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A post-hoc analysis of the phase-3 LATITUDE study assessed the impact of abiraterone acetate plus prednisone (AA+P) on overall survival (OS) and radiographic progression-free survival (rPFS) in men with metastatic castration-sensitive prostate cancer (mCSPC) and visceral metastases (VM).Newly diagnosed mCSPC patients were randomized (1:1) to AA+P and androgen deprivation therapy (ADT) or placebo+ADT. Patients with VM in liver or lungs with or without other soft tissue and bone metastases (based on CT/MRI) at baseline were analyzed, after 51.8 months' median follow-up. Co-primary endpoints, OS and rPFS, were analyzed.Among 1199 patients enrolled, 228 (19%) had VM at baseline (114 each in AA+P and placebo groups), of which 53 (23.2%; AA+P = 29, Placebo = 24) had liver metastases and 117 (51.3%; AA+P = 60, Placebo = 57) had lung metastases. In patients with VM, treatment with AA+P versus placebo showed an improvement in OS (median 55.4 vs 33.0 months; HR = 0.582; 95%CI = 0.406-0.835;P = 0.0029) and rPFS (median 30.7 vs 18.3 months; HR = 0.527; 95%CI = 0.366-0.759;P = 0.0005), comparable to that of patients without VM. AA+P versus placebo in lung metastases patients was associated with greater improvement in OS (HR = 0.60; 95%CI = 0.35-1.04;P = 0.0678) than in liver metastases patients (HR = 0.82; 95%CI = 0.41-1.66;P = 0.5814). AA+P versus placebo showed improvement in rPFS in lung metastases patients (HR = 0.50; 95%CI = 0.29-0.89;P = 0.0157), but not in liver metastases patients (HR = 1.05; 95%CI = 0.53-2.09; P = 0.8970).AA+P treatment improved both rPFS and OS in men with mCSPC and visceral disease, especially those with lung metastases. Men with liver metastases had a poorer prognosis and their optimal treatment remains to be defined.ClinicalTrials.gov, number NCT01715285.

This study was conducted based on a request from the European Medicines Agency to generate robust data on domperidone efficacy in children in the relief of symptoms of nausea and vomiting by assessing the effect of a low-dose and short treatment duration.In this randomized, double-blind, phase 3 study, children ages 6 months to 12 years with acute gastroenteritis randomly (1:1) received oral domperidone 0.25 mg/kg with oral rehydration therapy (ORT) or matching placebo thrice daily for 2 to 7 days. The proportion of patients with no vomiting episodes (primary endpoint) and patients ages ≥4 years with no nausea episodes (key secondary endpoint) within 48 hours of first treatment administration were evaluated.The study was terminated early following futility analysis. At early termination, 292 patients randomly received domperidone (n = 147) or placebo (n = 145). The proportion of patients with no vomiting episodes within 48-hours of first treatment administration was similar between domperidone (32.0%) and placebo groups (33.8%). Similarly, there was no significant difference in proportion of patients ages ≥4 years with no nausea episodes within 48 hours of first treatment administration between domperidone (35.7%) and placebo (38.6%). Total 13 patients (domperidone, 3.4% [5/147] vs placebo, 5.5% [8/145]) reported ≥1 treatment-emergent adverse events. No deaths or adverse events of special interest (extrapyramidal symptoms and QT prolongation) were reported.Low-dose of domperidone with ORT did not significantly differ from placebo in reducing vomiting and nausea episodes in pediatric patients with acute gastroenteritis (AG), and the safety profile was similar between both groups.

