Juan José Pérez-Ruixo

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.

Population pharmacokinetics meta-analysis of recombinant human erythropoietin in healthy subjects.

ObjectiveThe aim of this analysis was to develop a population pharmacokinetic model to describe the pharmacokinetics of recombinant human erythropoietin (rHuEPO) in healthy subjects, after intravenous and subcutaneous administration over a wide dose range, and to examine the influence of demographic characteristics and other covariates on the pharmacokinetic parameters of rHuEPO.MethodsErythropoietin serum concentration data were available from 16 studies comprising 49 healthy subjects who received rHuEPO intravenous doses from 10 to 300 IU/kg, 427 healthy subjects who received rHuEPO subcutaneous doses from 1 to 2400 IU/kg, and 57 healthy subjects who received placebo and where endogenous erythropoietin concentrations were measured. Different pharmacokinetic models were fitted to the dataset using nonlinear mixed-effects modeling software (NONMEM, Version V, Level 1). Several patient covariates were tested in order to quantify the effect on rHuEPO pharmacokinetic parameters. Model evaluation was examined using a posterior predictive check.ResultsErythropoietin showed a diurnal baseline variation of ±20%, described with a dual cosine model. Disposition was described with a two-compartment model with a small volume of distribution (6L) and parallel linear and nonlinear clearance. Total clearance varied between 0.3 and 0.9 L/h over the concentration range studied. A dual absorption model was used to characterise the rHuEPO absorption from the subcutaneous formulation and consisted of a faster pathway described as a sequential zero- and first-order absorption process and a parallel slower pathway characterised as a zero-order process. The bioavailability of subcutaneous rHuEPO increased from 30% at low doses to 71% at the highest dose of 160 kIU and was described using a hyperbolic model. The most important covariate effects were a decrease in the first-order absorption rate constant (ka) with increasing age, an increase in subcutaneous bioavailability with increasing baseline haemoglobin, and a decrease in bioavailability with increasing bodyweight. A posterior predictive check showed no systematic deviation of the simulated data from the observed values.ConclusionThe population pharmacokinetic model developed is suitable to describe the pharmacokinetic behaviour of rHuEPO after intravenous and subcutaneous administration in healthy subjects, over a wide dose range.

Pharmacodynamic Analysis of Recombinant Human Erythropoietin Effect on Reticulocyte Production Rate and Age Distribution in Healthy Subjects

AbstractObjective: To evaluate the effect of recombinant human erythropoietin (rHuEPO) on the reticulocyte production rate and age distribution in healthy subjects. Methods: Extensive pharmacokinetic and pharmacodynamic data collected from 88 subjects who received a single subcutaneous dose of rHuEPO (dose range 20–160 kIU) were analysed. Four nonlinear mixed-effects models were evaluated to describe the time course of the percentage of reticulocytes and their age distribution in relation to rHuEPO pharmacokinetics. Model A accounted for stimulation of the production of progenitor cells in bone marrow, and model B implemented shortening of differentiation and maturation times of early progenitors in bone marrow. Model C was the combination of models A and B, and model D was the combination of model A with an increase in the maturation times of the circulating reticulocytes. Model evaluation was performed using goodness-of-fit plots, a nonparametric bootstrap and a posterior predictive check. Results: Model D was selected as the best model, and evidenced accurate and precise estimation of model parameters and prediction of the time course of the percentage of reticulocytes. At baseline, the estimated circulating reticulocyte maturation time was 2.6 days, whereas the lifespan of the precursors in the bone marrow was about 5 days. The rHuEPO potency for the stimulatory effect (7.61 IU/L) was higher than that for the increase in reticulocyte maturation times (56.3 IU/L). There was a significant 1- to 2-day lag time in the reticulocyte response. The effect of rHuEPO on the reticulocyte age distribution consisted of a transient increase in the reticulocyte maturation time from baseline up to 6–7 days, occurring 1 day after administration. The dose-dependent amplitude of the changes in the age distribution lasted for 12–14 days. The model-predicted peak increase in the reticulocyte release rate ranged from 140% to 160% of the baseline value and was maximal on days 7–8 following rHuEPO administration. Conclusions: A semiphysiological model quantifying the effect of rHuEPO on the reticulocyte production rate and age distribution was developed. The validated model predicts that rHuEPO increases the reticulocyte production rate and modifies the reticulocyte age distribution in a dose-dependent manner.

