Graham Jang

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.

Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans

&NA; The vanilloid receptor TRPV1 has been identified as a molecular target for the treatment of pain associated with inflammatory diseases and cancer. Hence, TRPV1 antagonists have been considered for therapeutic evaluation in such diseases. During Phase I clinical trials with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicited marked, but reversible, and generally plasma concentration‐dependent hyperthermia. Similar to what was observed in rats, dogs, and monkeys, hyperthermia was attenuated after repeated dosing of AMG 517 (at the highest dose tested) in humans during a second Phase I trial. However, AMG 517 administered after molar extraction (a surgical cause of acute pain) elicited long‐lasting hyperthermia with maximal body temperature surpassing 40 °C, suggesting that TRPV1 blockade elicits undesirable hyperthermia in susceptible individuals. Mechanisms of AMG 517‐induced hyperthermia were then studied in rats. AMG 517 caused hyperthermia by inducing tail skin vasoconstriction and increasing thermogenesis, which suggests that TRPV1 regulates vasomotor tone and metabolic heat production. In conclusion, these results demonstrate that: (a) TRPV1‐selective antagonists like AMG 517 cannot be developed for systemic use as stand alone agents for treatment of pain and other diseases, (b) individual susceptibility influences magnitude of hyperthermia observed after TRPV1 blockade, and (c) TRPV1 plays a pivotal role as a molecular regulator for body temperature in humans.

Dietary effects on drug metabolism and transport.

Metabolic food-drug interactions occur when the consumption of a particular food modulates the activity of a drug-metabolising enzyme system, resulting in an alteration of the pharmacokinetics of drugs metabolised by that system. A number of these interactions have been reported. Foods that contain complex mixtures of phytochemicals, such as fruits, vegetables, herbs, spices and teas, have the greatest potential to induce or inhibit the activity of drug-metabolising enzymes, although dietary macroconstituents (i.e. total protein, fat and carbohydrate ratios, and total energy intake) can also have effects. Particularly large interactions may result from the consumption of herbal dietary supplements.Cytochrome P450 (CYP) 3A4 appears to be especially sensitive to dietary effects, as demonstrated by reports of potentially clinically important interactions involving orally administered drugs that are substrates of this enzyme. For example, interactions of grapefruit juice with cyclosporin and felodipine, St John’s wort with cyclosporin and indinavir, and red wine with cyclosporin, have the potential to require dosage adjustment to maintain drug concentrations within their therapeutic windows. The susceptibility of CYP3A4 to modulation by food constituents may be related to its high level of expression in the intestine, as well as its broad substrate specificity. Reported ethnic differences in the activity of this enzyme may be partly due to dietary factors.Food-drug interactions involving CYP1A2, CYP2E1, glucuronosyltransferases and glutathione S-transferases have also been documented, although most of these interactions are modest in magnitude and clinically relevant only for drugs that have a narrow therapeutic range. Recently, interactions involving drug transporters, including P-glycoprotein and the organic anion transporting polypeptide, have also been identified. Further research is needed to determine the scope, magnitude and clinical importance of food effects on drug metabolism and transport.

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.

Population Pharmacokinetic Meta-Analysis of Denosumab in Healthy Subjects and Postmenopausal Women with Osteopenia or Osteoporosis