Domperidone effects on QTc duration were assessed in a single-center, double-blind, four-way crossover study of 44 healthy participants randomized to one of four treatment sequences consisting of four treatment periods separated by 4–9 days washout. On Day 1 of each 4-day period, participants began oral domperidone 10 or 20 mg q.i.d., matching placebo q.i.d., or single-dose moxifloxacin 400 mg (positive control)/placebo q.i.d. In each period, triplicate 12-lead electrocardiograms were recorded at baseline (30, 20, and 10 minutes predose), 8 timepoints after dosing on Days 1 and 4, and predose on Day 4. In mixed effects models, the largest difference for domperidone in least squares means for change from baseline QTcP versus placebo was 3.4 milliseconds (20 mg q.i.d., Day 4), 90% CI: 1.0–5.9, and

The primary objective was to compare the pharmacokinetics (PK) of rabeprazole granules versus rabeprazole tablets, and assess the effect of food on the PK of rabeprazole granules. Data from three phase 1, open-label, single-dose, randomized, crossover studies in healthy adult participants are presented separately and as a cross-study comparison; study 1: PK of phase 1 rabeprazole granules versus rabeprazole tablets under fasting conditions; study 2: PK of phase 3 rabeprazole granules versus phase 1 rabeprazole granules; study 3: bioequivalence of to-be-marketed rabeprazole granules (sprinkle capsules) versus phase 3 rabeprazole granules; and assessment of the food effect for the to-be-marketed rabeprazole granules. Overall, 123 of 130 participants enrolled completed the studies. The overall plasma exposure as measured by area under the plasma concentration-time curve (AUC) was comparable between rabeprazole granules and tablets; mean peak plasma concentration (Cmax ) was lower for the granules compared with tablets. The plasma elimination half-life was short and independent of formulation. Food intake prior to administration of the to-be-marketed granules delayed the absorption and reduced the estimated parameters for bioavailability by 55% (Cmax ) and 28% (AUCinf ). Rabeprazole was well-tolerated.

Anemia, a common hematological abnormality in HIV, contributes to decreased quality of life (QOL). This study assessed once-every-2-week epoetin alfa on maintaining QOL and hemoglobin (Hb) in anemic HIV-infected patients in a 24-week, open-label, multicenter study. HIV-infected patients (Hbor =12 g/dl) received epoetin alfa 40,000 units subcutaneously once weekly, until reaching Hbor =13 g/dl. Patients then entered a maintenance phase (MP), in which epoetin alfa was administered every other week or at longer intervals. The trial objectives were to determine if QOL, as measured by the Medical Outcomes Study-HIV (MOS-HIV) general health perceptions (GHP) domain and Hb, was maintained. Safety was also assessed. A total of 292 patients were enrolled (72% on HAART). Mean baseline laboratory values were Hb = 10.8 g/dl, CD4(+) count = 280 cells/microl, and HIV RNA = 51,867 copies/ml. In all, 81% of patients reached Hbor =13 g/dl and 92% reached Hbor =12 g/dl. QOL was maintained from the beginning (GHP = 44.2 points) to the end of MP (GHP = 43.4 points) with every other week or longer dosing. Mean Hb at the beginning of MP was 13.4 +/- 0.5 g/dl and was 12.8 +/- 1.4 g/dl at study end. Epoetin alfa was well tolerated; adverse events were consistent with those reported in previous studies of epoetin alfa in HIV-infected patients. Although the clinical approach tested in this study is not consistent with current prescribing recommendations, the results confirm the efficacy of prolonged dosing intervals (every 2-4 weeks) in maintaining optimal Hb levels and QOL in anemic HIV-infected patients.

