Pancreatitis in tigecycline Phase 3 and 4 clinical studies.

OBJECTIVES: To examine the incidence of pancreatitis among subjects enrolled in the tigecycline clinical trial programme, summarize cases and examine concomitant use of other pancreatitis-causing medications. METHODS: Subject data from Phase 3 and 4 comparative tigecycline studies were included in the analysis; investigator-reported adverse events of 'pancreatitis', 'necrotizing pancreatitis' or 'pancreas disorder' were reviewed. Data were summarized and cases were reported. No statistical comparisons were made. The incidence of overall pancreatitis with 95% CIs was calculated. The Wilson score method was used to calculate CIs. RESULTS: Nineteen subjects with investigator-determined pancreatitis were identified from the programme database, which included 3788 subjects treated with tigecycline and 3646 subjects treated with a comparator. There were 9 cases identified among the tigecycline-treated subjects [9 of 3788 (0.24%; 95% CI, 0.11-0.45)] and 10 cases among the comparator-treated subjects [10 of 3646 (0.27%; 95% CI, 0.13-0.50)]. The demographic characteristics of the subjects with pancreatitis were similar between treatment groups. The median duration of tigecycline therapy was 8.0 days compared with 11.0 days of comparator treatment. Concomitant or prior exposure to a Badalov class I medication was evident in the majority of subjects who developed pancreatitis. A numerically higher number of tigecycline-treated subjects were exposed to furosemide prior to the onset of pancreatitis than comparator-treated subjects. CONCLUSIONS: Pancreatitis was uncommon in subjects treated with tigecycline, with an occurrence of <1%. Concomitant medications known to cause pancreatitis should be considered when prescribing tigecycline, but may not identify those at risk of developing pancreatitis.

Long-term evaluation of analytical methods used in sirolimus therapeutic drug monitoring.

Results of therapeutic monitoring of sirolimus blood concentrations are assay and laboratory dependent. This study compared performance over time of the IMx microparticle enzyme immunoassay (MEIA), Architect chemiluminescent microparticle immunoassay (CMIA), and liquid chromatography with mass spectrometric detection (LC/MS/MS) as part of a proficiency testing scheme. Pooled samples from sirolimus-treated patients and whole-blood samples spiked with known quantities of sirolimus were assayed monthly between 2004 and 2012. When results of pooled patient samples were compared with LC/MS/MS, the MEIA assay showed an overall mean percent bias of -2.3% ± 11.2% that, although initially positive, became increasingly negative from 2007 through 2009. The CMIA, which replaced the MEIA assay, had a mean percent bias of 21.9% ± 12.3%, remaining stable from 2007 through 2012. Similarly, for spiked samples, the MEIA showed an increasingly negative bias over time vs. LC/MS/MS, whereas CMIA maintained a stable positive bias. Based on comparison of immunoassay measurements on individual patient samples, CMIA values were more than 25% higher than MEIA values. These results highlight the importance of continued proficiency testing and regular monitoring of sirolimus assay performance. Clinicians must be aware of the methodology used and adjust target levels accordingly to avoid potential effects on efficacy and toxicity.

Tigecycline does not prolong corrected QT intervals in healthy subjects.

We evaluated the effect of tigecycline (50-mg and 200-mg doses) on corrected QT (QTc) intervals and assessed safety and tolerability in a randomized, placebo-controlled, four-period crossover study of 48 (44 male) healthy volunteers aged 22 to 53 years. Fed subjects received tigecycline (50 mg or 200 mg) or placebo in a blinded fashion or an open-label oral dose of moxifloxacin (400 mg) after 1 liter of intravenous fluid. Serial electrocardiograms were recorded before, and for 96 h after, dosing. Blood samples for tigecycline pharmacokinetics were collected after each recording. QTc intervals were corrected using Fridericia's correction (QTcF). Pharmacokinetic parameters were calculated using noncompartmental methods with potential relationships examined using linear mixed-effects modeling. Adverse events were recorded. The upper limits of the 90% confidence interval for the mean difference between both tigecycline doses and placebo for all time-matched QTcF interval changes from baseline were <5 ms. The tigecycline concentrations initially declined rapidly and then more slowly. In the group given 50 mg of tigecycline, the pharmacokinetic parameters and means were as follows: maximum concentration of drug in serum (C(max)), 432 ng/ml; area under the concentration-time curve from time zero extrapolated to infinity (AUC0-∞), 2,366 ng · h/ml; clearance (CL), 21.1 liters/h; volume of distribution at steady state (V(ss)), 610 liters; and terminal half-life (t(1/2)), 22.1 h. Proportional or similar values were found for the group given 200 mg of tigecycline. Linear mixed-effects modeling failed to show an effect on QTcF values by tigecycline concentrations (P = 0.755). Tigecycline does not prolong the QTc interval in healthy subjects. This study has been registered at ClinicalTrials.gov under registration no. NCT01287793.

