagonist, palonosetron, which is longer-acting than granisetron, was shown, as part of dual therapy with dexamethasone, to be superior to intravenous granisetron in the delayed phase of CINV.

Area covered: In an attempt to maintain plasma levels of granisetron during the delayed phase of CINV, longer-acting preparations of granisetron have been manufactured. In addition to comparing intravenous/oral granisetron with palonosetron, this review considers the new longer-acting preparations of granisetron (transdermal and subcutanous) with emphasis on whether they are effective in the delayed phase of CINV.

Expert opinion: Comparison of intravenous/oral granisetron and palonosetron, as part of triple therapy against the delayed phase of CINV, do not give clear-cut results as to non-inferiority or superiority of either agent. Subcutaneous granisetron is more convenient to use than transdermal granisetron, and has been shown to be non-inferior to palonosetron, as part of dual therapy, in the treatment of the acute and delayed phases of CINV. At present, it seems likely that there will be ongoing roles for intravenous and subcutaneous granisetron in CINV, but further data is required to ascertain the future of transdermal granisetron.     

A comparison of etodolac (Ultradol®) with acetaminophen plus codeine (Tylenol #3) in controlling post-surgical pain in vasectomy patients

Summary

The efficacy and safety of etodolac (Ultradol®) and acetaminophen plus codeine [A + C (Tylenol #3)] in controlling post-surgical pain were compared in an open-label, randomized, parallel-group outpatient study. Patients who were voluntarily having a vasectomy performed for sterilization were assigned to receive either etodolac 200?mg (20 patients) or A + C (20 patients). All medication was taken as required for up to 7 days. Efficacy assessments were made at 1, 6 and 24 hours after surgery and included pain measurement (Likert Visual Analogue scale), patient and physician global assessments and time to analgesic relief. Safety assessments were made throughout the study and included vital signs and adverse event monitoring. Results of the study indicated that patients taking etodolac were more likely to say they could return to work 24 hours after their vasectomy (p = 0.04). There were no other statistically significant differences between the two groups of patients. The results from this study indicate that etodolac and A + C are equally efficacious and well-tolerated for the control of post-vasectomy pain and that patients may observe an increased benefit with etodolac by being able to return to work sooner.     

Protein binding of 2-chloro 2′-deoxyadenosine (cladribine) in healthy subjects and in patients with leukaemia

The plasma protein binding of 2-chloro-2-deoxyadenosine (CdA) at 37°;C was studied by ultrafiltration in 5 healthy volunteers, in 11 patients with haematological malignancies and in purified protein preparations. In the patients, the binding of CdA to plasma proteins was 25.0% and in healthy subjects it was 21.1%. In a solution of human serum albumin (40 g·1^–1), 24.3% CdA was bound, but less than 5% was bound in a solution of ₁-acid-glycoprotein (0.7 g·1^–1). No dependence of binding on the concentration of CdA was found within a range 25–1000 nmol·1^–1.In conclusion, due to its limited binding to plasma proteins, any change in the binding of CdA is unlikely to have a major influence on its pharmacological effect.     

Efficacy and safety evaluation of once-daily OROS hydromorphone in patients with chronic low back pain: a pilot open-label study (DO‑127)

ABSTRACT

Objective: To evaluate the safety, tolerability, and efficacy of once-daily osmotic controlled-release oral delivery system (OROS) hydromorphone in patients with chronic low back pain of moderate-to-severe intensity.

Research design and methods: This was a 6-week, multicenter, nonrandomized, noncomparative, open-label, repeat-dose study of chronic (≥?6 weeks) low back pain. The study comprised three periods: prior opioid stabil­ization (2–7 days); OROS hydromorphone conversion, titration, and stabilization (3–14 days); and OROS hydro­morphone maintenance (28 days). Patients were evalu­ated weekly. Baseline pain assessment was performed at the end of prior opioid stabilization. For pain relief rating, endpoint was defined as the mean pain relief score from the last 2 nonmissing days before study termination. For other assessments, endpoint was defined as the last post-baseline evaluation.

