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.

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.

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.

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.

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.

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.

A single-dose study of denosumab in patients with various degrees of renal impairment.

This 16-week study evaluated pharmacokinetics and pharmacodynamics of denosumab in 55 subjects with renal function ranging from normal to dialysis-dependent kidney failure. Participants received a single 60-mg subcutaneous dose of denosumab. Kidney function groups were based on calculations using the Cockcroft-Gault equation and U.S. Food and Drug Administration (FDA) guidance in place when the study was designed. Renal function did not have a significant effect on denosumab pharmacokinetics or pharmacodynamics. These findings suggest denosumab dose adjustment based on glomerular filtration rate is not required. Rapid decreases in serum C-telopeptide in all groups were sustained throughout the study. The most common adverse events were hypocalcemia (15%), pain in extremity (15%), and nausea (11%). Most adverse events were mild to moderate in severity. Calcium and vitamin D supplementation was not initially required by the study protocol, but was added during the trial. No subject who received adequate calcium and vitamin D supplementation became hypocalcemic. Seven subjects had nadir serum calcium concentrations between 7.5 and <8.0 mg/dL (1.9 and <2.0 mmol/L), and 5 subjects (4 with advanced renal disease) had nadir serum calcium <7.5 mg/dL (<1.9 mmol/L). Two subjects (1 symptomatic, 1 asymptomatic) were hospitalized for intravenous calcium gluconate treatment. At the recommended dose, denosumab is a useful therapeutic option for patients with impaired renal function. Supplementation of calcium and vitamin D is strongly recommended when patients initiate denosumab therapy, particularly in patients with reduced renal function.

A randomized, double-blind, placebo-controlled, single-dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of denosumab administered subcutaneously to postmenopausal Japanese women.

Denosumab is a fully human monoclonal antibody that has high affinity for RANK ligand (RANKL). RANKL is the essential mediator of osteoclast formation, function and survival. The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of denosumab in healthy postmenopausal Japanese women were assessed. This was a randomized, double-blind, dose-escalation study in which 40 subjects received denosumab at doses of 0.03, 0.1, 0.3, 1.0 or 3.0mg/kg, or placebo administered subcutaneously. Blood and urine samples for determination of serum denosumab, CTX-I, NTX-I/Cr, bone specific alkaline phosphatase (bone ALP) and intact parathyroid hormone (iPTH) were collected. The PK and PD time profiles were compared to those obtained in separate studies conducted in the US. No serious adverse events occurred and all subjects completed this study. Denosumab demonstrated nonlinear PK and dose- and concentration-dependent dispositions. The maximum mean decrease from baseline ranged from 65% to 95% for CTX-I concentrations and from 50% to 85% for NTX-I/Cr. Additionally, the changes were dose-dependent. The suppression of bone turnover markers was rapid (within 2 days after dosing) and duration of suppression was dose-dependent. No marked differences in the PK and PD profiles between Japanese and non-Japanese subjects were noted. The observed results indicate that denosumab may have therapeutic potential for conditions resulting from increased bone turnover, such as osteoporosis in Japanese.

Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody.

Sclerostin, an osteocyte-secreted protein, negatively regulates osteoblasts and inhibits bone formation. In this first-in-human study, a sclerostin monoclonal antibody (AMG 785) was administered to healthy men and postmenopausal women. In this phase I, randomized, double-blind, placebo-controlled, ascending, single-dose study, 72 healthy subjects received AMG 785 or placebo (3:1) subcutaneously (0.1, 0.3, 1, 3, 5, or 10 mg/kg) or intravenously (1 or 5 mg/kg). Depending on dose, subjects were followed for up to 85 days. The effects of AMG 785 on safety and tolerability (primary objectives) and pharmacokinetics, bone turnover markers, and bone mineral density (secondary objectives) were evaluated. AMG 785 generally was well tolerated. One treatment-related serious adverse event of nonspecific hepatitis was reported and was resolved. No deaths or study discontinuations occurred. AMG 785 pharmacokinetics were nonlinear with dose. Dose-related increases in the bone-formation markers procollagen type 1 N-propeptide (P1NP), bone-specific alkaline phosphatase (BAP), and osteocalcin were observed, along with a dose-related decrease in the bone-resorption marker serum C-telopeptide (sCTx), resulting in a large anabolic window. In addition, statistically significant increases in bone mineral density of up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo were observed on day 85. Six subjects in the higher-dose groups developed anti-AMG 785 antibodies, 2 of which were neutralizing, with no discernible effect on the pharmacokinetics or pharmacodynamics. In summary, single doses of AMG 785 generally were well tolerated, and the data support further clinical investigation of sclerostin inhibition as a potential therapeutic strategy for conditions that could benefit from increased bone formation.

