An open-label study in healthy men to evaluate the risk of seminal fluid transmission of denosumab to pregnant partners.

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.

An open-label study to evaluate a single-dose of cinacalcet in pediatric dialysis subjects.

BACKGROUND: There is limited knowledge of the effectiveness and safety profile of cinacalcet in pediatric patients with secondary hyperparathyroidism (sHPT) treated with dialysis. METHODS: This was an open-label, single-dose study conducted on 12 pediatric subjects with chronic kidney disease treated with dialysis. Subjects were stratified by four age cohorts and given a single 15-mg oral dose of cinacalcet. Multiple blood samples were collected up to 72 h post-dose for the assessment of serum calcium (Ca), serum intact parathyroid hormone (iPTH), and plasma cinacalcet concentrations. RESULTS: Overall, cinacalcet was well tolerated with no serious adverse events. Mean (standard deviation) percentage change in serum Ca over the first 12 h post-dose was -2.93 % (5.70 %) with a nadir of -4.34 % (6.04 %) at 8 h; Ca values returned to baseline by 48 h post-dose. Mean percentage change in iPTH over the first 12 h post-dose was 57.94 % (71.82 %) with a nadir of -35.65 % (55.82 %) at 2 h. There was an inverse relationship between peak serum Ca concentration and body surface area (BSA) (r (2) = 0.41), although no relationship was found between area under the curve and age or BSA. CONCLUSIONS: These data support future analysis to determine the therapeutic starting dose of cinacalcet for pediatric patients with sHPT on dialysis.

Electrocardiographic assessment for therapeutic proteins--scientific discussion.

Electrocardiographic monitoring is an integral component of the clinical assessment of cardiac safety of all compounds in development. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 guideline recommends a dedicated study to evaluate drug-induced effects on cardiac repolarization ("thorough QT/QTc study"). There has been limited published information on QT interval changes secondary to therapeutic proteins; however, in theory, biologic therapies may affect cardiac electrical activity either directly or indirectly. This article summarizes scientific discussions of members of the Cardiac Safety Research Consortium and includes possible approaches to consider for the clinical evaluation of drug-induced QT prolongation in development programs of therapeutic proteins.

Cinacalcet does not affect the activity of cytochrome P450 3A enzymes, a metabolic pathway for common immunosuppressive agents : a randomized, open-label, crossover, single-centre study in healthy volunteers.

BACKGROUND AND OBJECTIVE: Cinacalcet HCl (cinacalcet) is approved for the treatment of secondary hyperparathyroidism in subjects receiving dialysis and for the reduction of hypercalcaemia in patients with parathyroid carcinoma. The drug may also be co-administered with medications used in the renal transplantation setting, such as immunosuppressants. Cinacalcet, as well as some immunosuppressants such as ciclosporin, tacrolimus and sirolimus, is partially metabolized by the cytochrome P450 3A enzymes (CYP3A). This study aimed to evaluate the potential inhibitory effects of cinacalcet on CYP3A activity using midazolam as a probe substrate in healthy volunteers. METHODS: In this randomized, open-label, crossover, two-treatment, two-period, single-centre study, 12 healthy volunteers received either oral cinacalcet 90 mg once daily for 5 days plus a single oral dose of midazolam 2 mg on day 5, or a single oral dose of midazolam 2 mg on day 1. Following a 10-day washout period, subjects received the alternate treatment. Blood samples were collected predose and at selected time points up to 24 hours after dosing with midazolam for measurement of midazolam pharmacokinetic parameters. RESULTS: Eleven subjects completed the study. Mean (standard deviation) midazolam maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) were 9.31 (3.09) ng/mL and 24.1 (7.7) ng . h/mL, respectively, when administered in combination with cinacalcet, compared with 9.76 (2.81) ng/mL and 22.8 (6.1) ng . h/mL when administered alone. The mean geometric ratios (90% confidence interval) were 0.95 (0.84, 1.06) and 1.05 (0.95, 1.16) for C(max) and AUC(infinity), respectively. All adverse events were mild to moderate in severity, and consistent with the safety profile of cinacalcet. CONCLUSION: Once-daily administration of cinacalcet did not alter the pharmacokinetics of midazolam relative to administration of midazolam alone. These data suggest that cinacalcet administration does not affect CYP3A activity, and thus would not have an effect on any drug eliminated via CYP3A, including some commonly used immunosuppressant therapies.

