Estimation of time to progression and post progression survival using joint modeling of summary level OS and PFS data with an ordinary differential equation model.

measures such as progression-free survival (PFS) and overall survival (OS) are commonly reported in literature for oncology trials, while time to progression (TTP) and post progression survival (PPS) are not usually reported. A time-variant transition hazard model was developed using an ordinary differential equation (ODE) model to estimate TTP and PPS from summary level PFS and OS. The model was applied to published data from immune checkpoint inhibitor trials for non-small cell lung cancer (NSCLC) in a meta-analysis framework. This model-based method was able to robustly estimate TTP and PPS from summary level OS and PFS data, provided a quantitative approach for understanding the patterns of disease progression across different treatments through the time-variant disease progression rate function, and provided a summary of how different treatments affect TTP and PPS. The proposed method can be generalized to characterize and quantify multiple time-to-event endpoints jointly in oncology trials and improve our understanding of disease prognostics for different treatments.

Quantification of Radiation Injury on Neutropenia and the Link between Absolute Neutrophil Count Time Course and Overall Survival in Nonhuman Primates Treated with G-CSF.

PURPOSE: To model absolute neutrophil count (ANC) suppression in response to acute radiation (AR) exposure and evaluate ANC time course as a predictor of overall survival (OS) in response to AR exposure with or without treatment with granulocyte colony-stimulating factor in nonhuman primates. METHODS: Source data were obtained from two pivotal studies conducted in rhesus macaques exposed to 750 cGy of whole body irradiation on day 0 that received either placebo, daily filgrastim, or pegfilgrastim (days 1 and 8 after irradiation). Animals were observed for 60 days with ANC measured every 1 to 2 days. The population model of ANC response to AR and the link between observed ANC time course and OS consisted of three submodels characterizing injury due to radiation, granulopoiesis, and a time-to-event model of OS. RESULTS: The ANC response model accurately described the effects of AR exposure on the duration of neutropenia. ANC was a valid surrogate for survival because it explained 76% (95% CI, 41%-97%) and 73.2% (95% CI, 38.7%-99.9%) of the treatment effect for filgrastim and pegfilgrastim, respectively. CONCLUSION: The current model linking radiation injury to neutropenia and ANC time course to OS can be used as a basis for translating these effects to humans.

Exposure-response analysis of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukaemia and comparison with standard of care chemotherapy.

AIMS: The relationship between blinatumomab exposure and efficacy endpoints (occurrence of complete remission [CR] and duration of overall survival [OS]) or adverse events (occurrence of cytokine release syndrome [CRS] and neurological events) were investigated in adult patients with relapsed/refractory acute lymphoblastic leukaemia (r/r ALL) receiving blinatumomab or standard of care (SOC) chemotherapy to evaluate appropriateness of the blinatumomab dosing regimen. METHODS: Exposure, efficacy and safety data from adult patients (n = 646) with r/r ALL receiving stepwise (9 then 28 µg/day, 4-week cycle) continuous intravenous infusion (n = 537) of blinatumomab or SOC (n = 109) chemotherapy were pooled from phase 2 and 3 studies. The occurrence of CR, neurological and CRS events, and duration of OS were analysed using Cox proportional hazards models or logistic regression, as appropriate. Confounding factors were tested multivariately as needed. RESULTS: Blinatumomab steady-state concentration following 28 µg/day dosing was associated with the probability of achieving CR (odds ratio and 95% confidence interval: 1.073 [1.033-1.114]), and a longer duration of OS compared to SOC (hazard ratio and 95% confidence interval: 0.954 [0.936-0.973], P < .05) in multivariate analyses. The exposure-safety analyses indicated that blinatumomab steady-state concentration following the 9 or 28 µg/day dose was not associated with increased probability of CRS or neurological events, after accounting for blinatumomab treatment effect (P > .05). CONCLUSIONS: Blinatumomab step-dosing regimen of 9/28 µg/day provided treatment benefit in achieving CR and increasing the duration of OS over SOC and was appropriate in management of CRS and neurological events in patients with r/r ALL.

