Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial.

BACKGROUND AND OBJECTIVES: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants' treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10-60 µg once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40-52 in the intent-to-treat population. RESULTS: Of 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40-52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, -0.1 to 0.2 g/dl) was greater than the noninferiority criterion of -1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0-12.0 g/dl) during weeks 40-52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (-37%; 95% CI, -49 to -23) than with darbepoetin alfa (-20%; 95% CI, -36 to -1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa. CONCLUSIONS: Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40-52 in Japanese patients receiving hemodialysis switched from ESAs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: 201754, Clinicaltrials.gov, NCT02969655.

Effects of Daprodustat, a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Anemia Management in Japanese Hemodialysis Subjects.

BACKGROUND: Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients with anemia has not been previously investigated. METHODS: We evaluated the relationship between daprodustat dose and hemoglobin response in Japanese patients on hemodialysis (HD) with anemia in a 4-week, phase II, double-blind, placebo-controlled study. After interrupting their erythropoiesis-stimulating agent for between 2 and 8 weeks, subjects with hemoglobin 8.5-10.5 g/dL were randomized to placebo or daprodustat 4, 6, 8, or 10 mg orally once daily. Hemoglobin, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) levels during therapy were evaluated. RESULTS: Eighty-six of 97 randomized subjects completed the study. Mean baseline hemoglobin ranged from 9.68 to 9.92 g/dL across groups. After 4-week administration, mean hemoglobin changes were -0.28, -0.01, 0.54, and 0.97 g/dL in the 4, 6, 8, and 10 mg groups, respectively, as compared to -1.41 g/dL for placebo. Dose-dependent increase in plasma EPO concentration were observed up to 8 mg, with the 10 mg dose responses being similar to 8 mg. Plasma VEGF concentrations were minimally changed, even though 5 subjects treated with 6-10 mg reached EPO >500 mIU/mL. CONCLUSION: Daprodustat 4-10 mg once-daily produced dose-dependent increase in hemoglobin relative to placebo in Japanese HD subjects. The doses evaluated in the study have moderately increased endogenous EPO without changes in circulating VEGF levels.

Cement Anchors With Screw Holes For Liner Cementation Into Cementless Acetabular Metal Shells.

This mechanical study was conducted with the shellcement interface in order to construct an acetabular metal shell, and to fix a polyethylene liner with bone cement. Six types of models were tested, with all cementations performed under similar conditions. The "lever out" test was conducted 3 times for each group in order to measure the dissociation strength. The average dissociation strength values were 11.5 N• m for those without screw holes; 33.6, 34.7, and 78.7 N• m for those with single holes at 1, 3, and 6 mm depth, respectively; and 41.3 and 101.1 N• m for 2 different configurations with 3 holes at 3 mm depth. The strength of adhesion increased with the use of a cement anchor, and with an increasing length and number of anchors. The application of a cement anchor with a screw hole is clinically useful for increasing the mechanical strength of the shellcement interface.

Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects.

This study was performed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of GSK1278863, a novel prolyl hydroxylase inhibitor, following a single oral administration of GSK1278863 from 10 to 100 mg or placebo in Japanese (n = 19), and 10, 25 and 100 mg in Caucasians (n = 14). Dose-proportional increases were observed in AUCinf of GSK1278863 in both ethnic groups, with a 1.3-1.5-fold higher exposure seen in Japanese relative to Caucasians for all doses. This difference in exposure can be mainly explained by the observed differences in body weights between the two groups. Statistically significant increases in erythropoietin (EPO), vascular endothelial growth factor (VEGF) and reticulocyte counts were observed in Japanese subjects after the 50 and 100 mg dose as compared to placebo. In Caucasians, similar to Japanese, EPO and VEGF levels were observed to be increased in response to the 100 mg dose. Drug-related adverse events, including headache and abdominal pain were reported in 3 Japanese subjects, while headache was reported in 3 Caucasians. In conclusion, GSK1278863 was well tolerated, with dose-proportional increases in exposure observed in both groups. There was no evidence of ethnic differences between Japanese and Caucasian with regard to PK or PD.

Contact between the acetabulum and dome of a Kerboull-type plate influences the stress on the plate and screw.