Regulatory Framework for Drug Development in Rare Diseases.

Drug development is a highly regulated industry. Therapeutic options for rare diseases must meet the same high standards for the demonstration of safety and efficacy as do those for more common diseases. The approval of the Orphan Drug Act in 1983 has resulted in many more resources for preclinical research, the standardization of patient registries, and the use of real-world data, among other measures, that, along with the advances in drug development, has resulted in the approval of therapies for some of the most unusual diseases. Increased attention to the diagnosis and treatment of rare diseases has also accelerated the development of gene therapies that may offer significant amelioration and even cures for such diseases in the near future. Rare diseases disproportionately affect children, with severe and debilitating effects. Few effective treatments are available for most rare diseases. To avoid the unnecessary waste of data collected in studies of these patients, and to promote efficient drug development, there is a growing collaboration among patient communities, investigators, clinicians, sponsors, and regulatory authorities. All interested parties are working together to identify the most appropriate research questions and move quickly to make available safe and effective treatments. This article is a survey of the most commonly used regulatory remedies that have been put in place to serve as a framework for drug development in rare diseases.

Excretion of moxidectin into breast milk and pharmacokinetics in healthy lactating women.

Moxidectin, registered worldwide as a veterinary antiparasitic agent, is currently under development for humans for the treatment of onchocerciasis in collaboration with the World Health Organization. The objective of this study was to assess the pharmacokinetics of moxidectin in healthy lactating women, including the excretion into breast milk. Twelve women, ages 23 to 38 years, weighing 54 to 79 kg, all more than 5 months postpartum, were enrolled, following their plan to wean their infants and provision of informed consent. A single 8-mg, open-label dose was administered orally after consumption of a standard breakfast. Complete milk collection was done for approximately 28 days, and plasma samples were collected for 90 days. Moxidectin concentrations were measured by high-performance liquid chromatography (HPLC) with fluorescence detection, with a validated range of 0.08 to 120 ng/ml. Noncompartmental pharmacokinetic methods were used to find the following results: peak concentration in plasma (C(max)), 87 ± 25 ng/ml; time to C(max) (t(max)), 4.18 ± 1.59 h; terminal-phase elimination half-life (t(1/2)), 832 ± 321 h; total area under the concentration-time curve (AUC), 4,046 ± 1,796 ng · h/ml; apparent oral dose clearance (CL/F), 2.35 ± 1.07 l/h; ratio of CL/F to the terminal-phase disposition rate constant, λ(z) (Vλ(z)/F), 2,526 ± 772 liters; percentage of maternal dose excreted in milk, 0.701 ± 0.299%; absolute amount excreted in milk, 0.056 ± 0.024 mg; relative infant dose, 8.73 ± 3.17% of maternal dose assuming complete absorption; clearance in milk (CL(milk)), 0.016 ± 0.009 liter/h. Nine of 12 subjects reported adverse events, all of which were considered treatment emergent but not drug related and were mostly reported during the long outpatient period 8 to 90 days after dose administration. The most frequently reported adverse events were headache and nausea (n = 4), oropharyngeal pain (n = 2), rhinitis, viral pharyngitis, and viral upper respiratory tract infection (n = 2).

First open-label, single-arm, prospective study of real-world use of FIX replacement therapy in a predominantly pediatric hemophilia B population in China.