Pharmacokinetics and pharmacodynamics of cinacalcet in hepatic impairment : phase I, open-label, parallel-group, single-dose, single-centre study.

BACKGROUND AND OBJECTIVE: The calcimimetic cinacalcet lowers blood para-thyroid hormone (PTH), calcium and phosphorus levels and calcium-phosphorus product in patients with chronic kidney disease receiving dialysis. Cinacalcet is metabolized primarily through oxidative and conjugative pathways. Hepatic disease has the potential to alter cinacalcet metabolism. Thus, it is important to establish the potential for altered cinacalcet metabolism according to the level of hepatic function. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of cinacalcet in subjects with different degrees of hepatic function. METHODS: This was a phase I, open-label, single-dose, parallel-group, single-centre study that included 24 subjects (six with normal hepatic function and six each with mild, moderate and severe hepatic impairment according to Child-Pugh criteria). Subjects were given a single 50 mg oral dose of cinacalcet. Blood samples were taken for pharmacokinetic (pre-dose and up to 120 hours post-dose) and pharmacodynamic (pre-dose and up to 72 hours post-dose) evaluations. Plasma concentrations of cinacalcet were determined using a validated normal phase turbo ion spray liquid chromatography-mass spectrometry/mass spectrometry assay. Serum ionized calcium levels were determined by standard biochemical measures, and PTH levels were determined using an immunometric intact PTH (iPTH) assay. The primary endpoints of the study were area under the concentration-time curve from 0 to time t (AUC(t)), AUC from 0 to infinity (AUC(infinity)) and maximum plasma concentration (C(max)). Other pharmacokinetic parameters (time to C(max) [t(max)], terminal half-life [t((1/2))(beta)], total body clearance [CL/F] and protein binding) and the effect of cinacalcet on plasma PTH and serum calcium were secondary endpoints. RESULTS: Total cinacalcet exposure (AUC(infinity)) was comparable in subjects with normal hepatic function and mild hepatic impairment. In subjects with moderate and severe hepatic impairment, mean AUC(infinity) was 2.4- and 4.2-fold higher, respectively, than in healthy subjects. Cinacalcet t((1/2))(beta) was 1.3- and 1.7-fold longer in subjects with moderate and severe hepatic impairment, respectively, compared with subjects with normal hepatic function. Mean C(max) and t(max), as well as protein binding, were similar in all groups. Consistent with the increase in cinacalcet exposure, decreases in iPTH tended to be greater and prolonged in subjects with moderate and severe hepatic impairment. In this study, cinacalcet was well tolerated. CONCLUSION: These data demonstrate that cinacalcet can be used without dose adjustment in patients with mild hepatic impairment. However, increased drug exposure observed in subjects with moderate to severe hepatic impairment indicates that iPTH and serum calcium levels should be monitored closely and physicians should be more cautious about dose titration in patients with moderate or severe hepatic impairment.

Pharmacokinetics of cinacalcet hydrochloride when administered with ketoconazole.