The natural history of anemia related to interferon/ribavirin (IFN/RBV) treatment in patients with human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection is not completely understood. The current 8-week, multicenter, observational study characterized anemia over the course of HCV treatment in patients with HIV/HCV coinfection. Eligible HIV/HCV coinfected patients were receiving care in community-based and academic institutions and were on stable antiretroviral therapy and initiating IFN/RBV therapy. Hb, sEPO, reticulocytes, transfusions, laboratory values (e.g., total bilirubin), and IFN and RBV dosages were monitored weekly. Ninety-one patients were analyzed (mean age, 46 years; 71% on HAART) and 53 patients completed the study. Mean Hb decreased significantly (5.0 g/dl) within 1 week of initiating IFN/RBV therapy (p = 0.0002); Hb nadir occurred at a median of 37 days. Maximum Hb decreases ofor =2.0 g/dl occurred in 56 (62%) patients andor =3.0 g/dl occurred in 45 (49%) patients. Reticulocyte count increased within the first 2 weeks and sEPO peaked at week 3. Mean increase from baseline to week 2 in reticulocyte count and sEPO, respectively, was 1.3% (n = 74) and 45.0 mIU/ml (n = 80) (p0.0001 for each parameter), and from baseline to week 8 was 0.9% (n = 48) and 41.0 mIU/ml (n = 52) (por = 0.0001 for each parameter). Adverse events (AEs) were the most common reason for study discontinuation (66% of discontinuing patients). Among the 25 patients who discontinued due to AEs, 84% discontinued due to anemia (n = 21). Significant decreases in Hb were observed in HIV/HCV-coinfected patients within 1 week of initiating IFN/RBV therapy. sEPO and reticulocyte increases were blunted in response to anemia; Hb levels did not return to baseline values and anemia was a frequent reason for discontinuing the study.

Despite the availability of highly active antiretroviral therapy and the resulting reduction in severe anemia associated with HIV infection, epoetin alfa has continued to play an important role in the management of HIV-infected patients. Mild-to-moderate anemia remains common, and its correction with epoetin alfa has resulted in significant improvements in quality of life, physical functioning, and possibly prolongation of survival. New research has demonstrated that epoetin alfa may have therapeutic potential beyond its ability to stimulate erythropoiesis due to its neuroprotective and antiapoptotic properties. Current and future research will further clarify the role of epoetin alfa in the clinical management of the HIV-infected population.

This prospective, open-label, multicenter trial evaluated the effects of once-weekly (qw) epoetin alfa on quality of life (QOL) and hemoglobin (Hb) levels in anemic human immunodeficiency virus (HIV)-infected adult receiving antiretroviral therapy. A total of 650 patients with Hbor = 11 g/dl received epoetin alfa 40,000 U qw subcutaneously, with dose escalation to 60,000 qw if Hb increase was1 g/dl after 4 weeks. The linear Analog Scale Assessment (LASA) overall QOL score, LASA energy score, and LASA activity score each significantly improved from baseline to final measurement (p0.0001 for each parameter). Improvements in the Medical Outcomes Study (MOS)-HIV physical and mental health summary scores were also significant (p0.0001), and coincided with Hb increases. Mean Hb increased from baseline to final measurement by 2.5 g/dl (95% CI: 2.3, 2.6 g/dl; p0.0001). Objective hematological response rate, defined as aor = 1 g/dl Hb increase from baseline to week 8, was 86%. Hemoglobin increased significantly in all subgroups of race, zidovudine use, CD4+ cell count, and viral load. Once-weekly epoetin alfa was well tolerated. Once-weekly epoetin alfa is effective in improving QOL and Hb measures.

The purpose of this parallel treatment group, double-blind, multicenter study was to characterize the pharmacokinetics of nevirapine and lamivudine when coadministered to patients with the HIV-1 infection. This pharmacokinetic interaction study was nested within a larger Phase III clinical trial conducted to characterize the safety and efficacy of coadministered nevirapine and lamivudine. One hundred HIV-1 infected patients with CD4+ lymphocyte counts200 cells/mm3and who were on a background of nucleoside (zidovudine [ZDV], didanosine [ddI], zalcitabine [ddC], stavudine [d4T]) therapy were randomly assigned to be treated with either nucleoside + lamivudine + nevirapine or nucleoside + lamivudine + placebo. Each patient underwent blood sampling at defined times for the purpose of determining the concentration of nevirapine in plasma and lamivudine in serum under steady-state conditions. Each patient was also monitored closely for concomitant administration of other drugs, including ZDV, ddI, ddC, d4T and cotrimoxazole. The pharmacokinetics of nevirapine and lamivudine were characterized using nonlinear mixed-effects modeling. There were no reported serious adverse events during the 40-day pharmacokinetic study. The results of the modeling analysis revealed that nevirapine had no effect on the pharmacokinetics of lamivudine. Estimates of the apparent clearance for nevirapine (CL/F = 3.3 L/hour; 95% confidence interval [CI] 2.9 to 3.7 L/hour) and lamivudine (CL/F 27.6 L/hour; 95% CI 22 to 33.2 L/hour) were consistent with the values reported in earlier trials. However, the results also showed that concomitant administration of lamivudine with cotrimoxazole resulted in a 31% reduction in the apparent clearance of lamivudine, resulting in a 43% increase in the average steady-state lamivudine serum concentrations. These results indicate that chronic concurrent administration of cotrimoxazole with lamivudine may significantly affect the steady-state pharmacokinetics of lamivudine.