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.

Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride.

Cinacalcet hydrochloride (cinacalcet) is a calcimimetic approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) receiving dialysis and for the treatment of hypercalcaemia in patients with parathyroid carcinoma. Following oral administration, peak plasma concentrations of cinacalcet occur within 2-6 hours. The absolute bioavailability is 20-25%, and administration of cinacalcet with low- or high-fat meals increases exposure (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)]) 1.5- to 1.8-fold. Cinacalcet has no significant interaction with calcium carbonate or sevelamer hydrochloride, phosphate binders commonly used in the treatment of patients with CKD receiving dialysis. The terminal elimination half-life is 30-40 hours, and steady-state concentrations are achieved within 7 days. The pharmacokinetics of cinacalcet are dose proportional over the dose range of 30-180 mg. The pharmacokinetic profile of cinacalcet is not notably affected by varying degrees of renal impairment. The pharmacokinetics of cinacalcet are comparable between healthy subjects, patients with primary hyperparathyroidism and patients with secondary hyperparathyroidism with reduced renal function (including those patients with secondary hyperparathyroidism receiving dialysis). Additionally, the pharmacokinetics of cinacalcet are similar in patients with secondary hyperparathyroidism receiving haemodialysis and patients with secondary hyperparathyroidism receiving peritoneal dialysis. Mild hepatic impairment does not affect the pharmacokinetics of cinacalcet, whereas moderate or severe hepatic impairment increases the exposure (AUC(infinity)) by approximately 2- and 4-fold, respectively. Age, sex, bodyweight and race do not notably affect the pharmacokinetics of cinacalcet. Cinacalcet is extensively metabolized by multiple hepatic cytochrome P450 (CYP) enzymes (primarily 3A4, 2D6 and 1A2) with <1% of the parent drug excreted in the urine. Dose adjustments of cinacalcet may be necessary, and parathyroid hormone (PTH) and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g. ketoconazole, erythromycin, itraconazole). Cinacalcet is a strong inhibitor of CYP2D6; therefore, dose adjustment of concomitant medications that are predominantly metabolized by CYP2D6 and have a narrow therapeutic index (e.g. flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required. Cinacalcet does not appreciably inhibit or induce the activities of CYP3A4, 1A2, 2C9 or 2C19. An inverse relationship exists between plasma PTH and cinacalcet concentrations. PTH concentrations are greatest before dose administration when the cinacalcet concentration is lowest (24 hours after the previous day's dose). Nadir PTH levels occur approximately 2-3 hours after dosing.

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.

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 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.

Pharmacology of darbepoetin alfa.

The distinct molecular structure of darbepoetin alfa, in both its amino acid sequence and its carbohydrate content, results in a biologic profile with lower binding affinity, longer circulating half-life, and higher in vivo potency compared with the epoetins. The mechanisms responsible for these differences in biological effects have not been fully explained. Pharmacokinetic investigations of darbepoetin alfa using prolonged blood sampling times established that the mean terminal half-life after subcutaneous (SC) administration is 70 to 105 hours. Pharmacodynamic studies were conducted to assess the suitability of darbepoetin alfa for use in weekly or less frequent (once every other week or once a month) dosing regimens to maintain haemoglobin levels in patients with anaemia of renal disease. Regardless of dialysis status, route of administration, or prior treatment with an erythropoiesis-stimulating agent, darbepoetin alfa administered at extended intervals was able to raise or maintain hemoglobin levels to target. More rigorous studies will be needed to confirm these findings.