BACKGROUND AND OBJECTIVE: The calcimimetic cinacalcet hydrochloride (cinacalcet) is used for treatment of patients with chronic kidney disease with secondary hyperparathyroidism, a population that commonly receives multiple concurrent medications. Cinacalcet is eliminated primarily via oxidative metabolism mediated, in part, through cytochrome P450 (CYP) 3A4. Thus, the potential for an inhibitor of CYP3A4 to alter the pharmacokinetics of cinacalcet is of clinical importance. The objective of this study was to evaluate the pharmacokinetics of cinacalcet during treatment with a potent CYP3A4 inhibitor, ketoconazole. SUBJECTS AND METHODS: Twenty-four healthy subjects were enrolled in an open-label, crossover, phase I study to receive a single oral dose of cinacalcet (90 mg) alone and with 7 days of ketoconazole (200mg twice daily). Blood samples for pharmacokinetics were collected for up to 72 hours postdose. Cinacalcet plasma concentration-time data were analysed by noncompartmental methods. Pharmacokinetic parameters were analysed using a crossover ANOVA model that included subjects who completed both treatment arms. RESULTS: Twenty subjects completed both treatment arms. The mean area under the plasma concentration-time curve of cinacalcet increased 2.3-fold (90% CI 1.92, 2.67) [range 1.15- to 7.12-fold] and the mean maximum plasma concentration increased 2.2-fold (90% CI 1.67, 2.78) [range 0.904- to 10.8-fold] when administered with ketoconazole, relative to when administered alone. The time to reach the maximum plasma concentration was not significantly affected, and the terminal elimination half-lives were similar between treatments. CONCLUSIONS: Co-administration of a potent CYP3A4 inhibitor moderately increased cinacalcet exposure in study subjects. This suggests that clinicians should monitor parathyroid hormone and calcium concentrations when a patient receiving cinacalcet initiates or discontinues therapy with a strong CYP3A4 inhibitor.

Cinacalcet does not affect the pharmacokinetics or pharmacodynamics of warfarin.

BACKGROUND AND OBJECTIVE: Cinacalcet HCl (cinacalcet), approved for secondary hyperparathyroidism and parathyroid carcinoma-associated hypercalcaemia, may be coadministered with warfarin. The purpose of this study was to determine the pharmacokinetics/pharmacodynamics and tolerability of warfarin during cinacalcet coadministration. SUBJECTS AND METHODS: In this phase 1, randomised, double-blind, placebo-controlled, two-treatment, two-period crossover study, 21 healthy subjects received oral cinacalcet (30 mg) or placebo twice a day for 7 days and once on day 8, with a single warfarin dose (25mg) on day 5. After a 3-week washout, subjects received the alternative treatment. Samples for warfarin pharmacokinetics/pharmacodynamics were obtained until 144 hours post-dose. RESULTS: Single-dose administration of warfarin to subjects receiving cinacalcet did not demonstrate altered pharmacodynamics of either the R- or S-enantiomer. Geometric means ratio (90% CIs) for R- and S-warfarin were 1.01 (0.95, 1.07) and 1.00 (0.94, 1.04), respectively, for the area under the plasma concentration-time curve from time 0 to infinity (AUC(infinity)) and 0.90 (0.84, 0.96) and 0.88 (0.83, 0.94), respectively, for observed maximum plasma concentrations (C(max)). Additionally, the pharmacokinetic profiles of R- or S-warfarin were similar for all subjects. The ratio for the AUC from time 0 to the last measurable concentration (AUC(t)) for prothrombin time and factor VII were 1.03 (1.01, 1.04) and 0.97 (0.93, 1.01), respectively. The maximum rise (R(max)) and maximum change (Delta(max)) were 1.04 (1.02, 1.05) and 1.00 (0.96, 1.03), respectively. All treatment-emergent and treatment-related adverse events were mild to moderate in severity. There were no obvious differences in adverse events according to treatment. CONCLUSION: Warfarin pharmacokinetics/pharmacodynamics were not affected in subjects treated with warfarin 25mg who received cinacalcet 30 mg twice daily, thus suggesting that dose adjustment is not required.

An extended terminal half-life for darbepoetin alfa: results from a single-dose pharmacokinetic study in patients with chronic kidney disease not receiving dialysis.