The primary objective was to compare the pharmacokinetics (PK) of rabeprazole granules versus rabeprazole tablets, and assess the effect of food on the PK of rabeprazole granules. Data from three phase 1, open-label, single-dose, randomized, crossover studies in healthy adult participants are presented separately and as a cross-study comparison; study 1: PK of phase 1 rabeprazole granules versus rabeprazole tablets under fasting conditions; study 2: PK of phase 3 rabeprazole granules versus phase 1 rabeprazole granules; study 3: bioequivalence of to-be-marketed rabeprazole granules (sprinkle capsules) versus phase 3 rabeprazole granules; and assessment of the food effect for the to-be-marketed rabeprazole granules. Overall, 123 of 130 participants enrolled completed the studies. The overall plasma exposure as measured by area under the plasma concentration-time curve (AUC) was comparable between rabeprazole granules and tablets; mean peak plasma concentration (Cmax ) was lower for the granules compared with tablets. The plasma elimination half-life was short and independent of formulation. Food intake prior to administration of the to-be-marketed granules delayed the absorption and reduced the estimated parameters for bioavailability by 55% (Cmax ) and 28% (AUCinf ). Rabeprazole was well-tolerated.

Study Design. Prospective, open-label, randomized, parallel-group study at 80 centers. Objective. To demonstrate there is no clinically impor - tant additional risk for deep vein thrombosis with perioperative use of epoetin alfa versus standard of care in spine surgery without prophylactic anticoagulation. Summary of Background Data. Trials of epoetin alfa in orthopedic surgery that demonstrated no additional risk of thrombovascular events included perioperative pharmacologic anticoagulation. Methods. Subjects received epoe t in alfa 600 U/kg subcutaneously once weekly starting 3 weeks before spinal surgery plus standard of care for blood conservation, or standard of care alone. Perioperative anticoagulation therapy was not permitted; mechanical deep vein thrombosis prophylaxis was allowed. Doppler imaging for deep vein thrombosis was done on postoperative day 4 (or day of discharge), or for suspected deep vein thrombosis. Deep vein thrombosis was diagnosed by Doppler result or adverse event report. The criterion for no additional risk of deep vein thrombosis was a 1-sided 97.5% upper confidence limit ≤4% between groups. Results. Of the 680 subjects analyzed (340 in each treatment group), 16 (4.7%) in the epoetin alfa group and 7 (2.1%) in the standard of care group had a diagnosis of deep vein thrombosis either by Doppler or by adverse event report with normal Doppler. The between-group difference was 2.6% (97.5% upper confidence limit, 5.4%). Deep vein thrombosis confirmed by Doppler (4.1% vs. 2.1%), other clinically relevant thrombovascular events (1.5% vs. 0.9%), and all adverse events combined (76.5% vs. 73.2%) occurred with similar frequency in the 2 treatment groups. Conclusion. This study documented a higher incidence of deep vein thrombosis and similar rates of other clinically relevant thrombovascular events with epoetin alfa versus standard of care for blood conservation in subjects who did not receive prophylactic anticoagulation before spinal surgery. Antithrombotic prophylaxis should be considered when erythropoietin is used in the surgical setting