Population pharmacokinetics and exposure-response modeling and simulation for evolocumab in healthy volunteers and patients with hypercholesterolemia.

Evolocumab, a novel human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets low-density lipoprotein-cholesterol (LDL-C) receptors for the treatment of hyperlipidemia. The primary objective of this analysis was to characterize the population pharmacokinetics (popPK) and exposure-response relationship of evolocumab to assess if dose adjustment is needed across differing patient populations. Data were pooled for 5474 patients in 11 clinical studies who received evolocumab doses of 7-420 mg at various frequencies, either intravenously or subcutaneously. Evolocumab area under concentration-time curve from 8 to 12 weeks (AUCwk8-12) was simulated for individuals using the popPK model and was used to predict the LDL-C response in relation to AUCwk8-12. Evolocumab was eliminated through nonspecific (linear) and target-mediated (nonlinear) clearance. PopPK parameters and associated variabilities of evolocumab were similar to those of other monoclonal antibodies. The exposure-response model predicted a maximal 66% reduction in LDL-C from baseline to the mean of weeks 10 and 12 for doses of evolocumab 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. After inclusion of statistically significant covariates in an uncertainty-based simulation, LDL-C reduction from baseline at the mean of weeks 10 and 12 was predicted to be within 74% to 126% of the reference patient for all simulated patient groups. Evolocumab had nonlinear pharmacokinetics. The range of responses based on intrinsic and extrinsic factors was not predicted to be sufficiently different from the reference patient to warrant evolocumab dose adjustment.

Assessment of pharmacokinetic interaction between rilotumumab and epirubicin, cisplatin and capecitabine (ECX) in a Phase 3 study in gastric cancer.

AIMS: Rilotumumab is a fully human monoclonal antibody investigated for the treatment of MET-positive gastric cancer. The aim of this study was to evaluate the potential pharmacokinetic (PK)-based drug-drug interaction (DDI) between rilotumumab and epirubicin (E), cisplatin(C) and capecitabine (X). METHODS: This was a Phase 3 double-blind, placebo-controlled study, in which rilotumumab, epirubicin and cisplatin were administered intravenously at 15 mg kg-1 , 50 mg m-2 , and 60 mg m-2 Q3W, respectively, while capecitabine was given orally at 625 mg m-2 twice daily. Rilotumumab PK samples were taken at pre-dose and at the end-of-infusion from all patients in cycles 1, 3, 5 and 7. ECX PK samples were taken in cycle 3 from patients who participated in the intensive PK assessment. ECX PK was assessed by non-compartmental (NCA) analyses and PK parameters were compared between two arms. Rilotumumab PK was assessed by comparing the observed rilotumumab serum concentrations with model-predicted concentrations using a population PK model developed from previous Phase 1 and Phase 2 studies. RESULTS: The study enrolled 609 patients. ECX plasma concentrations in the presence and absence of rilotumumab were similar, as demonstrated by the geometric mean ratios for Cmax and AUC, which were close to 1.0, suggesting ECX PK was not affected by co-administration of rilotumumab. The observed rilotumumab serum concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, indicating rilotumumab exposure was not affected by co-administration of ECX. CONCLUSIONS: The results suggest lack of PK-based DDI between rilotumumab and ECX.

A multistate platform model for time-to-event endpoints in oncology clinical trials.