Population Pharmacokinetic Meta-Analysis of Trabectedin (ET-743, Yondelis®) in Cancer Patients

ObjectiveTo characterise the population pharmacokinetics of trabectedin (ET-743, Yondelis®) in cancer patients.MethodsA total of 603 patients (945 cycles) receiving intravenous trabectedin as monotherapy at doses ranging from 0.024 to 1.8 mg/m2 and given as a 1-, 3- or 24-hour infusion every 21 days; a 1- or 3-hour infusion on days 1, 8 and 15 of a 28-day cycle; or a 1-hour infusion daily for 5 consecutive days every 21 days were included in the analysis. An open four-compartment pharmacokinetic model with linear elimination, linear and nonlinear distribution to the deep and shallow peripheral compartments, respectively, and a catenary compartment off the shallow compartment was developed to best describe the index dataset using NONMEM V software. The effect of selected patient covariates on trabectedin pharmacokinetics was investigated. Model evaluation was performed using good-ness-of-fit plots and relative error measurements for the test dataset. Simulations were undertaken to evaluate covariate effects on trabectedin pharmacokinetics.ResultsThe mean (SD) trabectedin elimination half-life was approximately 180 (61.4) hours. Plasma accumulation was limited when trabectedin was given every 3 weeks. Systemic clearance (31.5 L/h, coefficient of variation 51%) was 19.2% higher in patients receiving concomitant dexamethasone. The typical values of the volume of distribution at steady state for male and female patients were 6070L and 5240L, respectively. Within the range studied, age, body size variables, AST, ALT, alkaline Phosphatase, lactate dehydrogenase, total bilirubin, Creatinine clearance, albumin, total protein, Eastern Cooperative Oncology Group performance status and presence of liver metastases were not statistically related to trabectedin pharmacokinetic parameters. The pharmacokinetic parameters of trabectedin were consistent across the infusion durations and dose regimens evaluated.ConclusionsThe integration of trabectedin pharmacokinetic data demonstrated linear elimination, dose-proportionality up to 1.8 mg/m2 and time-independent pharmacokinetics. The pharmacokinetic impact of dexamethasone and sex covariates is probably limited given the moderate to large interindividual pharmacokinetic variability of trabectedin. The antiemetic and hepatoprotective effects are still a valid rationale to recommend dexamethasone as a supportive treatment for trabectedin.

Pharmacokinetic and Pharmacodynamic Modeling of Pegylated Thrombopoietin Mimetic Peptide (PEG-TPOm) After Single Intravenous Dose Administration in Healthy Subjects

Pegylated thrombopoietin mimetic peptide (PEG‐TPOm) is a novel, potent thrombopoietin receptor agonist with low immunotoxicity potential that protects against chemotherapy‐induced thrombocytopenia in preclinical animal models. The aim of this study was to develop a population pharmacokinetic and pharmacodynamic model of PEG‐TPOm following single intravenous doses in healthy subjects. Data were obtained from a double‐blind, randomized, placebo‐controlled study. A model based on target‐mediated drug disposition and precursor pool life spans was applied. Model evaluation was performed through predictive checks and bootstrap analysis. The half‐life of PEG‐TPOm ranged between 18 and 36 hours, and the estimated distributional volume was 5 L. The increase in platelet counts was observed after a 4‐day delay, consistent with the megakaryocyte cell life span. The platelet life span was estimated to be 5 days. After maximum platelets counts were achieved on day 9, platelets returned back to baseline on day 29. Modelbased simulations were undertaken to explore pharmacodynamic effects after multiple dosing. Weekly dosing produced a sustained pharmacodynamic response, whereas an interdosing interval ≥2 weeks resulted in fluctuating pharmacodynamic profiles. Thus, the mechanistic pharmacokinetic/pharmacodynamic model was suitable for describing the complex PEG‐TPOm pharmacokinetics/pharmacodynamics, including target‐mediated disposition, dose‐dependent platelet stimulation, and mean life spans of thrombopoietic cell populations.