To describe anemia prevalence and correlates with biomarkers and antiretroviral therapy (ART) in HIV/AIDS.Multicenter, cross-sectional study; clinical laboratory data collected at single visits, including hemoglobin (Hb), CD4+ count, HIV-1 RNA. Patients receiving care at US physician offices during the year 2000. Main outcome measure was anemia (Hb14 g/dL [men];12 g/dL [women]) and marked anemia (Hb11 g/dL [men];10 g/dL [women]) prevalence. Multivariable models examined association of anemia prevalence with HIV-1 biomarkers and ART.Among 9690 patients, prevalence of anemia and marked anemia was 36% and 5%, respectively. Among 1721 patients receiving no ART, 39.7% were anemic; among 7252 receiving highly active antiretroviral therapy (HAART), 35.5% were anemic (p = 0.001). Anemia was most prevalent among men (37.3 vs. 32.3%; p = 0.0008), blacks (49 vs. 26% [whites]; p0.0001), patients with CD4+200 cells/mm(3) (57 vs. 23% [or = 500 CD4+]; p0.00001), and HIV-1 RNA30 000 copies/ml (53 vs. 30% [500 copies/ml]; p0.00001). Marked anemia was more common in women (6.8 vs. 4.3%; p0.0001). Among treated patients, logistic regression analysis controlling for CD4+, HIV-1 RNA, sex, and ethnicity, zidovudine (ZDV)-containing regimens (except combination with saquinavir/ZDV/lamivudine) were associated with increased overall anemia risk (odds ratio, 1.39 : 1.74). No regimen was associated with increased risk for marked anemia. Multivariable logistic regression showed CD4+, sex, and ethnicity more strongly associated with anemia than any ART regimen.This large, single-visit, cross-sectional, US-based study shows that anemia remains highly prevalent in HIV-infected patients. Data from this analysis suggest low CD4+ count, black ethnicity, and male sex are consistently strongest correlates of overall anemia; women are significantly more likely to have marked anemia.

In hepatitis C virus (HCV)-infected patients receiving pegylated interferon (PEG-IFN)/ribavirin (RBV) combination therapy, anemia is a well-known side effect. The purpose of this study was to describe the time course and extent of hemoglobin (Hb) changes and the erythropoietic response to PEG-IFN/RBV-induced anemia.In this multicenter, observational, 8-wk study, laboratory parameters were measured weekly for 8 wk or until early withdrawal. Primary endpoints included changes in Hb and serum erythropoietin (sEPO) from baseline to week 8; other measures were changes in reticulocytes and RBV dose. The predictive value of baseline factors for maximum Hb decline was assessed.In the 97 evaluable patients, mean Hb decreased from 14.4 +/- 1.4 g/dl (baseline) to 11.9 +/- 1.3 g/dl (week 8). Twenty-one percent of patients withdrew before week 8. The estimated erythropoietic response was lower than that seen in two historic control populations of iron deficiency anemia patients. Mean RBV dose decreased from 986 +/- 190 mg/day (baseline) to 913 +/- 228 mg/day (week 8). Fifty-seven out of 77 (74%) patients who completed the study maintained their initial prescribed RBV dose. Patients maintained on the initial dose of RBV who had a higher baseline Hb and viral load showed a trend toward larger Hb declines. Platelets and white blood cells (WBCs) also declined during the study.HCV-infected patients receiving PEG-IFN/RBV therapy have reductions in Hb, platelets, and WBCs, possibly due to bone marrow suppression. They also have diminished endogenous sEPO production for their degree of anemia.