We used a three-dimensional finite element method to investigate the conditions behind the Kerboull-type (KT) dome. The KT plate dome was divided into five areas, and 14 models were created to examine different conditions of dome contact with the acetabulum. The maximum stress on the KT plate and screws was estimated for each model. Furthermore, to investigate the impact of the contact area with the acetabulum on the KT plate, a multiple regression analysis was conducted using the analysis results. The dome-acetabulum contact area affected the maximum equivalent stress on the KT plate; good contact with two specific areas of the vertical and horizontal beams (Areas 3 and 5) reduced the maximum equivalent stress. The maximum equivalent stress on the hook increased when the hardness of the bone representing the acetabulum varied. Thus, we confirmed the technical importance of providing a plate with a broad area of appropriate support from the bone and cement in the posterior portion of the dome and also proved the importance of supporting the area of the plate in the direction of the load at the center of the cross-plate and near the hook.

Initial stability of cementless acetabular cups: press-fit and screw fixation interaction--an in vitro biomechanical study.

BACKGROUND: Press-fit and screw fixation are important technical factors to achieve initial stability of a cementless acetabular cup for good clinical results of total hip arthroplasty. However, how these factors affect one another in initial cup fixation remains unclear. Therefore, this study aimed to evaluate the mutual influence between press-fit and screw fixation on initial cup stability. METHODS: Foam bone was subjected to exact hemispherical-shape machining to diameters of 48, 48.5 and 49 mm. A compressive force was applied to ensure seating of a 48-mm-diameter acetabular cup in the foam bone prior to testing. Screws were inserted in six different conditions and tightened in a radial direction at the same torque strength. Then, the socket was rotated with a twist-testing machine, and the torque value at the start of axial rotation between the socket and the foam bone was measured under each screw condition. RESULTS: The torque values for the 48-mm-diameter reaming were >20 N m higher than those for the 48.5- and 49-mm-diameter reaming in each screw condition, indicating that press-fit fixation is stronger than screw fixation. Meanwhile, torque values for the 48.5- and 49-mm-diameter reaming tended to increase with increasing the number of screws. CONCLUSIONS: According to our experiment, press-fit fixation of a cementless acetabular cup achieved rigid stability. Although the supplemental screws increased stability of the implant under good press-fit conditions, they showed little impact on whole-cup stability. In the case of insufficient press-fit fixation, cup stability depends on screw stability and increasing the number of additional screws increases cup stability.

Influence of the volume of bone defect, bone grafting methods, and hook fixation on stress on the Kerboull-type plate and screw in total hip arthroplasty: three-dimensional finite element analysis.

For total hip arthroplasty or revision surgery using acetabular reinforcement cross-plates, choosing between bulk and morselized bone grafts for filling acetabular defects is challenging. We used finite element model (FEM) analysis to clarify various stresses on the cross-plate based on bone defect size, bone graft type, and presence or absence of hook fixation to the bone. We constructed 12-pattern FEMs and calculated the maximum stress generated on the Kerboull-type (KT) plate and screw. Bone defects were classified into four patterns according to the volume. Regarding the bone graft type, bulk bone grafts were considered as cortical bone, and morselized bone grafts were considered to consist of cancellous bone. Models were compared based on whether hook fixation was used and whether a gap was present behind the plate. The upper surface of the host bone was fixed, and a 1,000-N load was imposed on the horizontal axis at 71°. Larger bone defects increased the stress on the KT plate and screws. This stress increased when no bone was grafted; it was lower when bulk cortical bone grafts were used for filling than when morselized cancellous bone grafts were used. For cortical bone grafts, the increased stress on the KT plate and screws was lowered with hook removal. Attaching the hook to the bone and filling the gap behind the KT plate with an adequate bone graft reduced the stress on the KT plate and screws, particularly for large bone defects filled by bulk bone grafting.

Comparison of levocetirizine pharmacokinetics after single doses of levocetirizine oral solution and cetirizine dry syrup in healthy Japanese male subjects.

