Clinical Pharmacokinetics and Pharmacodynamics of Etelcalcetide, a Novel Calcimimetic for Treatment of Secondary Hyperparathyroidism in Patients With Chronic Kidney Disease on Hemodialysis.

Etelcalcetide, a d-amino acid peptide, is an intravenous calcimimetic approved for the treatment of secondary hyperparathyroidism. Etelcalcetide binds the calcium-sensing receptor and increases its sensitivity to extracellular calcium, thereby decreasing secretion of parathyroid hormone (PTH) by chief cells. Etelcalcetide and its low-molecular-weight transformation products are rapidly cleared by renal excretion in healthy subjects, but clearance is substantially reduced and dependent on hemodialysis in end-stage renal disease. The effective half-life is 3-5 days in patients undergoing hemodialysis 3 times a week. A clinical study using a single microtracer intravenous dose of [14 C]etelcalcetide indicated that 60% of the administered dose was eliminated in dialysate. Etelcalcetide undergoes reversible disulfide exchange with serum albumin to form a serum albumin peptide conjugate that is too large (67 kDa) to be dialyzed, until a subsequent exchange forms etelcalcetide or a low-molecular-weight transformation product. This exchange from albumin is apparent after hemodialysis, when it partially restores etelcalcetide concentrations in plasma. Etelcalcetide has no known risks for drug-drug interactions. In phase 3 studies, 74%-75% of hemodialysis patients with secondary hyperparathyroidism who received etelcalcetide achieved a >30% PTH reduction from baseline versus 8%-10% of patients who received placebo. The pharmacokinetics and pharmacodynamics of etelcalcetide in hemodialysis patients supports a 5-mg starting dose administered after hemodialysis and uptitration in 2.5- or 5-mg increments every 4 weeks to a maximum dose of 15 mg 3 times a week.

Population Pharmacokinetic and Pharmacodynamic Modeling of Etelcalcetide in Patients with Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis.

INTRODUCTION: Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). METHODS: To assess titrated dosing regimens, population pharmacokinetic (PK) and PK/pharmacodynamic (PKPD) modeling of etelcalcetide was performed using NONMEM 7.2. In this analysis, plasma etelcalcetide, serum parathyroid hormone (PTH) and calcium (Ca) concentration-time data were collected from five phase I, II, and III clinical trials following single or multiple intravenous doses of etelcalcetide ranging from 2.5 to 60 mg. A semi-mechanistic model was used to describe the relationship between etelcalcetide, PTH, and Ca. This model included the role of PTH in Ca regulation, the feedback of Ca onto PTH production via the CaSR, and the activity of etelcalcetide plasma levels in increasing the sensitivity of the CaSR to Ca via the cooperative binding model. The impact of relevant covariates was evaluated by stepwise forward/backward selection. Model evaluation was based on standard goodness-of-fit plots and prediction-corrected visual predictive checks (pcVPCs). Simulation was conducted to evaluate titrated dosing regimens. RESULTS AND DISCUSSION: The time courses of etelcalcetide, PTH, and Ca were well-described by the model. The clearance and central volume of distribution (Vc) of etelcalcetide were 0.472 L/h and 49.9 L, respectively, while estimates of the turnover half-lives of PTH and Ca were 0.36 and 23 h, respectively. The extent of interindividual variability in model parameters was low to moderate (6-67%), and no covariates were identified as significant predictors of PK and PD variability. pcVPCs confirmed the predictive ability of the model. CONCLUSIONS: The current analysis confirms the putative mechanism of action of etelcalcetide as an allosteric activator of CaSR. Simulations showed that dose titration of etelcalcetide, rather than fixed dose, is needed to effectively decrease the PTH level in patient populations.

Development of Romiplostim for Treatment of Primary Immune Thrombocytopenia From a Pharmacokinetic and Pharmacodynamic Perspective.

Romiplostim is a novel thrombopoiesis-stimulating peptibody consisting of a carrier Fc domain and a peptide domain that binds to the thrombopoietin receptor (TPOR) on platelets and platelet precursors. Similar to endogenous thrombopoietin, romiplostim activates the TPOR to stimulate the growth and maturation of megakaryocytes, resulting in increased production of platelets in the circulation. Binding of romiplostim to TPOR on the platelets and megakaryocytes presumably triggers subsequent internalization and degradation. Therefore, increased platelet counts following romiplostim treatment results in increased elimination of the drug. The TPOR target-mediated process is saturable, resulting in nonlinear volume of distribution and clearance of romiplostim. Therefore, target-mediated disposition plays a decreasing role in drug elimination with increasing romiplostim serum concentration. Conversely, nonspecific elimination processes such as renal clearance play an increasing role with increasing romiplostim serum concentration. Limited pharmacokinetics data demonstrated that the exposure to romiplostim was lower after multiple dose administrations than after the first dose, although large inter-subject variability was observed. Large inter- and intra-subject variability in the platelet response was also observed at a given dose. These findings suggest considerable heterogeneity of disease in patients with primary immune thrombocytopenia and support the need for individual dose adjustments based on platelet counts.