A multistate platform model was developed to describe time-to-event (TTE) endpoints in an oncology trial through the following states: initial, tumor response (TR), progressive disease (PD), overall survival (OS) event (death), censor to the last evaluable tumor assessment (progression-free survival [PFS] censor), and censor to study end (OS censor), using an ordinary differential equation framework. Two types of piecewise functions were used to describe the hazards for different events. Piecewise surge functions were used for events that require tumor assessments at the scheduled study visit times (TR, PD, and PFS censor). Piecewise constant functions were used to describe hazards for events that occur evenly throughout the study (OS event and OS censor). The multistate TTE model was applied to describe TTE endpoints from a published phase III study. The piecewise surge functions well-described the observed surges of hazards/events for TR, PD, PFS, and OS occurring near scheduled tumor assessments and showed good agreement with all Kaplan-Meier curves. With the flexibility of piecewise hazard functions, the model was able to evaluate covariate effects in a time-variant fashion to better understand the temporal patterns of disease prognosis through different disease states. This model can be applied to advance the field of oncology trial design and optimization by: (1) enabling robust estimations of baseline hazards and covariate effects for multiple TTE endpoints, (2) providing a platform model for understanding the composition and correlations between different TTE endpoints, and (3) facilitating oncology trial design optimization through clinical trial simulations.

Romiplostim dose-response in patients with myelodysplastic syndromes.

AIM: To characterize the romiplostim dose-response in subjects with low or intermediate-1 risk myelodysplastic syndromes (MDS) receiving subcutaneous romiplostim. METHODS: Data from 44 MDS subjects receiving subcutaneous romiplostim (dose range 300-1500 µg week(-1) ) were used to develop a pharmacodynamic model consisting of a romiplostim-sensitive progenitor cell compartment linked to the peripheral blood compartment through four transit compartments representing the maturation in the bone marrow from megakaryocytes to platelets. A kinetics of drug effect model was used to quantify the stimulatory effect of romiplostim on the proliferation of sensitive progenitor cells and pharmacodynamics-mediated disposition was modelled by assuming the kinetics of drug effect constant (kDE ) to be proportional to the change in platelet count relative to baseline. RESULTS: The estimated values (between subject variability) for baseline platelet count, mean transit time, and kDE were 24 × 10(9) l(-1) (47%), 9.6 days (44%) and 0.28 days(-1) , respectively. MDS subjects had a shorter platelet lifespan (42 h) than healthy subjects (257 h). Romiplostim effect was described for responders (78%) and non-responders (22%). The average weekly stimulatory effect of romiplostim on the production rate of sensitive progenitor cells at baseline was 269% per 100 µg week(-1) for responders. Body weight, age, gender and race were not statistically related to romiplostim pharmacodynamic parameters. Visual predictive checks confirmed the model adequacy. CONCLUSION: The time course of platelet counts in MDS subjects receiving subcutaneous administration of escalating doses of romiplostim was characterized and showed a linear dose-response for romiplostim responders to increase the platelet counts.

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Properties of Rozibafusp Alfa, a Bispecific Inhibitor of BAFF and ICOSL: Analyses of Phase I Clinical Trials.

Rozibafusp alfa (AMG 570) is a first-in-class bispecific IgG2-peptide fusion designed to inhibit inducible T-cell costimulator ligand (ICOSL) and B-cell activating factor (BAFF). The pharmacokinetics (PK) and pharmacodynamics (PD) of rozibafusp alfa were investigated in two randomized, placebo-controlled clinical studies: a phase Ia single ascending-dose study (7-700 mg subcutaneously (s.c.)) in healthy subjects and a phase Ib multiple ascending-dose study (70-420 mg s.c. every 2 weeks (q2w)) in patients with rheumatoid arthritis. Rozibafusp alfa exhibited nonlinear PK and dose-related and reversible dual-target engagement. Maximal reduction of naïve B cells from baseline (> 40%), reflective of BAFF inhibition, was achieved with rozibafusp alfa exposure (area under the concentration-time curve from time 0 to time infinity (AUCinf ) and AUC within a dosing interval from day 0 to day 14 (AUCtau )) above 51 and 57 days•µg/mL for the single-dose (≥ 70 mg) and multiple-dose studies (≥ 70 mg q2w), respectively. ICOSL receptor occupancy on circulating B cells, a surrogate PD end point for ICOSL inhibition, was directly related to drug concentration. PK/PD analysis showed > 90% RO at rozibafusp alfa ≥ 22.2 µg/mL (≥ 420-mg single dose or ≥ 210 mg q2w multiple dose), with saturation occurring at higher drug concentrations. These results informed the design and dose selection of a phase IIb study assessing the safety and efficacy of rozibafusp alfa in patients with active systemic lupus erythematosus.

