Sameer Doshi

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 Pharmacokinetics of Rilotumumab, a Fully Human Monoclonal Antibody Against Hepatocyte Growth Factor, in Cancer Patients

Rilotumumab is an investigational, fully human, monoclonal antibody immunoglobulin G2 against hepatocyte growth factor (HGF) that blocks the binding of HGF to its receptor MET and has shown trends toward improved survival in a phase 2 clinical trial in gastric cancer. To characterize rilotumumab pharmacokinetics in patients with cancer and to identify factors affecting the pharmacokinetics, rilotumumab concentration data from seven clinical trials were analyzed with a nonlinear mixed-effect model. We found that rilotumumab exhibited linear and time-invariant kinetics over a dose range of 0.5-20 mg/kg. Typical systemic clearance and central volume of distribution were 0.184 L/day and 3.56 L, respectively. Body weight is the most significant covariate, and sex, cancer type, coadministration of chemotherapeutics, baseline plasma HGF and tumor MET levels, and renal and hepatic functions did not have an effect on rilotumumab pharmacokinetics. The concentration-time profiles for the rilotumumab clinical regimens were projected well with the model.

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.

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.

Exposure-response analysis of rilotumumab in gastric cancer: The role of tumour MET expression

Background:Rilotumumab, an investigational, monoclonal antibody, inhibits MET-mediated signalling. In a randomized phase 2 trial of rilotumumab±epirubicin/cisplatin/capecitabine in gastric or oesophagogastric junction cancer, patients receiving rilotumumab showed a trend towards improved survival, especially in MET-positive patients, but no clear dose–response relationship was observed. Exposure-response and biomarker analyses were used for dose selection and to differentiate patient subpopulations that may benefit most from treatment. Here, we analyse rilotumumab exposure–survival and exposure–safety and the impact of MET expression on these relationships.Methods:Individual rilotumumab exposure parameters were generated using population pharmacokinetic modelling. Relationships among rilotumumab dose (7.5 and 15 mg kg−1), exposure, and clinical outcomes (progression-free survival (PFS) and overall survival (OS)) were evaluated with Cox regression models and Kaplan–Meier plots. MET status and other baseline covariates were evaluated in subgroup and multivariate analyses. Treatment-emergent adverse events were summarised by exposure.Results:Among MET-positive patients, higher rilotumumab exposure, vs placebo and low exposure, was associated with improved median PFS (80% CI: 7.0 (5.7–9.7) vs 4.4 (2.9–4.9) and 5.5 (4.2–6.8) months) and OS (13.4 (10.6–18.6) vs 5.7 (4.7–10.2) and 8.1 (6.9–11.1) months) without increased toxicity. No rilotumumab benefit was seen among MET-negative patients.Conclusions:Rilotumumab had an exposure-dependent treatment effect in patients with MET-positive gastric or oesophagogastric junction cancer.

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.

Exposure‐Response Modeling of Darbepoetin Alfa in Anemic Patients With Chronic Kidney Disease Not Receiving Dialysis

A population pharmacokinetic and pharmacodynamic model (PK/PD) of darbepoetin alfa following intravenous (IV) or subcutaneous (SC) administration in participants with chronic kidney disease (CKD) was developed. Darbepoetin alfa concentrations from 96 CKD participants, who received IV or SC darbepoetin alfa, and Hgb concentration from 332 CKD participants not on dialysis, who received SC doses of darbepoetin alfa, were used to develop the PK/PD model. An open 2‐compartment model with sequential zero‐ and first‐order absorption was used to characterize darbepoetin alfa pharmacokinetics. Darbepoetin alfa was assumed to trigger concentration‐dependent stimulation of production of progenitor cells of red blood cells (RBCs) in bone marrow, which become red blood cells and died after life span expiration. Model evaluation was performed through nonparametric bootstrap and posterior predictive checks. Absolute bioavailability, total mean absorption time, clearance, and volume of distribution were estimated to be 44%, 52 h, 3.4 L/d/70 kg, and 5.9 L/70 kg, respectively. The estimates of drug potency, efficacy, and RBC life span were 0.41 ng/mL, 64%, and 77 days, respectively. Pharmacokinetic or pharmacodynamic parameters of darbepoetin alfa were not affected by age and sex. The qualified model supports the use of darbepoetin alfa administered biweekly (SC) in CKD patients for anemia correction and monthly (SC) for hemoglobin maintenance. In addition, the model is deemed appropriate to conduct simulations to support dose selection for additional clinical studies.