Pharmacokinetic and pharmacodynamic modeling of romiplostim in animals.

PURPOSE: Romiplostim is a novel thrombopoiesis-stimulating peptibody that targets the thrombopoietin c-Mpl receptor, resulting in increased platelet production. The pharmacodynamic-mediated disposition (PDMDD) and its stimulatory effect on platelet production in Sprague-Dawley rats, rhesus monkeys, and cynomolgus monkeys following IV bolus and SC administration at various dose levels were determined. METHODS: The pharmacokinetic (PK) profile was described by a PDMDD model that accounts for romiplostim binding to the c-Mpl receptor. The PD model contained a series of aging compartments for precursor cells in bone marrow and platelets. The stimulatory function was described by an on-and-off function operating on the fractional receptor occupancy (RO). The threshold effect, RO(thr), and K(D) parameters were determinants of drug potency, whereas S(max) reflected drug efficacy. RESULTS: The model implicated that receptor-mediated clearance was negligible. RO(thr) estimated occupancies were 0.288, 0.385, 0.771 for rats, rhesus, and cynomolgus monkeys, respectively. The analogous estimated values of K(D) were 4.05, 2320, and 429 ng/mL, implying that romiplostim was much more potent in rats, which was confirmed by a dose-response (ratio of peak platelet count to baseline) relationship. CONCLUSIONS: The model adequately described romiplostim serum concentrations and platelet counts in rats, rhesus monkeys, and cynomolgus monkeys, and quantified linear clearance, PDMDD, and potency of romiplostim.

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours.

BACKGROUND AND OBJECTIVE: Denosumab (XGEVA®; AMG 162) is a fully human IgG2 monoclonal antibody, which binds to the receptor activator of nuclear factor κ-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. METHODS: A 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. RESULTS: After 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 2.62 L/66 kg and 3.25 mL/h/66 kg, 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, 208 ng/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. CONCLUSIONS: The 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.

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 I(Max) 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.

Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis.

BACKGROUND AND OBJECTIVE: Inhibition of the receptor activator of nuclear factor κ-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 postmenopausal 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 (k(a)), 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 k(a) 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 614 ng/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.

Pharmacodynamics-mediated drug disposition (PDMDD) and precursor pool lifespan model for single dose of romiplostim in healthy subjects.

The objective of this study was to characterize the pharmacokinetics and pharmacodynamics (PK-PD) of romiplostim after single-dose administration in healthy subjects. The mean serum romiplostim concentrations (PK data) and mean platelet counts (PD data) collected from 32 subjects receiving a single intravenous (0.3, 1 and 10 µg/kg) or subcutaneous (0.1, 0.3, 1, and 2 µg/kg) dose were fitted simultaneously to a mechanistic PK-PD model based on pharmacodynamics-mediated drug disposition (PDMDD) and a precursor pool lifespan concept. The two-compartment PK model incorporated receptor-mediated endocytosis and linear mechanisms as parallel elimination pathways. The maximal concentration of receptors (assumed to be proportional to the platelet count), the equilibrium dissociation constant, and the first-order internalization rate constant for endocytosis of the drug-receptor complex were 0.022 fg/platelet, 0.131 ng/mL, and 0.173 h⁻¹, respectively. Romiplostim concentration stimulates the production of platelet precursors via the Hill function, where the SC50 was 0.052 ng/mL and S (max) was 11.2. The estimated precursor cell and platelet lifespans were 5.9 and 10.5 days, respectively. Model-based simulations revealed that the romiplostim exposure and the platelet response are both dependent on the dose administered and the baseline platelet counts. Also, weekly dosing produced a sustained PD response while dosing intervals ≥2 weeks resulted in fluctuating platelet counts. Thus, the mechanistic PK-PD model was suitable for describing the romiplostim PK-PD interplay (PDMDD), the dose-dependent platelet stimulation, and the lifespans of thrombopoietic cell populations.

Population cell life span models for effects of drugs following indirect mechanisms of action.

Pharmacokinetic/pharmacodynamic (PK/PD) models for hematological drug effects exist that assume that cells are produced by a zero- or first-order process, survive for a specific duration (cell lifespan), and then are lost. Due to the fact that delay differential equations (DDE) are needed for cell lifespan models, their software implementation is not straightforward. Our objective is to demonstrate methods to implement three different cell lifespan models for dealing with hematological drug effects and to evaluate the performance of NONMEM to estimate the model parameters. For the basic lifespan indirect response (LIDR) model, cells are produced by a zero-order process and removed due to senescence. The modified LIDR model adds a precursor pool. The LIDR model of cytotoxicity assumes a three-pool indirect model to account for the cell proliferation with capacity-limited cytotoxicity followed by maturation, and removal from the circulation. A numerical method (method of steps) implementing DDE in NONMEM was introduced. Simulation followed by estimation was used to evaluate NONMEM performance and the impact of the minimization algorithm (first-order method vs. first-order conditional estimation method) and the model for residual variability on the estimates of the population parameters. The FOCE method combined with log-transformation of data was found to be superior. This report provides methodology that will assist in application of population methods for assessing hematological responses to various types of drugs.