BACKGROUND AND OBJECTIVE: Anaemia is a major and persistent manifestation of chronic kidney disease (CKD) caused by the deficient production of erythropoietin in the kidneys, the prevalence of which is proportional to the deterioration in kidney function. Darbepoetin alfa, an erythropoiesis-stimulating protein, exhibits a lower clearance and longer terminal half-life in serum than recombinant human erythropoietin, thereby allowing for a reduced dosing frequency. A recent study in patients with CKD, using a 4-week sampling period, suggested that the terminal half-life of darbepoetin alfa in serum is longer than that reported in previous studies, which were based on a 1-week sampling period. This study was conducted to characterise the pharmacokinetic profile of a single subcutaneous dose of darbepoetin alfa 1 microg/kg in patients with CKD, using a sampling duration of 4 weeks, which was hypothesised to allow better characterisation of the terminal half-life in serum. METHODS: Twenty patients with CKD not on dialysis, with a calculated glomerular filtration rate of 20-60 mL/min and who had not been treated with erythropoietic agents in the previous 12 weeks, were enrolled into this single-dose, open-label study. Patients received a single subcutaneous dose of darbepoetin alfa (Aranesp) 1 microg/kg on day 1, and blood samples were collected for pharmacokinetic analyses predose, 6 and 12 hours postdose and up to 28 days postdose. Seroreactivity sampling and further safety laboratory tests (clinical chemistry and urinalysis) were also performed. Patients were assessed for adverse events at each study visit. The primary endpoint was characterisation of the terminal half-life following a single subcutaneous dose of darbepoetin alfa 1 microg/kg. RESULTS: The mean terminal half-life in serum of darbepoetin alfa was determined to be 69.6 hours. Peak serum concentrations were reached in a median time of 36 hours postdose, and a mean apparent clearance of 3.51 mL/h/kg was comparable to that observed previously in this patient population. CONCLUSION: Based on an extended sampling schedule of 4 weeks, the terminal half-life of darbepoetin alfa was approximately 70 hours. This is longer than the 48.8 hours reported previously in patients with CKD on dialysis. These data suggest that the pharmacokinetic properties of darbepoetin alfa make this erythropoietic agent well suited to an extended dosing regimen.

No effect of renal function or dialysis on pharmacokinetics of cinacalcet (Sensipar/Mimpara).

OBJECTIVE: Cinacalcet (cinacalcet HCl; Sensipar/Mimpara) is a calcimimetic that is a treatment for secondary hyperparathyroidism in patients with renal failure. The objective of this study was to assess the effects of renal function and dialysis on the pharmacokinetics and pharmacodynamics of cinacalcet. METHODS: Two open-label, single-dose (75 mg) studies of cinacalcet were performed: study 1 examined 36 subjects who had renal function ranging from normal to requiring haemodialysis, and study 2 examined ten subjects who were receiving continuous ambulatory peritoneal dialysis. Cinacalcet plasma concentrations were determined using a liquid chromatography-mass spectrometry/mass spectrometry assay. Cinacalcet pharmacokinetics were assessed using noncompartmental analyses. RESULTS: Following single-dose administration of cinacalcet, there was no evidence of increasing exposure with increasing degree of renal impairment, and the pharmacokinetic profile was similar for all subjects regardless of whether they were receiving haemodialysis (no difference on dialysis or nondialysis days detected) or peritoneal dialysis. Protein binding of cinacalcet, determined in study 1 only, was similar in all groups and the level of renal function did not affect the pharmacodynamics (as determined by intact parathyroid hormone and calcium levels). No serious adverse events occurred during either study. CONCLUSION: The degree of renal impairment and mode of dialysis do not affect the pharmacokinetics or pharmacodynamics of cinacalcet. Therefore, the dose of cinacalcet does not need to be altered for degree of renal impairment or dialysis modality.

Comparison of pharmacokinetics and safety of pegfilgrastim administered by two delivery methods: on-body injector and manual injection with a prefilled syringe.