Rilotumumab Exposure-Response Relationship in Patients With Advanced or Metastatic Gastric Cancer

Purpose: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase II study, trends toward improved survival were observed with rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure–response [tumor growth (TG) and overall survival (OS)] relationship for rilotumumab. Experimental Design: Rilotumumab concentrations, tumor sizes, and survival time from the phase II study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, nonparametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between rilotumumab dose and OS. Results: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to rilotumumab than MET-negative patients. Simulations predicted a median (95% confidence interval) HR of 0.38 (0.18–0.60) in MET-positive patients treated with 15 mg/kg rilotumumab Q3W. Conclusions: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase II testing of rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072). Clin Cancer Res; 21(11); 2453–61. ©2015 AACR.

Tumor penetration and epidermal growth factor receptor saturation by panitumumab correlate with antitumor activity in a preclinical model of human cancer

BackgroundSuccessful treatment of solid tumors relies on the ability of drugs to penetrate into the tumor tissue.MethodsWe examined the correlation of panitumumab (an anti-epidermal growth factor [EGFR] antibody) tumor penetration and EGFR saturation, a potential obstacle in large molecule drug delivery, using pharmacokinetics, pharmacodynamics, and tumor growth rate in an A431 epidermoid carcinoma xenograft model of human cancer. To determine receptor saturation, receptor occupancy, and levels of proliferation markers, immunohistochemical and flow cytometric methods were used. Pharmacokinetic data and modeling were used to calculate growth characteristics of panitumumab-treated tumors.ResultsTreatment with panitumumab in vivo inhibited pEGFR, Ki67 and pMAPK levels vs control. Tumor penetration and receptor saturation were dose- and time-dependent, reaching 100% and 78%, respectively. Significant tumor inhibition and eradication (p < 0.05) were observed; plasma concentration associated with tumor eradication was estimated to be 0.2 μg/ml. The tumor inhibition model was able to describe the mean tumor growth and death rates.ConclusionsThese data demonstrate that the antitumor activity of panitumumab correlates with its ability to penetrate into tumor tissue, occupy and inhibit activation of EGFR, and inhibit markers of proliferation and MAPK signaling.

Impact of Target-Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9).

Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) relationship of a therapeutic monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) exhibiting target‐mediated drug disposition (TMDD) is critical for selecting optimal dosing regimens. We describe the PK/PD relationship of evolocumab using a mathematical model that captures evolocumab binding and removal of unbound PCSK9 as well as reduction in circulating low‐density lipoprotein cholesterol (LDL‐C). Data were pooled from 2 clinical studies: a single‐dose escalation study in healthy subjects (7‐420 mg SC; n = 44) and a multiple‐dose escalation study in statin‐treated hypercholesterolemic patients (14 mg weekly to 420 mg monthly [QM] SC; n = 57). A TMDD model described the time course of unbound evolocumab concentrations and removal of unbound PCSK9. The estimated linear clearance and volume of evolocumab were 0.256 L/day and 2.66 L, respectively, consistent with other monoclonal antibodies. The time course of LDL‐C reduction was described by an indirect response model with the elimination rate of LDL‐C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with half‐maximal inhibition (IC50) of LDL‐C elimination was 1.46 nM. Based on simulations, 140 mg every 2 weeks (Q2W) and 420 mg QM were predicted to achieve a similar time‐averaged effect of 69% reduction in LDL‐C in patients on statin therapy, suggesting that an approximate 3‐fold dose increase is required for a 2‐fold extension in the dosing interval. Evolocumab dosing regimens of 140 mg Q2W or 420 mg QM were predicted to result in comparable reductions in LDL‐C over a monthly period, consistent with results from recently completed phase 3 studies.