OBJECTIVE: Levocetirizine, the R-enantiomer of cetirizine, is classified as a second generation antihistamine used for the treatment of allergic disorders. This study aimed to compare exposure to levocetirizine when given as levocetirizine oral solution (OS) 5 mg to that when given as cetirizine dry syrup (DS) 10 mg, which contains equal proportions of levocetirizine and dextrocetirizine, in healthy Japanese male subjects. METHODS: The study was conducted in an open-label, single dose, randomized and two-way cross-over design. Eligible subjects were allocated to one of two groups and received either levocetirizine OS 5 mg or cetirizine DS 10 mg under fasting conditions, and the alternate treatment after a 7-days washout period. Serial blood samples were taken after each administration, and plasma levocetirizine concentrations were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were calculated by using non-compartmental analysis. Comparisons of levocetirizine pharmacokinetics were conducted with maximum concentration (C max) and the area under the plasma concentration-time curve from dosing until 48 h post-dose (AUC0-48) after each treatment. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier is NCT01622283. RESULTS: The mean C max and AUC0-48 of levocetirizine after a single dose of levocetirizine OS 5 mg and cetirizine DS 10 mg were 203.3 ± 42.49 ng/mL and 1814.9 ± 304.22 ng.hr/mL, and 196.5 ± 31.31 ng/mL and 1710.5 ± 263.31 ng hr/mL, respectively. The ratios and the 90% CIs of the geometric least squares means ratios of C max and AUC0-48 were 1.027 (0.968-1.091) and 1.059 (1.024-1.094), respectively. LIMITATION: The small sample size and single dose design of this study prevent definitive conclusions regarding the pharmacokinetics and safety of levocetirizine OS in a Japanese patient population being made. Study limitations include conducting the study in adult males, not in children. CONCLUSIONS: Levocetirizine exposure in plasma was equivalent when given as levocetirizine OS 5 mg and as cetirizine DS 10 mg. Both preparations were safe and well-tolerated in healthy Japanese male subjects.

Fixation strength at the interface between Kerboull-type plate and bone cement.

PURPOSE: To evaluate the fixation strength at the interface between the Kerboull-type plate and bone cement in 6 experimental conditions. METHODS: Experimental materials comprised a simulated acetabular block, a simulated Kerboulltype plate, a pressuriser cover, a pressuriser arm, and bone cement. The simulated Kerboull-type plate was placed on the simulated acetabular block, with the pressuriser cover. Bone cement was added and the pressuriser arm was inserted. After 6 days of curing, pulling tests were performed to measure the fixation strength at the interface between the plate and the bone cement. Six experimental conditions were evaluated. In condition 1, a 1-mm plate was used with no gap between the plate and the acetabular block. In condition 2, a 2.5-mm plate was used with no gap. In condition 3, a 2.5-mm plate was used with a 2-mm gap. In condition 4, the plate was not used. In condition 5, condition 2 was tested with the model rotated 45º. In condition 6, condition 3 was tested with the model rotated 45º. RESULTS: The maximum fixation strengths in conditions 1, 2, 3, 5, and 6 were 44.4 N, 59.1 N, 122.5 N, 86.9 N, and 185.2 N, respectively. The most important factor affecting the maximum fixation strength was bone cement at the interface between the plate and the acetabular block, followed by 45º rotation during testing, and then thickness of the plate. CONCLUSION: To enhance fixation of the Kerboull-type plate with cemented acetabular cup, penetration of cement into the outer side of the Kerboull-type plate should be minimised.

Safety and pharmacokinetic evaluation of intravenous colistin methanesulfonate sodium in Japanese healthy male subjects.

OBJECTIVES: The study aimed at evaluating the pharmacokinetics of colistin methanesulfonate sodium (CMS-Na) and describing observed safety findings in Japanese healthy male subjects. METHODS: A total of 22 Japanese healthy males were enrolled in this randomized double-blind, placebo controlled study. Dosing regimens of a single dose and twice-daily repeat doses of CMS-Na (2.5 mg/kg as colistin activity, 75,000 IU/kg) were employed. Safety variables included urinary N-acetyl-ß-D-glucosaminidase, protein and ß(2)-microblobulin. Concentrations of CMS and colistin were determined by LC-MS/MS. Pharmacokinetic parameters were obtained by noncompartmental analysis. CLINICAL TRIAL REGISTRATION NUMBER: NCT01449838. RESULT: The urinary N-acetyl-ß-D-glucosaminidase for the detection of early renal damage showed transient increases during the repeat dose period. Otherwise, no clinically significant findings related to study medication were observed. After 2.5-day twice-daily dosing, mean t(1/2) and CL(R) of colistin were 4.98 h and 0.0073 L/h/kg, respectively. Repeat dose C(max) and AUC(0-12) were increased by 72% and 63%, respectively, compared to single dose. The dosing regimen had little effect on renal excretion rate (fe) of both CMS and colistin. The previously reported area under the unbound concentration-time curve to minimum inhibitory concentration (MIC) ratio (fAUC/MIC) target values in mouse lung and thigh infection models compared with the distribution of fAUC/MIC in humans estimated by a Monte Carlo simulation indicated that a bacteriostatic effect was predicted in 84% and 96% of patients, respectively, whereas bactericidal effect was predicted in 65% and 78% of patients, respectively. As this study was conducted with a relatively small number of healthy subjects, safety and PK profiles in critically ill patient population may be different than was observed in this study. CONCLUSION: CMS-Na was safely administered to healthy volunteers but resulted in transient increase of urinary N-acetyl-ß-D-glucosaminidase (NAG) and protein. Based on this study, the highest recommended dose of CMS-Na had sufficient bacteriostatic effect.