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

BACKGROUND: Successful treatment of solid tumors relies on the ability of drugs to penetrate into the tumor tissue. METHODS: We 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. RESULTS: Treatment 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. CONCLUSIONS: These 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.

Establishing PK Equivalence Between Adalimumab and ABP 501 in the Presence of Antidrug Antibodies Using Population PK Modeling.

PURPOSE: ABP 501 (European Union, adalimumab; United States, adalimumab-atto) is a biosimilar to the adalimumab reference product (RP). A model was developed characterizing population pharmacokinetic (PK) variables of ABP 501 and adalimumab RP to include the impact of antidrug antibodies (ADAs). METHODS: Data were retrospectively analyzed from a single-dose, parallel-group bioequivalence study in healthy adults who received a single 40-mg SC injection of ABP 501 or adalimumab RP. Modeling was performed by using NONMEM 7.2. The impact of ADAs on PK similarity was assessed from population model-based AUC0-∞ values using ANCOVA. FINDINGS: Linear compartment models with various clearance pathways were compared with a one-compartment distribution, first-order subcutaneous absorption model. The final model, a one-compartment model with first-order subcutaneous absorption and linear clearance from the central compartment with an additional time-dependent linear clearance for ADA-positive subjects, described ABP 501 and adalimumab RP population PK variables. Model-derived estimates confirmed PK similarity for ABP 501 and adalimumab RP despite the impact of ADAs. IMPLICATIONS: A traditional approach for evaluating bioequivalence based on noncompartmental analysis may be inappropriate for drugs with a high incidence of ADAs because accounting for the effect of ADAs on noncompartmental analysis parameters is challenging. Use of a population PK model to discern the effect of ADAs on drug PK variables allows for assessment of PK similarity accounting for the presence or absence of ADAs.

Population Pharmacokinetics of Blinatumomab in Pediatric and Adult Patients with Hematological Malignancies.

BACKGROUND AND OBJECTIVES: Blinatumomab (BLINCYTO®) is a novel bispecific T cell engager (BiTE®) approved in the USA for the treatment of relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL) in children and adults, as well as minimal residual disease ALL in adults. This analysis characterized the population pharmacokinetics of intravenous blinatumomab in pediatric and adult patients. METHODS: A total of 2417 serum concentrations of blinatumomab from 674 patients, including adult (n = 628) and pediatric patients (n = 46), from eight clinical studies were analyzed. The impact of covariates on pharmacokinetic parameters were explored, and significant covariates were further evaluated using a simulation approach. RESULTS: Blinatumomab pharmacokinetics were described by a one-compartment linear model with first-order elimination, a clearance (CL) of 2.22 L/h, and a central volume of 5.98 L. A statistically significant effect of body surface area (BSA) on CL was observed. The smallest BSA of 0.37 m2 in the pediatric population was associated with a 63% reduction in blinatumomab systemic CL, relative to an adult patient with the median BSA (1.88 m2), supporting the use of BSA-based dosing in patients of lower bodyweight. The BSA effect was minimal, with a ≤ 25% change in CL over the range of BSA in adults, supporting no need for BSA-based dosing. CONCLUSIONS: Blinatumomab pharmacokinetics were adequately described by a one-compartment linear model with first-order elimination. No covariates other than BSA on CL were identified as significant. BSA-based dosing should be considered for lightweight patients to minimize inter-subject variability in blinatumomab exposure.