The pharmacokinetics of cinacalcet are unaffected following consumption of high- and low-fat meals.

Cinacalcet HCl reduces iPTH, serum calcium, serum phosphorus, and the calcium-phosphorus product in patients with chronic kidney disease and secondary hyperparathyroidism who are receiving dialysis, and reduces elevated serum calcium associated with primary hyperparathyroidism and parathyroid carcinoma. Cinacalcet is administered orally, and thus concomitant administration with food may affect its bioavailability. The objective of this study was to examine the effect of fat and caloric intake on cinacalcet exposure. This phase 1, randomized, open-label, single-dose, 3-period, 3-treatment, 6-sequence crossover study enrolled 30 healthy subjects (19 men, 11 women) to receive a single oral dose of cinacalcet HCl (Sensipar/Mimpara; Amgen Inc. Thousand Oaks, CA) (90 mg) on 3 separate occasions: following a high-fat, high-caloric meal, a low-fat, low-caloric meal, and a 10-hour fast. Blood samples were obtained predose and up to 72 hours postdose for pharmacokinetic (AUCinfinity, Cmax) and safety evaluations. Twenty-nine subjects completed all the 3 treatment conditions. The mean (90% confidence intervals) AUCinfinity following high- and low-fat meals was increased by 68 (48 to 89)% and 50 (33 to 70)%, respectively, relative to fasting. The difference in mean AUCinfinity between high- and low-fat meals was small [12 (9.9-26)%]. The mean tmax of cinacalcet was prolonged in fasting subjects (6 h) in relation to high-fat (4 h) and low-fat (3.5 h) fed subjects. The mean t1/2beta was similar between treatment conditions. Adverse events (AE) were observed at a similar frequency across the treatment conditions [high fat (34%), low fat (23%), and fasting (31%)]; the type of AE did not differ among the treatment conditions. The most common treatment-related AEs were headache 6/30 (20%), nausea 5/30 (17%), and dyspepsia 4/30 (13%) subjects. Administration of cinacalcet with either high- or low-fat meals results in significant increases in exposure, relative to administration under fasting conditions. However, the small differences observed in exposure following the ingestion of the different types of meals suggest that although food has a significant effect, the type of food does not. The observed effect supports the labeling statement that cinacalcet be taken with food, or shortly after a meal.

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.

Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl.

OBJECTIVE: In vitro work has demonstrated that cinacalcet is a strong inhibitor of cytochrome P450 isoenzyme (CYP) 2D6. The purpose of this study was to evaluate the effect of cinacalcet on CYP2D6 activity, using desipramine as a probe substrate, in healthy subjects. METHODS: Seventeen subjects who were genotyped as CYP2D6 extensive metabolizers were enrolled in this randomized, open-label, crossover study to receive a single oral dose of desipramine (50 mg) on two separate occasions, once alone and once after multiple doses of cinacalcet (90 mg for 7 days). Blood samples were obtained predose and up to 72 h postdose. RESULTS: Fourteen subjects completed both treatment arms. Relative to desipramine alone, mean AUC and C(max) of desipramine increased 3.6- and 1.8-fold when coadministered with cinacalcet. The t (1/2,z) of desipramine was longer when desipramine was coadministered with cinacalcet (21.0 versus 43.3 hs). The t (max) was similar between the regimens. Fewer subjects reported adverse events following treatment with desipramine alone than when receiving desipramine with cinacalcet (33 versus 86%), the most frequent of which (nausea and headache) have been reported for patients treated with either desipramine or cinacalcet. CONCLUSION: This study demonstrates that cinacalcet is a strong inhibitor of CYP2D6. These data suggest that during concomitant treatment with cinacalcet, dose adjustment may be necessary for drugs that demonstrate a narrow therapeutic index and are metabolized by CYP2D6.