Manipulation of the anabolic and catabolic responses with BMP-2 and zoledronic acid in a rat femoral fracture model.

Bone repair involves a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone matrix at the fracture site. It has been reported that the optimal time point for single-dose zoledronic acid (ZA) administration systemically increased the strength of bone morphogenetic protein (BMP)-7-mediated callus. However, its repair mechanism during bone fracture healing remains unknown. We aimed to investigate the synergic effect of recombinant human (rh) BMP-2 and ZA in a rat femoral fracture model. Fifty-eight rats were divided into 4 groups. Group I (n=14) animals were implanted with a carrier alone. Group II (n=15) animals were implanted with a carrier containing 1-µg rhBMP-2. Group III (n=14) animals were implanted with a carrier and a subcutaneous systemic ZA injection 2 weeks after surgery. Group IV (n=15) animals were implanted with a carrier containing 1-µg rhBMP-2 and ZA subcutaneous injection 2 weeks after surgery. The rats were euthanized after 6 weeks and their fractured femurs were explanted and assessed by manual palpation, radiographs, and high-resolution micro-computerized tomography (micro-CT) and were subjected to biomechanical and histological analysis. The fusion rates in Group IV (93.3%) were considerably higher than those in Groups I (28.6%), II (53.3%), and III (57.1%). Additionally, the radiographic scores of Group IV were higher than those in Groups I, II, and III. In micro-CT analysis, the tissue volume (TV) of the callus was higher in Group IV than in Groups I and II (p<0.05). New bone volume (BV) and trabecular spacing (Tb.Sp) also showed essentially the same trend as that of TV. The ratio of BV to TV (BV/TV), the trabecular number (Tb.N), and the trabecular thickness (Tb.Th) was higher in Groups III and IV than in Groups I and II (p<0.05). In biomechanical analysis, the ultimate loads at failure and stiffness in Groups III and IV were on average higher than those in Groups I and II (p<0.05), while the energy absorption of Group IV was higher than those of Groups I and II (p<0.05). The synergic effect of rhBMP-2 and ZA given systemically as a single dose at the optimal time was efficacious for fracture repair and significantly enhanced bone fusion. Our results suggest that this combination facilitates bone healing and has potential clinical application.

Influence of ALDH2 genetic polymorphisms on aciclovir pharmacokinetics following oral administration of valaciclovir in Japanese end-stage renal disease patients.

This study was performed to investigate the pharmacokinetics of valaciclovir (VACV), aciclovir (ACV) and 9-(carboxymethoxy)methylguanine (CMMG) in Japanese chronic hemodialysis patients following a single oral administration of 1000 mg VACV and the influence of genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2) on their pharmacokinetics. A total of eighteen individuals genotyped as ALDH2*1/*1, ALDH2*1/*2 or ALDH2*2/*2 were enrolled in this study. Blood samples were obtained pre-dose and up to 48 hour post-dose. ACV t(1/2) was significantly affected by ALDH2 genotype and prolonged in the order of ALDH2*1/*1 (18.1 hr)

Analysis of wear and oxidation on retrieved bipolar polyethylene liner.

BACKGROUND: For bipolar prostheses, most of the previous studies attributed the occurrence of osteolysis to wear debris generated from the bearing surface. We looked closely into the wear debris and reported on our findings with respect to the oxidation index and the rate of wear in ultra-high molecular weight polyethylene (UHMWPE) inserts retrieved from bipolar prostheses after various spans of time in vivo. METHOD: The inserts were retrieved from the heads of three types of bipolar prosthesis (UH1, UPF1, UPF2). We retrieved 24 bipolar prostheses from 23 patients whose mean implantation period was 10.0 years (2.7-15.4 years). RESULTS: All the retrieved polyethylene had a burnished bearing surface. In all, 92% (22/24) of these inserts had indentation and roughness at the rim and flange, suggesting neck-cup impingement; periprosthetic fracture occurred in the other two inserts. The mean linear wear rate was 0.035 mm per year. The average maximum oxidation index for the inserts with osteolysis was 3.34, and it was was 3.49 for the inserts without osteolysis. We, therefore, could not detect any significant difference between the aforesaid groups of inserts. CONCLUSIONS: The results strongly suggest that most of the polyethylene wear debris was not generated from the bearing surface. Moreover, the wear debris generated from neck-cup impingement may well be the cause of an inflammatory reaction, which in turn has a strong potential to become the primary cause of osteolysis.