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We evaluated the pharmacokinetics, pharmacodynamics, and safety of evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open‐label, parallel‐design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end‐stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140‐mg dose of evolocumab. The effects of evolocumab treatment on low‐density lipoprotein cholesterol (LDL‐C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean Cmax and AUClast values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere‐Terpstra trend test; Cmax, P = .23; AUClast, P = .22) and within 26% after adjusting for body weight (mean body weight was approximately 9% higher in the renally impaired groups compared with the normal renal function group). No correlations were observed between exposure and baseline creatinine clearance. No adverse event was determined by the investigators to be related to evolocumab, and there were no trends indicative of clinically important effects on laboratory variables or vital signs. Overall, there were no meaningful differences in evolocumab exposure, as assessed by Cmax and AUClast, in patients with severe RI and ESRD hemodialysis compared with patients with normal renal function, and LDL‐C‐lowering effects were similar across groups. These results support the use of evolocumab without dose adjustment in patients who have severe RI or ESRD.

Evolocumab binds PCSK9, increasing low-density lipoprotein cholesterol (LDL-C) receptors and lowering LDL-C. Target-mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL-C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, and safety in individuals with and without hepatic impairment. Open-label, parallel-group study evaluating the pharmacokinetics of evolocumab in hepatic-impaired (Child–Pugh Class A or B) or healthy adults. Participants were classified as having no, mild, or moderate hepatic impairment (n = 8/group), and received a single 140-mg evolocumab dose. Assessments of unbound evolocumab and PCSK9 were made pre- and post-dose. Adverse events were monitored throughout the study. No significant association was observed between baseline PCSK9 and increasing level of hepatic impairment. No difference in extent and time-course of PCSK9 or LDL-C reduction was observed, despite an apparent decrease in mean unbound evolocumab exposure with increasing hepatic impairment (Jonckheere–Terpstra trend test; maximum serum concentration: P = .18; area under the curve: P = .09). Maximum reductions were observed in moderately impaired subjects versus healthy individuals: mean maximum serum concentration, –34%; mean area under the concentration-time curve (AUC), –47%. On average, unbound PCSK9 serum concentrations fell by >80% at 4 hours after a single evolocumab dose. Mean (95% confidence interval) maximum LDL-C reductions in the healthy, mild, and moderate groups were –57% (–64%, –48%), –70% (–75%, –63%), and –53% (–61%, –43%), respectively. No safety risks were identified. These results support evolocumab use without dose adjustment in patients with active liver disease and mild or moderate hepatic impairment. This article is protected by copyright. All rights reserved

Aims Denosumab is a fully human monoclonal immunoglobulin G2 antibody that inhibits bone resorption and increases bone mass and strength. The present clinical study assessed serum and seminal fluid pharmacokinetics following a single denosumab dose in healthy men, and evaluated whether denosumab in seminal fluid poses any risk to a fetus in the event of unprotected sexual intercourse with a pregnant partner. Methods An open-label, single-dose study in 12 healthy men was conducted over a 106-day period. Subjects received a single subcutaneous dose of 60-mg denosumab on day 1. Serum and seminal fluid samples were collected at specified time points to assess denosumab pharmacokinetics. Adverse events were recorded. Results Denosumab was measurable at low concentrations in seminal fluid (~2% of serum concentrations). The mean [standard deviation (SD)] maximum observed drug concentration (Cmax ) was 6170 (2070) ng ml(-1) (serum) and 100 (81.9) ng ml(-1) (seminal fluid). The median time to Cmax (tmax ) was 8 days (serum) and 21 days (seminal fluid). The mean (SD) area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast ) was 333 000 (122 000) day•ng ml(-1) (serum) and 5220 (4880) day•ng ml(-1) (seminal fluid). The mean (SD) Cmax and AUC ratios between seminal fluid and serum were 0.0217 (0.0154) and 0.0170 (0.0148), respectively. Using conservative assumptions for ejaculate volume (6 ml), vaginal absorption (100%) and placental transfer (100%), the measured mean denosumab seminal fluid Cmax would result in fetal exposure that was more than 110 times below the preclinically derived 'no effect level' for denosumab. Conclusions These results indicate a negligible risk to a fetus exposed to denosumab via seminal fluid transfer to a pregnant partner.