BACKGROUND: Nonacog alfa (recombinant factor IX [FIX]) is approved in China for the control and prevention of bleeding events in patients with hemophilia B. This was the first study to assess prophylaxis and on-demand therapy with recombinant FIX replacement in a real-world setting in China. This study aimed to evaluate the safety and efficacy of nonacog alfa in Chinese patients with hemophilia B. METHODS: In this open-label, multicenter study (clinicaltrials.gov identifier NCT02336178), patients received on-demand or prophylactic treatment with intravenous nonacog alfa for approximately 6 months or 50 exposure days, whichever occurred first. The primary safety outcome was medically important events (i.e., development of FIX inhibitors, allergic reactions, and thrombotic events). Key secondary efficacy outcomes included the annualized bleeding rate for on-demand treatment and prophylaxis, response to on-demand treatment, the number of infusions per bleeding event, and the number of breakthrough bleeding events within 48 hours of prophylaxis. RESULTS: Seventy male patients (mean [standard deviation] age 7.8 [7.2] years) were enrolled (on-demand, n = 37; prophylaxis, n = 57 [24 patients were included in both groups]). Thirty-eight (54%) patients had up to 50 FIX exposure days before the study. The only medically important event was a transient low-titer FIX inhibitor (incidence 1.4%, 95% confidence interval, 0-7.7). The mean annualized bleeding rate was 26.3 for on-demand treatment and 6.5 for prophylaxis. A mean (standard deviation) of 1.5 (1.7) nonacog alfa infusions were given per bleeding episode; 78.8% of episodes resolved with 1 infusion. Response was "excellent" or "good" for 88% of the on-demand infusions. Twenty-three bleeding events (n = 11 patients) occurred within 48 hours of 2032 prophylaxis doses (1.13%). CONCLUSION: In the real-world setting, nonacog alfa is safe and effective for on-demand treatment and for prophylaxis for patients with hemophilia B in China.

Effect of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intravenous Rivipansel.

Two studies evaluated the effects of renal and hepatic impairment on pharmacokinetics and safety of rivipansel (NCT02813798, NCT02871570). A single intravenous 840-mg rivipansel dose was administered to subjects with renal impairment or normal renal function in study 1005 and subjects with moderate hepatic impairment or normal hepatic function in study 1006. Plasma (both studies) and urine (study 1005) samples were collected for 96 hours postdose. All subjects in studies 1005 (n = 28) and 1006 (n = 16) completed all study procedures. Rivipansel exposure (AUCinf ) was 47%, 124%, and 437% higher and total clearance 30%, 57%, and 82% lower in the mild, moderate, and severe renal impairment groups, respectively, than in the normal renal function group. Overall rivipansel exposure was 20% lower and total clearance 31% higher in the moderate hepatic impairment group than in the normal hepatic function group. Ten treatment-emergent adverse events occurred in studies 1005 and 1006; no event was considered treatment related. As expected, clearance of rivipansel decreased with increasing renal impairment. The difference observed between rivipansel pharmacokinetics in subjects with moderate hepatic impairment and subjects with normal hepatic function was not considered clinically significant. Single doses of rivipansel were well tolerated in subjects with either renal or hepatic impairment.

Safety and Efficacy of Moroctocog Alfa (AF-CC) in Chinese Patients with Hemophilia A: Results of Two Open-Label Studies.

INTRODUCTION: Moroctocog alfa albumin-free cell culture (AF-CC) increases plasma levels of factor VIII (FVIII) activity and, in China, is indicated for the control and prevention of bleeding episodes in patients with hemophilia A. This study aimed to evaluate the efficacy, safety, and recovery data of moroctocog alfa (AF-CC) in patients with hemophilia participating in two open-label studies, both conducted in China. METHODS: The authorization study (clinicaltrials.gov identifier NCT00868530) enrolled patients aged ≥6 years, previously treated with ≥1 exposure day of FVIII replacement therapy. The real-world study (clinicaltrials.gov identifier NCT02492984) enrolled patients of any age who were previously untreated or requiring surgical prophylaxis. In both studies, on-demand treatment was administered over 6 months. Key assessments included response to treatment, FVIII inhibitor development, and recovery. RESULTS: In the authorization study (N = 53; mean age, 23.2 years; severe hemophilia, 23%), response was excellent/good for 90% of infusions at 24 hours. Seven patients developed inhibitors. Mean (SD) FVIII recovery at the initial and final visits was 1.77 (0.50) and 1.67 (0.45) (IU/dL)/(IU/kg), respectively. In the real-world study (N = 85; mean age, 9.5 years; severe hemophilia, 58%), response was rated as excellent or good for most (87%) on-demand infusions and for all surgical prophylaxis patients (n = 14). Seven patients developed FVIII inhibitors. Mean (SD) FVIII recovery at the initial and final visits was 1.71 (0.50) and 1.68 (0.31) (IU/dL)/(IU/kg), respectively. No new safety signals were observed in either study. CONCLUSION: On-demand treatment and surgical prophylaxis with moroctocog alfa (AF-CC) is safe and effective for both previously treated and previously untreated Chinese patients with hemophilia A.