AbstractBackground and Objective: Inhibition of the receptor activator of nuclear factor k-B ligand (RANKL) is a therapeutic target for treatment of bone disorders associated with increased bone resorption, such as osteoporosis. The objective of this analysis was to characterize the population pharmacokinetics of denosumab (AMG 162; Prolia®), a fully human IgG2 monoclonal antibody that binds to RANKL, in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Methods: A total of 22944 serum free denosumab concentrations from 495 healthy subjects and 1069 post-menopausal women with osteopenia or osteoporosis were pooled. Denosumab was administered as either a single intravenous dose (n = 36), a single subcutaneous dose (n = 469) or multiple subcutaneous doses (n= 1059), ranging from 0.01 to 3 mg/kg (or 6–210 mg as fixed mass dosages), every 3 or 6 months for up to 48 months. An open, two-compartment pharmacokinetic model with a quasi-steady-state approximation of the target-mediated drug disposition model was used to describe denosumab pharmacokinetics, using NONMEM Version 7.1.0 software. Subcutaneous absorption was characterized by the first-order absorption rate constant (ka), with constant absolute bioavailability over the range of doses that were evaluated. Clearance and volume of distribution parameters were scaled by body weight, using a power model. Model evaluation was performed through visual predictive checks. Results: The subcutaneous bioavailability of denosumab was 64%, and the ka was 0.00883 h−1. The central volume of distribution and linear clearance were 2.49 L/66 kg and 3.06 mL/h/66 kg, respectively. The baseline RANKL level, quasi-steady-state constant and RANKL degradation rate were 614ng/mL, 138 ng/mL and 0.00148 h−1, respectively. Between-subject variability in model parameters was moderate. A fixed dose of 60 mg provided RANKL inhibition similar to that achieved by equivalent body weight-based dosing. The effects of age and race on the area under the serum concentration-time curve of denosumab were less than 15% over the range of covariate values that were evaluated. Conclusions: The non-linearity in denosumab pharmacokinetics is probably due to RANKL binding, and denosumab dose adjustment based on the patient demographics is not warranted.

Population Pharmacokinetic Analysis of Denosumab in Patients with Bone Metastases from Solid Tumours

Background and ObjectiveDenosumab (XGEVA®; AMG 162) is a fully human IgG2 monoclonal antibody, which binds to the receptor activator of nuclear factor K-B ligand (RANKL) and prevents terminal differentiation, activation and survival of osteoclasts. We aimed to characterize the population pharmacokinetics of denosumab in patients with advanced solid tumours and bone metastases.MethodsA total of 14 228 free serum concentrations of denosumab from 1076 subjects (495 healthy subjects and 581 advanced cancer patients with solid tumours and bone metastases) included in 14 clinical studies were pooled. Denosumab was administered as either single intravenous (n= 36), single subcutaneous (n= 490) or multiple subcutaneous doses (n = 550) ranging from 30 to 180 mg (or from 0.01 to 3 mg/kg) and was given every 4 or 12 weeks for up to 3 years. An open two-compartment pharmacokinetic model with first-order absorption, linear distribution to a peripheral compartment, linear clearance and quasi-steady-state approximation of the target-mediated drug disposition was used to describe denosumab pharmacokinetics, using NONMEM Version 7.1.0 software. The influence of covariates (body weight, age, race, tumour type) was investigated using the full model approach. Model evaluation was performed through visual predictive checks. Model-based simulations were conducted to explore the role of covariates on denosumab serum concentrations and inferred RANKL occupancy.ResultsAfter subcutaneous administration, the dose-independent bioavailability and mean absorption half-life of denosumab were estimated to be 61% and 2.7 days, respectively. The central volume of distribution and linear clearance were 2.62L/66kg and 3.25mL/h/66kg, respectively. Clearance and volume parameters were proportional to body weight. Assuming 1:1 denosumab-RANKL binding, the baseline RANKL level, quasi-steady-state constant and RANKL degradation rate were inferred to be 4.46 nmol/L, 208ng/mL and 0.00116 h-1, respectively. Between-subject variability in model parameters was moderate. Following 120 mg dosing every 4 weeks, the inferred RANKL occupancy at steady state exceeded 97% during the entire dosing interval in more than 95% of subjects, regardless of the patient covariates.ConclusionsThe integration of pharmacokinetic data from 14 clinical studies demonstrated denosumab RANKL-mediated pharmacokinetics. Pharmacokinetics-based dosage adjustments on the basis of body weight, age, race and tumour type are not necessary in patients with bone metastases from solid tumours.

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 objectiveAnaemia 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 µg/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.MethodsTwenty 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 µg/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 µg/kg.ResultsThe 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.ConclusionBased 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.