Immunogenicity of panitumumab in combination chemotherapy clinical trials

BackgroundPanitumumab is a fully human antibody against the epidermal growth factor receptor that is indicated for the treatment of metastatic colorectal cancer (mCRC) after disease progression on standard chemotherapy. The purpose of this analysis was to examine the immunogenicity of panitumumab and to evaluate the effect of anti-panitumumab antibodies on pharmacokinetic and safety profiles in patients with mCRC receiving panitumumab in combination with oxaliplatin- or irinotecan-based chemotherapies.MethodsThree validated assays (two screening immunoassays and a neutralizing antibody bioassay) were used to detect the presence of anti-panitumumab antibodies in serum samples collected from patients enrolled in four panitumumab combination chemotherapy clinical trials. The impact of anti-panitumumab antibodies on pharmacokinetic and safety profiles was analyzed using population pharmacokinetic analysis and descriptive statistics, respectively.ResultsOf 1124 patients treated with panitumumab in combination with oxaliplatin- or irinotecan-based chemotherapy with postbaseline samples available for testing, 20 (1.8%) patients developed binding antibodies and 2 (0.2%) developed neutralizing antibodies. The incidence of anti-panitumumab antibodies was similar in patients with tumors expressing wild-type or mutant KRAS and in patients receiving oxaliplatin- or irinotecan-based chemotherapies. No evidence of an altered pharmacokinetic or safety profile was found in patients who tested positive for anti-panitumumab antibodies.ConclusionsThe immunogenicity of panitumumab in the combination chemotherapy setting was infrequent and similar to the immunogenicity observed in the monotherapy setting. Panitumumab immunogenicity did not appear to alter pharmacokinetic or safety profiles. This low rate of immunogenicity may be attributed to the fully human nature of panitumumab.Trial registrationClinicalTrials.gov: NCT00339183 (study 20050181), NCT00411450 (study 20060277), NCT00332163 (study 20050184), and NCT00364013 (study 20050203).

Effect of grapefruit juice on the pharmacokinetics of docetaxel in cancer patients: a case report

Docetaxel is a taxane antineoplasic agent that acts by inducing microtubular stability and disrupting the dynamics of the microtubular network. It is approved for the adjuvant treatment of patients with breast cancer, non-small cell lung cancer (NSCLC), hormone refractory prostate cancer and gastric cancer (http://www.taxotere.com). Moreover, docetaxel is active against different types of solid tumours, including oesophageal squamous cell carcinoma and advanced squamous cell carcinoma of the head and neck [1]. Its dose limiting toxicity is neutropenia, peripheral neurotoxicity and oedema [2].

Modeling of delays in PKPD: classical approaches and a tutorial for delay differential equations.

In pharmacokinetics/pharmacodynamics (PKPD) the measured response is often delayed relative to drug administration, individuals in a population have a certain lifespan until they maturate or the change of biomarkers does not immediately affects the primary endpoint. The classical approach in PKPD is to apply transit compartment models (TCM) based on ordinary differential equations to handle such delays. However, an alternative approach to deal with delays are delay differential equations (DDE). DDEs feature additional flexibility and properties, realize more complex dynamics and can complementary be used together with TCMs. We introduce several delay based PKPD models and investigate mathematical properties of general DDE based models, which serve as subunits in order to build larger PKPD models. Finally, we review current PKPD software with respect to the implementation of DDEs for PKPD analysis.

Romiplostim Dose Response in Patients With Immune Thrombocytopenia

A pharmacodynamic model was developed for platelet counts in 52 patients with immune thrombocytopenia (ITP) receiving subcutaneous romiplostim in 3 phase I/II studies (dose range, 0.2–10 μg/kg). The model consisted of a drug‐sensitive progenitor cell compartment linked to a peripheral blood compartment through 4 transition compartments. The baseline platelet count, mean transit time, and kinetics of drug effect constant were 11.1 times 109/L, 170 hours, and 0.6 day−1, respectively. The ITP patients had a shorter platelet life span and lower progenitor cell production rates than healthy volunteers. Romiplostim response was described for 2 subpopulations. The romiplostim stimulatory effect in ITP patients was 351%/100 μg/wk and 12%/100 μg/wk in 68% and 32% of patients, respectively. Visual and numerical predictive checks suggested accurate prediction of platelet time course and durable response rate in ITP patients. Model‐based simulations confirmed the effectiveness of dose reduction to prevent platelet counts >400 times 109/L.