Safety and Efficacy of Tigecycline to Treat Multidrug-resistant Infections in Pediatrics: An Evidence Synthesis.

BACKGROUND: The need for antimicrobial therapies effective against multidrug resistant organisms for children remains unmet. Tigecycline shows antibacterial activity across a broad spectrum of bacteria and is approved for treating complicated skin and skin-structure infections, complicated intra-abdominal infections and, in the United States, community-acquired bacterial pneumonia for adult patients. No blinded, randomized phase 3 tigecycline clinical trials on neonates or children have been completed or planned. This review aimed to provide a comprehensive synthesis of all the existing data sources, both on-label and off-label, for tigecycline use in children. METHODS: Data on tigecycline use in children were identified from published and unpublished sources including clinical trials, expanded access and compassionate use programs, databases of healthcare records and patient safety monitoring. RESULTS: Pharmacokinetic simulations predicted that tigecycline 1.2 mg/kg (maximum dose 50 mg) every 12 hours (q12h) in children 8-11 years and 50 mg q12h in children 12 to <18 years would achieve exposure similar to adults receiving 50 mg q12h. Available phase 2 pediatric clinical trial data and data from other sources demonstrated similar clinical efficacy between adult and pediatric patients treated with tigecycline. These data showed no new or unexpected safety concerns with tigecycline in children. CONCLUSIONS: Information presented here may help guide the appropriate use of tigecycline in children with multidrug resistant infections. Continued pharmacovigilance from real-world observational studies may also further refine appropriate use of tigecycline.

The Education of Prescribers for Safe and Effective Use of Medications.

The transformation of medical education, with the disappearance of sequential lectures in pharmacology, clinical pharmacology, and therapeutics, has left gaps in skills needed for new physicians and other prescribers to safely incorporate medications into clinical practice. Brinkman et al. conducted a Delphi study of European Union (EU) medical school educators and practitioners to identify core competencies needed to prescribe medications. Their findings offer directions for learned societies, such as ASCPT, to enhance pharmacology education and practice.

The Path to Perfect Pediatric Posology - Drug Development in Pediatrics.

Reluctance to enroll pediatric subjects in clinical trials has left gaps in information about dosing, safety, and efficacy of medications. Pharmacotherapeutic information for pediatric patients may be available for only a small range of ages and may be deficient, as children respond differently as they grow and mature from prematurity to adolescence. Current regulations, however, require early planning for the participation of children in drug development, as pediatric plans must be submitted at the end of phase 1 (European Union) or the end of phase 2 (United States). These plans are extensive, outlining planned studies, subjects to be enrolled, dose and dosage form justification, planned observations, and statistical analysis as well as planned modeling, simulation, and extrapolation analyses. The extent to which efficacy information in adults can be extrapolated to children depends on how similar the disease is in adults and each of the 5 pediatric age groups. Extrapolation may not be possible for conditions that do not occur in adults, requiring a complete development plan in adults, or extrapolation may be complete because of similar pathology and response to treatment. Pharmacokinetic and safety information cannot be extrapolated and must be collected in children of all ages, unless a waiver is granted. Physiologically based pharmacokinetic modeling, optimal design, population pharmacokinetics, and scavenged samples are all examples of new methodologies being used to study pediatric therapeutics. Clinicaltrials.gov and EU Clinical Trials registry are good sources of results of pediatric trials, although sponsors are also working toward prompt publication of study results in peer-reviewed journals.