Investigation of the Effects of Altered Receptor Binding Activity on the Clearance of Erythropoiesis-Stimulating Proteins: Nonerythropoietin Receptor-Mediated Pathways may Play a Major Role

Erythropoietin (EPO) receptor-mediated endocytosis and degradation in the bone marrow has been hypothesized to be the major clearance pathway of erythropoiesis-stimulating agents (ESA). We investigated the role of this pathway in ESA clearance by determining the pharmacokinetic profiles after intravenous (IV) dosing in rats and mice of recombinant human EPO (rHuEPO) and rHuEPO derivatives with different receptor binding activities and biochemical properties. These derivatives included NM385 (no detectable receptor binding activity), hyperglycosylated analogs with different carbohydrate contents and receptor binding activities; (NM294: +1 carbohydrate chain; darbepoetin alfa: +2 carbohydrate chains) and polyethylene glycol (PEG) derivatives (PEG-darbepoetin alfa, PEG-rHuEPO and PEG-NM385). After IV administration in rats, NM385 had a mean clearance (CL) similar to rHuEPO. Hyperglycosylated ESAs, compared with rHuEPO, had a progressively longer half-life (t(1/2)) and a progressively slower CL with increasing number of carbohydrates or amount of added PEG that correlated more closely with carbohydrate and/or PEG content than receptor binding activity. Taken together, these results suggest that (1) EPO receptor-independent pathway(s) play a substantial role in ESA clearance; (2) the longer half-life and reduced clearance of hyperglycosylated and/or PEGylated ESAs are primarily the result of decreased susceptibility to receptor-independent elimination mechanisms.

Denosumab Dose Selection for Patients with Bone Metastases from Solid Tumors

Purpose: To quantitatively characterize the longitudinal dose exposure–response [urinary N-telopeptide normalized to urinary creatinine (uNTx/Cr) suppression] relationship for denosumab in patients with bone metastases from solid tumors. Experimental Design: Data from 373 patients who received denosumab as single or multiple subcutaneous doses ranging from 30 to 180 mg (or 0.01 to 3 mg/kg) administered every 4 or 12 weeks for up to 3 years were used in this analysis. An inhibitory sigmoid IMax model was used to characterize the time course of uNTx/Cr as a function of serum denosumab concentrations and the M3 method was used to analyze the 52% of uNTx/Cr values below the limit of quantification in the context of a mixed-effects model. Age, weight, sex, race, and cancer type were evaluated as potential covariates for model parameters. Model-based simulations were undertaken to explore and predict the role of denosumab dose and dosing intervals on uNTx/Cr suppression. Results: The typical value (between-subject variability; %) for uNTx/Cr at baseline was 49.2 nmol/L/mmol/L (76.8%), denosumab maximal uNTx/Cr suppression (efficacy) was 93.7% (127%), and the denosumab concentration providing half-maximal uNTx/Cr suppression (potency) was 31.8 ng/mL (287%). No effect of covariates on denosumab efficacy and potency was identified. Simulations indicated that a s.c. denosumab dose of 120 mg administered every 4 weeks provides more than 90% suppression of uNTx/Cr in the maximum proportion of patients relative to other every 4- and 12-week doses evaluated. Conclusions: Over the wide range of dosing regimens examined, a s.c. denosumab dose of 120 mg administered every 4 weeks is the optimal dosing regimen to suppress uNTx/Cr in patients with bone metastases from solid tumors. Clin Cancer Res; 18(9); 2648–57. ©2012 AACR.

Drug interactions involving ethanol and alcoholic beverages

Ethanol is likely among the most widely and extensively used drugs in the world. It has also been demonstrated to alter the expression or activity of some drug-metabolizing enzymes. Thus, marked ethanol-provoked drug interactions could be of notable clinical importance. To date, relatively few clinically important interactions have been reported, involving cocaine, disulfiram and tacrolimus. Limited or modest interactions with ethanol have also been reported for drugs such as abacavir, cisapride, ‘ecstasy’ (3,4-methylenedioxymetamfetamine), γ-hydroxybutyrate, methylyphenidate, metronidazole and verapamil. Most of these interactions do not seem to involve CYP2E1, the enzyme initially characterized and cloned based on its ability to metabolize and be induced by ethanol. Important work has elucidated the relationship between CYP2E1-mediated formation of the hepatotoxic metabolite of acetaminophen and alcohol consumption. Lastly, drug interactions involving other components of alcoholic beverages such as flavonoid and other polyphenolic components of red wine have been reported.