Juan Jose Perez-Ruixo

Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer

PURPOSEnR115777 is an orally active farnesyl transferase inhibitor that specifically blocks farnesylation of proteins involved in growth-factor-dependent cell-signal-transduction pathways. We conducted a phase II study in 76 patients with advanced breast cancer.nnnPATIENTS AND METHODSnTwo cohorts of patients were recruited sequentially. The first cohort (n = 41) received a continuous dosing [CD] regimen of R115777 400 or 300 mg bid. The second cohort (n = 35) received 300 mg bid in a cyclical regimen of 21 days of treatment followed by 7 days of rest (intermittent dosing [ID]).nnnRESULTSnIn the CD cohort, four patients (10%) had a partial response (PR) and six patients (15%) had stable disease at > or = 24 weeks (SD). In the ID cohort, five patients (14%) had a PR and three patients (9%) had prolonged SD. The first six patients in the CD cohort treated at 400 mg bid all developed grade 3 to 4 neutropenia, so the subsequent 35 patients were treated at 300 mg bid. The incidence of hematologic toxicity was significantly lower in the ID than in the CD (300-mg bid) cohort: grade 3 to 4 neutropenia (14% v 43%; P =.016) and grade 3 to 4 thrombocytopenia (3% v 26%; P =.013). One patient in the ID cohort developed grade 2 to 3 neurotoxicity compared with 15 patients in the CD cohort (3% v 37%; P =.0004).nnnCONCLUSIONnThe farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen.

Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma.

PURPOSEnR115777 is a selective nonpeptidomimetic inhibitor of farnesyltransferase (FTase), one of several enzymes responsible for posttranslational modification that is required for the function of p21(ras) and other proteins. Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma.nnnPATIENTS AND METHODSnTwenty patients who had not received prior therapy for metastatic disease were treated with 300 mg of R115777 orally every 12 hours for 21 of 28 days. Inhibition of FTase activity in peripheral-blood mononuclear cells was measured using a lamin B C-terminus peptide as substrate. Western blot analysis was performed to monitor farnesylation status of the chaperone protein HDJ-2.nnnRESULTSnNo objective responses were seen. Median time to progression was 4.9 weeks, and median survival time was 19.7 weeks. The estimated 6-month survival rate was 25%, with no patients progression-free at 6 months. Grade 3/4 toxicities were liver enzyme elevation, anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, rash, and anorexia. FTase activity (mean +/- SD) decreased by 49.8% +/- 9.8% 4 hours after treatment on day 1 and 36.1% +/- 24.8% before treatment on day 15. HDJ-2 farnesylation (mean +/- SD) decreased by 33.4% +/- 19.8% on day 15.nnnCONCLUSIONnAlthough treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.

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

Pharmacokinetics and pharmacodynamics of the erythropoietin Mimetibody construct CNTO 528 in healthy subjects.

Background and ObjectiveAnaemia is a serious comorbidity that is common in patients with renal failure or cancer. CNTO 528 is the first Mimetibody™ developed to mimic the effects of erythropoietin (EPO), a hormone that stimulates the production of red blood cells (RBCs). The objective of this study was to develop a pharmacokinetic and pharmacodynamic model for CNTO 528 in healthy male subjects.MethodsA pharmacokinetic/pharmacodynamic model for CNTO 528 was developed to describe the serum concentration versus time profile and the pharmacological responses of percentage of reticulocytes, total RBC counts and haemoglobin concentration after a single intravenous administration of CNTO 528 at 0.03, 0.09, 0.3 and 0.9 mg/kg in 24 healthy subjects. An open, linear, two-compartment model was used to characterize the pharmacokinetic parameters of CNTO 528. A catenary cell production and lifespan loss model was used to fit the pharmacodynamic data, yielding estimates of drug potency (SC50), efficacy (Smax) and other pharmacodynamic parameters. Bootstrap and posterior predictive checks (PPC) were used to evaluate the model.ResultsAdministration of CNTO 528 stimulated the production of reticulocytes, RBCs and haemoglobin. CNTO 528 exhibits a half-life of 141 hours, or approximately 5.9 days. The SC50 was estimated to be 0.37 mg/L, indicating that low serum CNTO 528 concentration was sufficient to produce pharmacological effects. Compared with historical controls, CNTO 528 Smax appears to be 2-fold higher than recombinant human EPO. Bootstrap analysis and PPCs confirmed the accuracy and precision in the parameter estimates and the adequacy of the model to describe the CNTO 528 pharmacokinetics and pharmacodynamics.ConclusionThe mechanistic population model was suitable to characterize the pharmacokinetics and pharmacodynamics of intravenously administered CNTO 528 in healthy subjects. This qualified model is deemed appropriate to conduct clinical trial simulations and to support the decision-making process for dose selection in studies of EPO-stimulating agents.

Basic pharmacodynamic models for agents that alter the lifespan distribution of natural cells.