Results: Of the 207 patients who received the study drug, 131 completed the trial. Scores (mean ± SD) for Brief Pain Inventory ‘worst pain in the last 24 hours’ decreased significantly from baseline to endpoint (–0.8 ± 2.06, p < 0.0001). The proportions of patients and investigators rating the global effectiveness as good, very good, or excellent increased from 31.6% at baseline while patients were on prior opioids to 63.2% at endpoint while patients received OROS hydromorphone, and from 29.8% at baseline while patients were on prior opioids to 65.8% at endpoint while patients received OROS hydromorphone, respectively. Daily pain relief ratings also increased significantly (+0.26 ± 1.084, p = 0.0008). Significant improvements in health-related quality of life and sleep problems were observed. Adverse events were mild to moderate in severity; the most common of these were constipation, nausea, headache, and somnolence. The limitations of this study include its pilot-type design and the lack of comparison of OROS hydromorphone with a placebo or another drug. Additional comparative and longer-term studies are needed to confirm these findings.

Conclusions: OROS hydromorphone may be an effective treatment for chronic low back pain of moderate-to-severe intensity. Adverse events were typical of those associated with opioid therapy.     

Dysfunction in the β2-adrenergic signal pathway in patients with insulin dependent diabetes mellitus (IDDM) and unawareness of hypoglycaemia

The majority of the impaired symptoms in hypoglycaemia unawareness, such as palpitations, tachycardia and tremor, are caused by increased release of adrenaline (ADR) and noradrenaline (NA), and induced by stimulation of -adrenergic receptors. Binding of ADR or NA to the -adrenergic receptor generates a signal, transmitted via a guanine nucleotide binding protein complex (G-protein), which in turn activates adenylate cyclase with increased production of cAMP. The aim of this study was to show whether IDDM-patients with hypoglycaemia unawareness had deficient coupling between ₂-adrenergic receptors and G-proteinscompared to IDDM-patients with hypoglycaemia awareness and healthy controls. The IDDM-patients were subgrouped as hypoglycaemia aware or unaware based on questionnaire answers, clinical information and the results of isoprenaline sensitivity tests. Mononuclear leukocytes (MNL) were isolated from venous blood. By saturation binding experiments, using [¹²⁵I]-(-)-iodopindolol ((-)-IPIN), total receptor number (B_max) and affinity (K_d) were determined. By displacement experiments the relative number of low-and high-affinity receptors for the -adrenergic agonist (-)-isoprenaline ((-)-ISO) were determined. We found no difference in B_max- or K_d-values for (-)-IPIN between the subgroups. However, there was a reduced capability to form high-affinity binding complexes with (-)-ISO in MNL from IDDM-patients with hypoglycaemia unawareness. It was concluded that hypoglycaemia unawareness in IDDM was associated with dysfunction of the proximal ₂-adrenergic signal pathway.     

Rationale and design of TeraViC-4 study: a phase III,randomized clinical trial to evaluate the effects of treatment duration with peginterferon alfa-2a (40-kDa) and ribavirin in naïve patients with chronic hepatitis C virus infection without early virological response at week 4

Several studies are available on the efficacy and safety of 40 kDa branched peginterferon alfa-2a (40-kDa) combined with ribavirin in the treatment of chronic hepatitis C patients. The TeraViC-4 study is a phase III, randomized, parallel group, multicenter study that includes two additional open arms. The main objective is to investigate if extended therapy over 72 weeks increases the rate of sustained virological response induced by a standard 48-week treatment period in na?ve patients with chronic hepatitis C who do not show an early virological response. All patients will be treated with peginterferon alfa-2a (40-kDa), 180 micrograms subcutaneous (s.c.) once-weekly, and ribavirin, 400 mg b.i.d. Virological response will be assessed by a hepatitis C virus ribonucleic acid (HCV-RNA) qualitative polymerase chain reaction (PCR) test. Non-early responders (HCV-RNA still detectable after 4 weeks of therapy) will be randomly separated to receive combination therapy for 44 or 68 additional weeks. Early responders (undetectable HCV-RNA at week 4) will be allocated into two open arms according to HCV genotype and basal viral load, and they will be treated for 20 or 44 additional weeks. All patients will be followed for 24 weeks on no therapy. A total of 504 patients are planned to be included in the study in order to reach the required sample size in the two randomized groups. Efficacy of treatment will be assessed by determination of HCV-RNA and the primary efficacy variable is the rate of sustained virological response (after 24 weeks of treatment-free follow-up) in patients without early virological response. Secondary efficacy variables are the rate of sustained biochemical response, the rate of response in function of HCV genotype, viral load and treatment duration. Safety data will also be recorded and analyzed.