Thrombogenicity evaluation in 221 patients with haemophilia B treated with nonacog alfa.

: Risk for thrombotic events with factor IX replacement therapy in patients with haemophilia B remains a concern for patients, those who treat them, and regulatory agencies, based on experience with early use of prothrombin complex concentrates. The current post hoc analysis assessed the incidence of thrombotic events and changes in prothrombin fragment 1 + 2, thrombin-antithrombin complex, and D-dimer in 221 patients with haemophilia B who received nonacog alfa in clinical studies. Thrombotic event and coagulation marker data were collected from 8 interventional studies utilizing on-demand, prophylactic, and preventive regimens in patients with haemophilia B. Mean age was 25 years (min-max, 0-69), with 51 (23%) patients aged less than 12 years and 15 (7%) aged less than 2 years. None tested positive for inhibitors. Mean time on study was 60.9 ±â€Š32 weeks and mean number of exposure days was 69.3 (min-max, 1-496). Sixty-nine (31%) patients regularly received infusions that were approximately 100 IU/kg as part of a routine prophylaxis regimen, and 29 (13%) patients underwent surgical procedures. No clinical thrombotic events were reported, and no patient experienced clinically significant changes in coagulation markers between baseline and end-of-study testing. These collective data support the low thrombotic risk associated with nonacog alfa in paediatric, adult, and surgical patients with haemophilia B receiving different treatment regimens, including doses of approximately 100 IU/kg. Although careful thrombotic clinical evaluation is important, regular coagulation marker monitoring does not appear to be warranted in patients with haemophilia B.

Optimising piperacillin/tazobactam dosing in paediatrics.

Piperacillin/tazobactam, an intravenous antibacterial combination product, has recently been approved for paediatric (age 2 months to 17 years) use in the USA. The purpose of this analysis is to describe the basis for the dosing recommendations in this age group. Pharmacokinetic (PK) parameters and demographic covariates from 53 children enrolled in two paediatric studies were used in the analysis. Individual drug clearance (CL) values calculated by non-compartmental methods were available. The influence of demographic covariates on CL was investigated by non-linear regression. The analysis identified CL to be dependent on body weight. CL was also found to be influenced by age in paediatric patientsor=9 months, a dose of 100/12.5 mg/kg every 8h showed exposures similar to adults; for paediatric patients aged 2-9 months, the dose of 100/12.5 mg/kg should be reduced by a factor of 0.8 (i.e. 80/10 mg/kg), likely due to immature renal function. Based upon this analysis, dosing recommendations for paediatric patients down to 2 months of age were incorporated in the labelling. No data were available to allow additional recommendations for paediatric patients<2 months of age to be made.

Core Entrustable Professional Activities in Clinical Pharmacology for Entering Residency: Biologics.

Biologicals are a rapidly expanding class of medications used in the treatment of many different conditions. This article reviews the common characteristics of this class and the requirements for safe and effective use in patients. Several vignettes are included to illustrate common challenges.

Lack of Effect of Rivipansel on QTc Interval in Healthy Adult African American Male Subjects.

Rivipansel is a pan-selectin inhibitor in phase 3 development for the treatment of vaso-occlusive crises in patients with sickle cell disease. This single-dose, randomized, 3-period, 3-treatment (400 mg moxifloxacin open-label, 4 g rivipansel-blinded, and placebo-blinded) crossover study evaluated the effect of rivipansel on the QT/QTc interval in 48 healthy male African American subjects (age, 21-53 years; weight, 60-115 kg). Time-matched, placebo-adjusted change from baseline QT interval using Fridericia's correction method (QTcF) was determined using a repeated-measures mixed-effects model. The highest upper bound of the 2-sided 90% confidence interval (CI) for QTcF change was 3.22 milliseconds 3 hours postdose. Moxifloxacin showed the anticipated QTcF effect, indicating that the study had adequate sensitivity to detect changes in the QTcF interval. The study concluded that no QTcF effect was demonstrated with rivipansel compared with placebo, as the upper bound of the 2-sided 90%CI was less than 10 milliseconds at all times. Exposure-response modeling for rivipansel concentrations and change from baseline in QTcF data corroborated a lack of effect with rivipansel compared with placebo. Single doses of rivipansel 4 g by intravenous infusion over 20 minutes were well tolerated in this study.