Pharmacodynamics of romiplostim alone and in combination with pegfilgrastim on acute radiation-induced thrombocytopenia and neutropenia in non-human primates.

Purpose: Evaluation of the pharmacodynamics (PD) and pharmacokinetics (PK) of romiplostim alone and in combination with pegfilgrastim in a non-human primate (NHP) model of acute radiation syndrome (ARS).Materials and methods: Male and female rhesus macaques were subjected to Cobalt-60 γ irradiation, at a dose of 550 cGy 24 h prior to subcutaneous administration of either romiplostim alone as a single (2.5 or 5.0 mg/kg on Day 1) or repeat dose (5.0 mg/kg on Days 1 and 8), pegfilgrastim alone as a repeat dose (0.3 µg/kg on Day 1 and 8), or a combination of both agents (romiplostim 5.0 mg/kg on Day 1; pegfilgrastim 0.3 µg/kg on Days 1 and 8). Clinical outcome, hematological parameters and PK were assessed throughout the 45 d study period post-irradiation.Results: Administration of romiplostim, pegfilgrastim or the combination of both resulted in significant improvements in hematological parameters, notably prevention of severe thrombocytopenia, compared with irradiated, vehicle control-treated NHPs. The largest hematologic benefit was observed when romiplostim and pegfilgrastim were administered as a combination therapy with much greater effects on both platelet and neutrophil recovery following irradiation compared to single agents alone.Conclusions: These results indicate that romiplostim alone or in combination with pegfilgrastim is effective at improving hematological parameters in an NHP model of ARS. This study supports further study of romiplostim as a medical countermeasure to improve primary hemostasis and survival in ARS.

Blinatumomab Pharmacodynamics and Exposure-Response Relationships in Relapsed/Refractory Acute Lymphoblastic Leukemia.

We evaluated blinatumomab pharmacokinetics, pharmacodynamics (CD3+ T-cell, CD19+ B-cell, and cytokine levels), and their associations with efficacy or safety in relapsed/refractory acute lymphoblastic leukemia. Blinatumomab pharmacokinetics (continuous intravenous infusion) from a phase 2 study (n = 189; NCT01466179) were assessed noncompartmentally. Associations between steady-state concentration (Css ) and efficacy (complete remission [CR] or CR with partial hematologic recovery [CRh]) or safety (cytokine release syndrome [CRS] and neurologic events [NEs]) were evaluated with statistical models. Blinatumomab mean ± SD Css was 621 ± 502 pg/mL (28 µg/day dose). Cytokines were transiently elevated in >50% of patients; B-cell levels decreased in most patients. Lower B-cell and bone marrow (BM) blast percentages and higher T-cell percentages were associated with higher CR/CRh (P < .001) in univariate analysis. Higher Css (OR, 1.90; 95%CI, 1.12-3.21), higher peak IL-10 level (1.59; 1.13-2.22), and lower BM blast percentage (0.78; 0.69-0.89) were associated with higher CR/CRh in multivariate analysis. Higher Css (HR, 1.40; 1.01-1.94) and lower B-cell level (0.90; 0.84-0.97) were associated with shorter time to NEs. Cytokine peaks were not associated with NEs or CRS. In conclusion, blinatumomab led to T cell-mediated depletion of target B cells in blood and blasts in the bone marrow. Immune system effectiveness was important for treatment responses.

Receiver Operating Characteristic Analysis and Clinical Trial Simulation to Inform Dose Titration Decisions.

Optimal dose selection in clinical trials is problematic when efficacious and toxic concentrations are close. A novel quantitative approach follows for optimizing dose titration in clinical trials. A system of pharmacokinetics (PK), pharmacodynamics, efficacy, and toxicity was simulated for scenarios characterized by varying degrees of different types of variability. Receiver operating characteristic (ROC) and clinical trial simulation (CTS) were used to optimize drug titration by maximizing efficacy/safety. The scenarios included were a low-variability base scenario, and high residual (20%), interoccasion (20%), interindividual (40%), and residual plus interindividual variability scenarios, and finally a shallow toxicity slope scenario. The percentage of subjects having toxicity was reduced by 87.4% to 93.5%, and those having efficacy was increased by 52.7% to 243%. Interindividual PK variability may have less impact on optimal cutoff values than other sources of variability. ROC/CTS methods for optimizing dose titration offer an individualized approach that leverages exposure-response relationships.