Anemia and decreased health-related quality of life (HRQL) are common in patients receiving combination therapy of interferon alfa (IFN) and ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. In a randomized, prospective study evaluating the effectiveness of epoetin alfa in maintaining RBV dose, alleviating anemia, and improving HRQL in anemic (Hb ≤ 12 g/dL) HCV-infected patients receiving combination therapy, patients receiving epoetin alfa had significant improvements in HRQL compared with placebo. In this study, 185 patients were randomized to 40,000 units of epoetin alfa subcutaneously weekly or placebo for an 8-week double-blind phase (DBP), followed by an 8-week open-label phase during which all patients received epoetin alfa. To further assess the impact of epoetin alfa on HRQL, post hoc analyses were conducted in the same patient population to compare the HRQL of these patients at randomization with norms of other populations, and to determine the critical relationship between hemoglobin (Hb) levels and HRQL. Mean HRQL scores of anemic HCV-infected patients receiving combination therapy at randomization were significantly lower than those of both the general population and patients who had other chronic conditions. Patients receiving epoetin alfa who had the greatest Hb increases from randomization to the end of the DBP also had the largest improvements in HRQL. Hb improvement was an independent predictor of HRQL improvement in these patients. In conclusion, epoetin alfa provided clinically significant HRQL improvement in HCV-infected patients receiving IFN/RBV therapy. (HEPATOLOGY 2004;40:1450–1458.)

The prevalence of anemia in HIV-infected persons has not been well characterized in the HAART era. In a single-center, retrospective study, anemia prevalence and risk factors, including use of HAART, were assessed in an ambulatory clinical cohort of 758 HIV-infected patients for the calendar year 2000. The relationships between anemia (hemoglobin level less than 12.5 g/dL) and demographic variables, antiretroviral treatment regimens, and disease markers were analyzed. Mean baseline patient characteristics were hemoglobin level, 13.7 +/- 1.9 g/dL; CD4+ cell count, 405 +/- 293/microL; and HIV RNA level, 77,841 +/- 148,394 copies/mL. Overall anemia prevalence was 30.3%. Multivariate logistic regression analysis demonstrated that anemia was associated with a CD4+ cell count below 50/microL, female sex, black race, a viral load above 100,000 copies/mL, zidovudine use, and older age. Severe anemia was less prevalent in this study population than in historical comparators; however, mild to moderate anemia rates remain high.

Interferons are naturally occurring proteins and share antiviral, immunomodulatory, and antiproliferative properties. They can be subdivided into 2 classes according to their acid stability. The first class which is acid-proof consists of 3 families; alpha, beta, and omega. The second class consists of interferon gamma which is not acid-proof (Table 1). Since the discovery and naming of Interferon by Isaacs and Lindenmann in 1957, Boehringer Ingelheim has for three decades now been a part of the world-wide interferon research, involving virology, immunology, cell biology, molecular genetics, biotechnological production, as well as experimental and clinical oncology. In the last few years, interferons have come of age and have found a respectable position among the most prominent new drugs.

Publisher Summary This chapter discusses the classification, pharmacology, clinical efficacy, and clinical toxicity of interferon (IF)- α and γ . Interferons can be subdivided into two classes according to their acid stability. The first class, which is acid-proof, consists of three families, namely, α , β , and ω . The second class consists of interferon- γ , which is not acid-proof interferon- γ , is predominantly produced by leukocytes, B cells, T cells, null cells, and macrophages following exposure to B cell mitogens, viruses, foreign cells, or tumor cells. Interferon- β is predominantly produced by fibroblasts following exposure to viruses or foreign nucleic acids. Interferon- ω is produced by lymphocytes after exposure to viruses, and interferon- γ is produced by T lymphocytes following stimulation with T cell mitogens, specific antigens, or interleukin-2. The use of interferon- α in the treatment of malignant hematological diseases and solid tumors is now well established in clinical practice. Adverse effects of interferon- α can be major obstacles to its clinical use. Particularly in early trials, the high dosage levels were associated with severe clinical toxicities in a typical pattern of early and late adverse effects. Several phase I studies and open studies with interferon- α -2c in patients suffering from advanced malignancies have identified a maximum tolerated dose of 32.5 × 10 6 U/day i.m.