Atherosclerosis and osteoporosis are chronic diseases that progress with age, and studies suggest aortic calcification, an indicator of atherosclerosis, is inversely associated with BMD. The OPG/RANK/RANKL system has been proposed as a shared regulatory system for bone and vasculature. Denosumab (DMAb), a monoclonal antibody against RANKL, improved BMD and reduced fracture risk in the FREEDOM trial. We evaluated whether or not treatment with DMAb influenced progression of aortic calcification (AC) and incidence of cardiovascular (CV) adverse events. We included 2,363 postmenopausal women with osteoporosis (1,142 placebo, 1,221 DMAb), selected from 7,808 participants in the FREEDOM trial (3,906 placebo, 3,902 DMAb), at high risk of CV events according to modified Raloxifene Use for the Heart (RUTH) criteria. CV adverse events were reported by participants. AC scores were assessed using a semi-quantitative method from lateral spine x-rays. Change in AC score from baseline to 12 (N = 1,377), 24 (N = 1,231) and 36 months (N = 1,045) was calculated as AC score at follow-up minus AC score at baseline. AC progression was defined as change in AC score > 0. Baseline characteristics, CV risk factors, and AC scores were similar between treatment groups. Mean age of participants was 74 years (range, 60–90), 88% were white, and 77% had AC score > 0 at baseline. Frequency of AC progression over 3 years did not differ between women in placebo (22%) and DMAb (22%) groups (p = 0.98). AC progression did not differ between treatment groups when analyzed by baseline estimated glomerular filtration rate or by baseline AC scores. Frequency of CV adverse events did not differ between placebo (40%) and DMAb (38%) groups (p = 0.26). In conclusion, DMAb treatment had no effect on progression of AC or incidence of CV adverse events compared to placebo.

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.

The long-term use of calcineurin inhibitors (CNI) leads to renal dysfunction in many liver transplant (LT) recipients. The purpose of this analysis is to evaluate renal function in patients converted from CNI to sirolimus (SRL). From May 2002-November 2006, 137 LT were performed in 125 patients, 72 of which were converted to SRL. Evaluation of SRL conversion was stratified by early conversion (

Drug-disease interactions involving therapeutic proteins that target cytokines and potentially impact cytochrome P450 (CYP) enzymes have been of increased interest to drug regulatory agencies and industry sponsors in recent years. This parallel-group open-label study evaluated the effects of the monoclonal antibody denosumab, an inhibitor of the cytokine RANKL, on the pharmacokinetics of the probe CYP3A4 substrate midazolam in postmenopausal women with osteoporosis. The pharmacokinetics of a 2 mg oral dose of midazolam was evaluated on days 1 and 16. Subjects in Group A received a 60 mg subcutaneous dose of denosumab on day 2, 2 weeks before the second midazolam dose, while subjects in Group B did not. For Group A (n = 17), point estimates for the ratio of least square means for midazolam exposures based on maximum observed plasma concentration (C max) and areas under the plasma concentration-time curve (AUCs) on day 16 versus day 1 ranged from 1.02 to 1.04 and 90% confidence intervals were within 0.80-1.25. No period effect was observed for Group B (n = 8). Midazolam and denosumab coadministration was safe and well tolerated. Inhibition of the cytokine RANKL by denosumab does not affect CYP3A4 in postmenopausal women with osteoporosis and will not alter the pharmacokinetics of drugs metabolized by this enzyme. These results are consistent with data suggesting that RANKL does not impact markers of inflammation and represent the first clinical data demonstrating a lack of effect on CYP3A4 of a therapeutic protein that is a cytokine modulator.