PURPOSE: For patients with clinically significant risk of febrile neutropenia, pegfilgrastim administration should occur the day after myelosuppressive chemotherapy; however, a variety of factors may preclude patients from returning to the clinic the next day for pegfilgrastim administration, necessitating other strategies. This study compared the pharmacokinetics and safety of pegfilgrastim administered via an on-body injector applied to the subject's skin versus manual injection using a prefilled syringe. METHODS: Healthy subjects aged 18-50 years were randomized 1:1 to receive a single 6-mg subcutaneous pegfilgrastim dose from an on-body injector or a prefilled syringe. Blood for pharmacokinetic measurements was collected at baseline and prespecified time points after pegfilgrastim administration; safety was assessed throughout the 6-week study. Primary endpoints were maximum concentration (C max) and area under the concentration curve from time 0 to infinity (AUC0-inf). Secondary endpoints included safety, tolerability, and immunogenicity. RESULTS: Pegfilgrastim mean AUC0-inf values for the on-body injector (n = 125) and manual injection (n = 128) were 10,900 and 11,100 h ng/mL, respectively; mean C max values were 248 and 262 ng/mL, respectively. The least squares geometric mean ratios were 0.97 for C max and 1.00 for AUC0-inf; the corresponding 90 % CIs were within the prespecified range (0.80-1.25), indicating comparable pegfilgrastim pharmacokinetics between delivery methods. Treatment-emergent adverse events (AEs) were similar between groups (injector, 86 %; manual, 85 %). Injector- or syringe-related AEs were more prevalent with the injector (13 %; manual, 4 %); none were serious. No pegfilgrastim-neutralizing antibodies were detected. CONCLUSIONS: Pegfilgrastim pharmacokinetics and safety were comparable between the on-body injector and manual injection groups.

Administration of romosozumab improves vertebral trabecular and cortical bone as assessed with quantitative computed tomography and finite element analysis.

Romosozumab inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. This dual effect of romosozumab leads to rapid and substantial increases in areal bone mineral density (aBMD) as measured by dual-energy X-ray absorptiometry (DXA). In a phase 1b, randomized, double-blind, placebo-controlled study, romosozumab or placebo was administered to 32 women and 16 men with low aBMD for 3 months, with a further 3-month follow-up: women received six doses of 1 or 2mg/kg every 2 weeks (Q2W) or three doses of 2 or 3mg/kg every 4 weeks (Q4W); men received 1mg/kg Q2W or 3mg/kg Q4W. Quantitative computed tomography (QCT) scans at lumbar (L1-2) vertebrae and high-resolution QCT (HR-QCT) scans at thoracic vertebra (T12) were analyzed in a subset of subjects at baseline, month 3, and month 6. The QCT subset included 24 romosozumab and 9 placebo subjects and the HR-QCT subset included 11 romosozumab and 3 placebo subjects. The analyses pooled the romosozumab doses. Linear finite element modeling of bone stiffness was performed. Compared with placebo, the romosozumab group showed improvements at month 3 for trabecular BMD by QCT and HR-QCT, HR-QCT trabecular bone volume fraction (BV/TV) and separation, density-weighted cortical thickness, and QCT stiffness (all p<0.05). At month 6, improvements from baseline were observed in QCT trabecular BMD and stiffness, and in HR-QCT BMD, trabecular BV/TV and separation, density-weighted cortical thickness, and stiffness in the romosozumab group (all p<0.05 compared with placebo). The mean (SE) increase in HR-QCT stiffness with romosozumab from baseline was 26.9% ± 6.8% and 35.0% ±6.8% at months 3 and 6, respectively; subjects administered placebo had changes of -2.7% ± 13.4% and -6.4% ± 13.4%, respectively. In conclusion, romosozumab administered for 3 months resulted in rapid and large improvements in trabecular and cortical bone mass and structure as well as whole bone stiffness, which continued 3 months after the last romosozumab dose.

Desloratadine has no clinically relevant electrocardiographic or pharmacodynamic interactions with ketoconazole.