An Open-label, Single-dose, Pharmacokinetic Study of Factor VIII Activity After Administration of Moroctocog Alfa (AF-CC) in Male Chinese Patients With Hemophilia A.

PURPOSE: Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. METHODS: This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C <1%) and a history of at least 150 exposure-days to any FVIII-containing product. Eligible patients received a single dose of moroctocog alfa (AF-CC) 50 IU/kg IV within 10 minutes. Blood samples were collected within 2 hours before administration and through 72 hours after dosing. FINDINGS: Pharmacokinetic parameters were assessed based on FVIII:C and were analyzed by age groups: ages 6 to <12 years (n = 3) and ≥12 years (n = 10). The mean plasma concentration-time profile for FVIII:C activity was consistently lower in patients aged 6 to <12 years compared with those aged ≥12 years. Geometric AUC0-∞ and Cmax were approximately 57% and 28% lower in the younger patients relative to the older patients, respectively. A total of 4 adverse events occurred in 4 patients. Low-titer, transient FVIII inhibitors were observed in 2 patients and were considered serious adverse events. Neither case resulted in clinical manifestations nor required treatment. IMPLICATIONS: This is the first report of the pharmacokinetic parameters of FVIII:C after moroctocog alfa (AF-CC) in an all-Chinese population of males with hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported with recombinant FVIII products in studies with a predominantly white population; younger patients had reduced exposure to FVIII:C. The single doses of moroctocog alfa (AF-CC) were well tolerated; 2 cases of transient, low-titer FVIII inhibitor development were observed. ClinicalTrials.gov identifier: NCT02461992.

Confirmation of longer FIX activity half-life with prolonged sample collection after single doses of nonacog alfa in patients with haemophilia B.

A multicentre, single-dose study enrolled 12 previously treated patients with moderately severe to severe (factor IX [FIX] levels ≤2 IU/dl) haemophilia B to assess FIX pharmacokinetics after nonacog alfa administration and to evaluate the impact of length of sampling time on half-life (t½). After refraining from FIX replacement for four days, patients received 50 IU/kg as an intravenous (IV) infusion over 10 minutes. Blood samples were collected predose and 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72, and 96 h post dose. Tolerability and safety were assessed by monitoring adverse events and were subsequently summary tabulated. FIX activity was measured by a one-stage clotting assay with a lower limit of quantification of 0.010 IU/ml, and inhibitors to FIX were measured using the Bethesda assay. Pharmacokinetic parameters were calculated by noncompartmental analysis and were descriptively summarised. Half-life estimates were calculated first using all available data, then excluding 96-h observations (truncated at 72 h) and, finally, excluding both 72- and 96-h observations (truncated at 50 h). No patient was positive for FIX inhibitors. No treatment-emergent adverse events were reported. Prolonging the duration of the sample collection to 96 h resulted in a terminal t½ estimate of 39.6 ±7.4 h in the eight patients aged 18 years and older, which was longer than the estimates obtained using shorter periods of observation: 29.6 ± 5.5 h (truncated at 72 h) and 27.2 ± 7.0 h (truncated at 50 h). To accurately assess an adult patient's t½, sampling should be continued for at least 96 h.

The comparability of etanercept pharmacokinetics in healthy Japanese and American subjects.

Thirty Japanese (J) and 32 American (A) healthy subjects received single doses of etanercept by subcutaneous injection, in 3 separate trials. Serum samples were collected for 480 hours after dosing. Concentrations were determined using enzyme-linked immunosorbent assay methods. Pharmacokinetic parameters were calculated using both non-compartmental and compartmental methods. Etanercept was slowly absorbed, with mean+/-SD time to maximum serum concentration of 47+/-15 hours (J), and 51+/-20 hours (A). The maximum serum concentration and area under the concentration time curve increased for doses 10 mg, 25 mg, and 50 mg, in a linear relationship. Etanercept was slowly eliminated, with observed mean+/-SD half-life of 80+/-25 hours (J) and 75+/-15 hours (A) and mean+/-SD apparent clearance of 144+/-65 mL/h (J) and 132+/-74 mL/h (A). Very low concentrations of etanercept were observed in the urine samples collected in the Japanese subjects. All adverse reactions observed resolved without issue, and none required discontinuation from the study.