Comparison of LDL-C Reduction Using Different Evolocumab Doses and Intervals: Biological Insights and Treatment Implications.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduces low-density lipoprotein cholesterol (LDL-C) and the risk of cardiovascular events. OBJECTIVES: To compare LDL-C reduction using evolocumab 140 mg once every 2 weeks (Q2W) or 420 mg monthly (QM) versus lower doses (70 mg Q2W or 280 mg QM) or placebo. METHODS: Patients received evolocumab 70 or 140 mg Q2W, 280 or 420 mg QM, or placebo Q2W or QM in two 12-week phase 2 studies: one with and one without statins. Changes from baseline in LDL-C were compared across Q2W doses and across QM doses. RESULTS: The analysis included 741 patients. Mean (95% confidence interval [CI]) reduction in LDL-C across Q2W visits through week 12 was 63.0% (60.3% to 65.7%) for evolocumab 140 mg Q2W, compared to 41.3% (38.6% to 44.0%) for 70 mg Q2W and 1.9% (4.6% reduction to 0.8% increase) for placebo Q2W (each P < .001 vs 140 mg Q2W), and 62.7% (60.1% to 65.3%) for 420 mg QM, compared to 55.5% (52.9% to 58.0%) for 280 mg QM and 2.5% (5.1% reduction to 0.1% increase) for placebo QM (each P < .001 vs 420 mg QM). Similar results were observed at the mean of weeks 10 and 12. In a subgroup (n = 151) with weekly assessments from weeks 8 to 12, mean (95% CI) peak effect on LDL-C reduction was 72.8% (67.7% to 77.9%) for 140 mg Q2W and 69.0% (63.6% to 74.3%) for 420 mg QM. Trough effect at week 12 underestimated LDL-C reduction. Median peak-trough variability was 20.5%, 21.1%, 31.9%, and 35.1% for evolocumab 140 mg Q2W, 420 mg QM, 70 mg Q2W, and 280 mg QM, respectively. CONCLUSION: Evolocumab 140 mg Q2W and 420 mg QM yielded similar LDL-C reduction. These doses sustained maximal LDL-C reduction, resulting in greater stability in LDL-C reduction over the dosing interval compared to lower doses. These results support evolocumab doses of either 140 mg Q2W or 420 mg QM.

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.

Population Pharmacokinetics and Exposure-Response Relationship of Carfilzomib in Patients With Multiple Myeloma.

A population pharmacokinetic (PK) model and exposure-response (E-R) analysis was developed using data collected from 5 phase 1b/2 and 2 phase 3 studies in subjects with multiple myeloma. Subjects receiving intravenous infusion on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) in each cycle at doses ranging from 15 to 20/56 mg/m2 (20 mg/m2 in cycle 1 and, if tolerated, escalated to 56 mg/m2 on day 8 of cycle 1). The population PK analysis indicated that among all the covariates tested, the only statistically significant covariate was body surface area on carfilzomib clearance; however, this covariate was unlikely to be clinically significant. Despite inclusion of different populations (relapsed or relapsed/refractory), treatments (carfilzomib monotherapy or combination therapy), infusion lengths (2 to 10 minutes or 30 minutes), and different doses, the E-R analysis of efficacy showed that after adjusting for baseline characteristics, higher area under the concentration-time curve was associated with improved overall response rate (ORR), from 15 to 20/56 mg/m2 . No positive relationships between maximum concentration and ORR were identified, indicating that ORR would not be expected to be impacted by infusion length. For safety end points, no statistically significant relationship between exposure and increasing risk of adverse events was identified. The results of an E-R analysis provided strong support for a carfilzomib dose at 20/56 mg/m2 as a 30-minute infusion for monotherapy and combination therapy. This article illustrates an example of application of E-R analysis to support labeling dose recommendation in the absence of extensive clinical data.