OBJECTIVE: This study was performed to assess the electrocardiographic safety and pharmacokinetics of desloratadine in combination with the CYP3A4 inhibitor ketoconazole. DESIGN: A randomised, placebo-controlled, third-party-blind, 2-way crossover study. PARTICIPANTS: 24 healthy volunteers (12 men, 12 women; age 19 to 50 years). INTERVENTIONS: 7.5mg of desloratadine orally per day in combination with placebo or with 200mg of ketoconazole every 12 hours for 10 days. After a minimum 7-day washout period, participants received the alternative treatment. MAIN OUTCOME MEASURES: ECG parameters. RESULTS: Comparable maximum corrected QT (QT(c)) intervals were observed after coadministration of desloratadine and placebo or ketoconazole (431 and 435 msec, respectively). The desloratadine/ketoconazole combination did not induce any statistically significant or clinically relevant changes in QT(c), QT, PR or QRS intervals compared with desloratadine alone; ventricular rate was slightly slower when desloratadine was given with ketoconazole. At steady state, coadministration of ketoconazole resulted in no significant change in area under the desloratadine concentration-time curve (AUC) from 0 to 24 hours compared with desloratadine/placebo. Coadministration of desloratadine and ketoconazole resulted in a 1.3-fold increase in desloratadine maximum concentration (C(max)) that was not clinically relevant. The most common adverse event was headache, reported in 42 and 38% of individuals, respectively, after coadministration of desloratadine/placebo and desloratadine/ketoconazole. There were no reports of dizziness or syncope. CONCLUSION: Coadministration of desloratadine and ketoconazole was well tolerated and was associated with minimal increase in AUC and C(max). The combination did not induce any clinically relevant electrocardiographic changes.

Desloratadine demonstrates dose proportionality in healthy adults after single doses.

OBJECTIVE: To evaluate the dose proportionality and linearity and pharmacokinetic profile of desloratadine after single oral doses over the range of 5 to 20mg. DESIGN: Single centre, randomised, open-label, 4-way crossover study in which healthy adults received single doses of desloratadine (5, 7.5, 10 and 20mg) in 4 different treatment periods. Desloratadine was administered each morning after a 10-hour fast. A washout period of at least 14 days separated each dose. Plasma concentrations were measured prior to each treatment and over the 168 hours after drug administration to determine the area under the plasma concentration-time curve (AUC) and maximum observed plasma concentration (C(max)). PARTICIPANTS: 20 healthy male volunteers (3 White, 17 Black) ranging in age from 19 to 45 (mean 37) years and weighing 54 to 91 (mean 75) kg were enrolled and completed this study. MAIN OUTCOME MEASURES: The primary parameter to assess dose proportionality and linearity was AUC from time zero to final concentration time point (AUC(S)). RESULTS: The C(max) for all doses was observed approximately 4 hours after administration, revealing no dose-related differences in absorption rate. The half-life (t((1/2))) ranged from 21.2 to 24.1 hours. C(max) and AUC(S) increased in a dose-proportional manner over a dose range of 5 to 20mg. Although the recommended clinical dose is 5mg, doses up to 20mg were well tolerated. CONCLUSION: In this study, single doses of desloratadine as high as 4 times the recommended clinical dose of 5mg were well tolerated. The C(max) and AUC(S) for doses of 5 to 20mg increased in a dose-proportional manner.

Oral bioavailability of desloratadine is unaffected by food.

OBJECTIVE: To determine the effect of coadministration of food on the bioavailability of oral desloratadine. DESIGN: A randomised, open-label, single dose crossover study in which healthy adults received a single, oral dose of desloratadine 7.5mg, 50% greater than the recommended dose of 5mg, under fed or fasted conditions and were then crossed over to receive the other treatment regimen. PARTICIPANTS: 18 healthy volunteers (11 men, 7 women) aged from 18 to 43 (mean 29) years and weighing 54 to 104 (mean 76.4) kg were enrolled and completed this study. MAIN OUTCOME MEASURES: C(max), AUC(S) and AUC(infinity ). RESULTS: Maximum mean plasma concentration (C(max)) was 3.53 microg/L in fed compared with 3.30 microg/L in fasted participants. Area under the plasma concentration-time curve from time 0 to time of final quantifiable sample (AUC(S)) mean values were 61.0 microg/L x h in fed and 61.9 microg/L x h in fasted participants. Fed individuals had mean AUC extrapolated to infinity (AUC(infinity )) of 62.5 microg/L x h compared with 63.5 microg/L x h in fasted participants. None of these differences between the fed and fasted state was statistically significant. The most frequently reported adverse event was headache. There were no statistically significant changes in ECG parameters. CONCLUSION: The results of this study indicate that food has no effect on the oral bioavailability of a single oral dose of desloratadine 7.5mg.