Pharmacokinetics, Efficacy, and Safety of Nonacog Alfa in Previously Treated Patients with Moderately Severe to Severe Hemophilia B.

PURPOSE: Nonacog alfa, a recombinant factor IX (FIX) product, is used for FIX replacement in the treatment and prevention of bleeding events in patients with hemophilia B. This study aimed to provide supplemental pharmacokinetic (PK), efficacy, and safety data for nonacog alfa when administered as part of usual hemophilia care, including on-demand treatment, routine prophylaxis, and surgical prophylaxis. METHODS: Men with previously treated severe or moderately severe hemophilia B (FIX activity ≤2%) were enrolled in this prospective, open-label, nonrandomized, multicenter study. An initial 72-hour PK assessment was performed wherein patients received a single dose of nonacog alfa (75 IU/kg) as an infusion over 10 minutes. A final 72-hour PK assessment was performed at the patient's last visit, after a minimum washout period of 4 days. Correlations between Cmax after the first dose and body weight and body mass index (BMI) were assessed post hoc using Spearman test after evaluating normality. FINDINGS: In total, 23 patients (age, 12-59 years; weight, 44-173 kg; and BMI, 16.3-45.1) with previous exposure to FIX products (median, 460 days; range, 150-2400 days) were enrolled; 21 were evaluable for efficacy. The median number of exposure days per efficacy-evaluable patient in this study was 48 (range, 31-103). The FIX activity profiles showed multiphasic disposition characteristics, with initial mean (SD) PK profiles as follows: Cmax, 61.4 (12.5) IU/dL; AUC∞, 1055 (227) IU·h/dL; t½, 23.7 (5.6) hours; and recovery, 0.818 (0.167) IU/dL. Mean plasma FIX activity versus time profiles were essentially identical upon initial exposure and after repeated use (n = 17), and bioequivalence was confirmed. No apparent relationship was observed between Cmax and either body weight (P > 0.1732) or BMI (P > 0.1235). IMPLICATIONS: The FIX activity profile after administration of nonacog alfa is predictable and is not altered after repeated exposure during usual hemophilia care. PK parameters are consistent with nonacog alfa use for FIX replacement in on-demand treatment, routine prophylaxis, and surgical prophylaxis in patients with hemophilia B.

Prospective surveillance study of haemophilia A patients switching from moroctocog alfa or other factor VIII products to moroctocog alfa albumin-free cell culture (AF-CC) in usual care settings.

This prospective, open-label, postauthorisation safety surveillance study assessed clinically significant inhibitor development in patients with severe haemophilia A transitioning from moroctocog alfa or other factor VIII (FVIII) replacement products to reformulated moroctocog alfa (AF-CC). Males aged ≥ 12 years with severe haemophilia A (FVIII:C) < 1 IU/dl), > 150 exposure days (EDs) to recombinant or plasma-derived FVIII products, and no detectable inhibitor at screening were enrolled. Primary end point was the incidence of clinically significant FVIII inhibitor development. Secondary end points included annualised bleeding rate (ABR), less-than-expected therapeutic effect (LETE), and FVIII recovery. Patients were assigned to one of two cohorts based on whether they were transitioning to moroctocog alfa (AF-CC) from moroctocog alfa (cohort 1; n=146) or from another recombinant or plasma-derived FVIII product (cohort 2; n=62). Mean number of EDs on study was 94 (range, 1-139). Six positive FVIII inhibitor results, as determined by local laboratories, were reported in four patients; none were confirmed by a central laboratory, no inhibitor-related clinical manifestations were reported, and all anti-FVIII antibody assays were negative. Median ABRs were 23.4 and 3.4 in patients categorised at baseline as following on-demand and prophylactic regimens, respectively; 86.5% of bleeding episodes resolved after one infusion. LETE incidence was 0.06% and 0.19% in the on-demand and prophylaxis settings, respectively. FVIII recovery remained constant throughout the study. No new safety concerns were identified. This study found no increased risk of clinically significant FVIII inhibitor development in patients transitioning from moroctocog alfa or other FVIII replacement products to moroctocog alfa (AF-CC).