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.

Blinatumomab, a Bispecific T-cell Engager (BiTE(®)) for CD-19 Targeted Cancer Immunotherapy: Clinical Pharmacology and Its Implications.

BACKGROUND AND OBJECTIVES: Blinatumomab is a bispecific T-cell engager (BiTE(®)) antibody construct that transiently links CD19-positive B cells to CD3-positive T cells, resulting in induction of T-cell-mediated serial lysis of B cells and concomitant T-cell proliferation. Blinatumomab showed anti-leukemia activity in clinical trials and was approved by the US Food and Drug Administration for the treatment of Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r ALL). The objectives of this work were to characterize blinatumomab pharmacokinetics and pharmacodynamics and to evaluate dosing regimens. METHODS: Data from six phase I and II trials in patients with r/r ALL, minimal residual disease-positive ALL, and non-Hodgkin's lymphoma (NHL) were analyzed. Blinatumomab pharmacokinetics was characterized by non-compartmental and population pharmacokinetic analyses and pharmacodynamics was described graphically. RESULTS: Blinatumomab exhibited linear pharmacokinetics under continuous intravenous infusion for 4-8 weeks per cycle over a dose range of 5-90 µg/m(2)/day, without target-mediated disposition. Estimated mean (standard deviation) volume of distribution, clearance, and elimination half-life were 4.52 (2.89) L, 2.72 (2.71) L/h, and 2.11 (1.42) h, respectively. Pharmacokinetics was similar in patients with ALL and NHL and was not affected by patient demographics, supporting fixed dosing in adults. Although creatinine clearance was a significant covariate of drug clearance, no dose adjustment was required in patients with mild or moderate renal impairment. Incidence of neutralizing antidrug antibodies was <1 %. Blinatumomab pharmacodynamics featured T-cell redistribution and activation, B-cell depletion, and transient dose-dependent cytokine elevation. Blinatumomab did not affect cytochrome P450 enzymes directly; cytokines may trigger transient cytochrome P450 suppression with low potential for inducing drug interactions. CONCLUSIONS: Blinatumomab has unique pharmacokinetic and immunological features that require indication-dependent dosing regimens. Stepped dosing is required to achieve adequate efficacy and minimize cytokine release in diseases with high tumor burden.

Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors.

Denosumab (XGEVA®) is a recombinant, fully human IgG2 monoclonal antibody directed against the receptor activator of nuclear factor kappa-B ligand (RANKL) that prevents differentiation of osteoclast precursors into mature osteoclasts and acceleration of bone resorption, resulting in the inhibition of osteoclast activation. Denosumab is indicated for the prevention of skeletal-related events (SREs) in adult patients with bone metastases from solid tumors at the dose of 120 mg administered subcutaneously (SC) every 4 weeks. This review is focused on describing its target-mediated disposition and direct inhibitory effect on bone resorption, as well as the modeling and simulation techniques used to integrate the PKPD information collected during clinical development of denosumab. In addition, this review further discusses the clinical relevance of patient covariate effects on denosumab systemic exposure, target engagement and downstream pharmacodynamics biomarkers, and the rationale for dosing regimen selection for Phase 3 studies. Phase 3 clinical studies demonstrated that denosumab was superior to zoledronic acid in inhibiting bone resorption and, consequently, delaying the time to first SRE by a median of 8.2 months in patients with bone metastases from solid tumors. Thus, denosumab may be considered a better alternative treatment than zoledronic acid for the prevention of SRE in patients with bone metastases from solid tumors.