Lack of clinically relevant interaction between desloratadine and erythromycin.

OBJECTIVE: To evaluate the bioavailability, cardiac safety and tolerability of desloratadine when given in combination with the CYP3A4 inhibitor erythromycin. DESIGN: A randomised, 2-way crossover, placebo-controlled, third party-blind, multiple dose study. PARTICIPANTS: 24 healthy volunteers (12 men, 12 women) aged 19 to 46 years. INTERVENTIONS: Oral desloratadine 7.5mg daily in combination with either placebo (n = 24) or erythromycin 500mg every 8 hours (n = 24) for 10 days. After a minimum 7-day washout period, participants crossed over to the alternative regimen. MAIN OUTCOME MEASURES: ECG parameters. RESULTS: Desloratadine/erythromycin did not induce clinically or statistically significant changes in any ECG parameter. The maximum corrected QT (QT(c)) interval was 445 msec for both treatments. The peak plasma concentration and area under the plasma concentration-time curve from 0 to 24 hours of desloratadine were slightly increased by 1.2- and 1.1-fold by concomitant administration of erythromycin compared with desloratadine/placebo. Gastrointestinal adverse events were more frequent after desloratadine/erythromycin than desloratadine/placebo (46 vs 4%), reflecting the poor gastrointestinal tolerability of erythromycin. There were no reports of syncope. CONCLUSION: Combined desloratadine/erythromycin therapy was well tolerated and had no clinically relevant electrocardiographic effects at a dose that was 50% higher than the recommended dose of 5mg. Although coadministration of erythromycin slightly increased plasma concentrations of desloratadine, this change did not correlate with any prolongation of the QT(c) interval, and no toxicity was observed clinically.

Pharmacokinetics, pharmacodynamics, and safety of cinacalcet hydrochloride in hemodialysis patients at doses up to 200 mg once daily.

BACKGROUND: Cinacalcet hydrochloride (HCl) can be used to manage the secondary hyperparathyroidism of patients with chronic kidney disease. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of cinacalcet HCl over a dose range of 25 to 300 mg/d in patients receiving dialysis. METHODS: Hemodialysis patients were randomly assigned 4:1 to receive cinacalcet HCl or placebo in this double-blind study. Cinacalcet HCl doses were escalated weekly in 25-mg increments from 25 to 300 mg/d. Noncompartmental methods were used to analyze the pharmacokinetic parameters of cinacalcet (the free-base). The effects of cinacalcet concentration on plasma parathyroid hormone (PTH) and serum calcium levels were evaluated. RESULTS: Of 23 patients enrolled (17 patients, cinacalcet HCl; 6 patients, placebo), 10 patients (8 patients, cinacalcet HCl; 2 patients, placebo) completed the study. Plasma concentration, median area under the plasma concentration-time curve from time 0 to 24 hours after dosing, and maximal plasma concentration (Cmax ) of cinacalcet increased with doses up to 200 mg once daily. Median oral clearance ranged from 222 to 599 L/h, and median time after dosing when C max occurred ranged from 2 to 3 hours across all doses. The pharmacokinetics were linear over the 25- to 200-mg once-daily dose range, with no substantial increase in exposure at greater than 200 mg. Changes in plasma PTH concentrations correlated inversely with cinacalcet concentration. The concentration-effect relationship was well described by an inhibitory maximal effect model. Cinacalcet HCl was reasonably tolerated, and the incidence of adverse events was similar between groups (76%, cinacalcet; 80%, placebo). Gastrointestinal events were noted at greater doses and may be dose related. CONCLUSION: Cinacalcet HCl shows a dose-proportional increase in exposure over the range of 25 to 200 mg once daily in patients on hemodialysis therapy, and kinetics were linear up to 200 mg once daily. The incidence of adverse events was similar between groups.

Effects of calcium carbonate, sevelamer hydrochloride or pantoprazole on the pharmacokinetics of cinacalcet.

BACKGROUND AND OBJECTIVES: Secondary hyperparathyroidism is a common consequence of chronic kidney disease. Cinacalcet (Sensipar(®)) is often prescribed in combination to reduce elevated levels of parathyroid hormone, calcium and phosphorus. The objective of this study was to assess the effects of concomitantly administered therapies of calcium carbonate (CaCO(3); TUMS(®)), sevelamer hydrochloride (HCl; Renagel(®)) and pantoprazole sodium (Protonix(®)) on the pharmacokinetics and safety of cinacalcet in healthy subjects. METHODS: Three randomized, open-label, two-way crossover pharmacokinetic studies were conducted in healthy subjects. Participants received single doses of cinacalcet alone or in combination with either CaCO(3), sevelamer HCl or pantoprazole. The pharmacokinetic profile of cinacalcet was characterized. Safety assessments including adverse event reporting, changes in vital signs and clinical laboratory measurements were conducted throughout the studies. RESULTS: The 90 % confidence intervals for the area under the concentration-time curve from time zero to the last quantifiable concentration (AUC(last)), area under the concentration-time curve from time zero to infinity (AUC(0-∞)) and maximum plasma concentration (C(max)) of cinacalcet were within the accepted range of 80-125 % for both CaCO(3) and sevelamer HCl co-administration with cinacalcet. No severe or serious adverse events or clinically relevant changes in physical or laboratory findings occurred during the studies. CONCLUSION: The pharmacokinetic parameters of cinacalcet were not affected by co-administration of CaCO(3), sevelamer HCl or pantoprazole. Co-administration of these agents with cinacalcet does not require an adjustment of the dose of cinacalcet.

Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study.

Romosozumab (formerly AMG 785/CDP7851) is a monoclonal antibody that blocks sclerostin from inhibiting osteoblast maturation and function. This double-blind, placebo-controlled, randomized, ascending multiple-dose study enrolled 32 postmenopausal women and 16 healthy men with low bone mass. Women received six doses of 1 or 2 mg/kg once every 2 weeks (Q2W) or three doses of 2 or 3 mg/kg once every 4 weeks (Q4W) or placebo; and men received 1 mg/kg Q2W or 3 mg/kg Q4W or placebo. Mean serum romosozumab exposures increased approximately dose-proportionally. Romosozumab increased serum type 1 aminoterminal propeptide (PINP) by 66-147%, decreased serum C-telopeptide (sCTX) by 15-50%, and increased lumbar spine bone mineral density by 4-7%. Two subjects developed neutralizing antibodies without discernable effects on pharmacokinetics, pharmacodynamics, or safety. Adverse event rates were balanced between groups without any significant safety findings. These data support continued investigation of sclerostin inhibition in disorders that could benefit from increased bone formation.

A clinical therapeutic protein drug-drug interaction study: coadministration of denosumab and midazolam in postmenopausal women with osteoporosis.

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.

Pharmacological inhibition of myostatin and changes in lean body mass and lower extremity muscle size in patients receiving androgen deprivation therapy for prostate cancer.

CONTEXT: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat, and currently available therapies have limited efficacy to treat this complication. The antimyostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice. OBJECTIVE: The objective of the study was to evaluate the safety, pharmacokinetics, and muscle efficacy of AMG 745 in men undergoing ADT for nonmetastatic prostate cancer. METHODS: This was a randomized, blinded, placebo-controlled, multiple-dose, phase 1 study of AMG 745 given for 28 days. The end point of percentage change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry was prespecified. RESULTS: Rates of adverse events (AMG 745 vs placebo) were the following: diarrhea (13% vs 9%), fatigue (13% vs 4%), contusion (10% vs 0%), and injection site bruising (6% vs 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg vs the placebo groups on day 29 by 2.2% (±0.8% SE, P = 0.008); in exploratory fat mass analysis, a decrease of -2.5% (±1.0% SE, P = 0.021) was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after day 29. CONCLUSION: Four weekly s.c. doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for nonmetastatic prostate cancer. RESULTS support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.