A new class of basic indirect pharmacodynamic models for agents that alter the loss of natural cells based on a lifespan concept are presented. The lifespan indirect response (LIDR) models assume that cells (R) are produced at a constant rate (kin), survive during a certain duration TR, and finally are lost. The rate of cell loss is equal to the production rate but is delayed by TR. A therapeutic agent can increase or decrease the baseline cell lifespan to a new cell lifespan, TD, by temporally changing the proportion of cells belonging to the two modes of the lifespan distribution. Therefore, the change of lifespan at time t is described according to the Hill function, H(C(t)), with capacity (Emax) and sensitivity (EC50), and the pharmacokinetic function C(t). A one-compartment cell model was examined through simulations to describe the role of pharmacokinetics, pharmacodynamics and cell properties for the cases where the drug increases (TDxa0>xa0TR) or decreases (TDxa0<xa0TR) the cell lifespan. The area under the effect curve (AUCE) and explicit solutions of LIDR models for large doses were derived. The applicability of the model was further illustrated using the effects of recombinant human erythropoietin (rHuEPO) on reticulocytes. The cases of both stimulation of the proliferation of bone marrow progenitor cells and the increase of reticulocyte lifespans were used to describe mean data from healthy subjects who received single subcutaneous doses of rHuEPO ranging from 20 to 160xa0kIU. rHuEPO is about 4.5-fold less potent in increasing reticulocyte survival than in stimulating the precursor production. A maximum increase of 4.1xa0days in the mean reticulocyte lifespan was estimated and the effect duration on the lifespan distribution was dose dependent. LIDR models share similar properties with basic indirect response models describing drug stimulation or inhibition of the response loss rate with the exception of the presence of a lag time and a dose independent peak time. The current concept can be applied to describe the pharmacodynamic effects of agents affecting survival of hematopoietic cell populations yielding realistic physiological parameters.

Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment

PurposeReversible transient elevations in transaminases have been observed after trabectedin administration. A semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed to evaluate the time course of alanine aminotransferase (ALT) elevation, tolerance development, and the hepatoprotective effect of dexamethasone on trabectedin-induced transient transaminitis following different dosing schedules in cancer patients.Patients and methodsTrabectedin was administered to 711 patients as monotherapy (dose range: 0.024–1.8xa0mg/m2) as 1-, 3-, or 24-h infusions every 21xa0days; 1- or 3-h infusions on days 1, 8, and 15 every 28xa0days; or 1-h infusions daily for five consecutive days every 21xa0days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711xa0pt), ECOG performance status scores (89.7% ptsxa0≤xa01), and body weight (36–122xa0kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected patient factors on the time course of ALT and the effectiveness of the dose reduction strategy.ResultsA precursor-dependent PKPD model described the temporal relationship between ALT elevation and trabectedin concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentrations. Overall, 66% of patients had transaminitis. Mean predicted (%SEM) baseline ALT (ALTo) and t1/2 in plasma were 31.5 (5.1) IU/L and 1.5xa0days, respectively. The magnitude of the trabectedin stimulation of the ALT transfer rate from hepatocytes to plasma was 11.4% per 100xa0pg/mL of trabectedin plasma concentration. Dexamethasone decreased the rate of trabectedin-induced ALT release from hepatocyte by 63% (Pxa0<xa00.001). Model evaluation showed that the model predicted incidence of grade 3/4 transaminase elevation was similar to the observed values. Simulations showed that severity of ALT elevation was dose- and schedule-dependent. The dose reduction strategy decreased the incidence of grade ≥3 toxicity by 13 and 39% following two and four cycles of therapy, respectively.ConclusionsA PKPD model quantifying the hepatoprotective effect of dexamethasone on transient and reversible transaminitis following trabectedin treatment has been developed. The model predicts that co-administration of dexamethasone and the suggested dose reduction strategy based on the serum concentration of liver enzymes will enhance the safe use of trabectedin in the clinic.

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.

Population pharmacokinetics meta-analysis of plitidepsin (Aplidin) in cancer subjects.

ObjectiveTo characterize the population pharmacokinetics of plitidepsin (Aplidin®) in cancer patients.MethodsA total of 283 patients (552 cycles) receiving intravenous plitidepsin as monotherapy at doses ranging from 0.13 to 8.0xa0mg/m2 and given as 1- or 24-h infusions every week; 3- or 24-h infusion biweekly; or 1-h infusion daily for 5 consecutive days every 21xa0days were included in the analysis. An open three-compartment pharmacokinetic model and a nonlinear binding to red blood cells model were used to describe the plitidepsin pharmacokinetics in plasma and blood, respectively, using NONMEM V software. The effect of selected covariates on plitidepsin pharmacokinetics was investigated. Model evaluation was performed using goodness-of-fit plots, posterior predictive check and bootstrap.ResultsPlasma clearance and its between subject variability (%) was 13.6xa0l/h (71). Volume of distribution at steady-state was calculated to be 4791xa0l (59). The parameters Bmax and C50 of the non-linear blood distribution were 471xa0μg/l (56) and 41.6xa0μg/l, respectively. Within the range of covariates studied, age, sex, body size variables, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, creatinine clearance, albumin, total protein, performance status, co-administration of inhibitors or inducers of CYP3A4 and presence of liver metastases were not statistically related to plitidepsin pharmacokinetic parameters. Bootstrap and posterior predictive check evidenced the model was deemed appropriate to describe the time course of plitidepsin blood and plasma concentrations in cancer patients.ConclusionsThe integration of phase I/II pharmacokinetic data demonstrated plitidepsin linear elimination from plasma, dose-proportionality up to 8.0xa0mg/m2, and time-independent pharmacokinetics. The distribution to red blood cells can be considered linear at doses lower than 5xa0mg/m2 administered as 3-h or longer infusion. No clinically relevant covariates were identified as predictors of plitidepsin pharmacokinetics.

Development and validation of an HPLC-UV method for sorafenib quantification in human plasma and application to patients with cancer in routine clinical practice.

Background: Several factors such as low therapeutic index, large interindividual variability in systemic exposure, and the relationships between exposure and toxicity for sorafenib could justify its therapeutic drug monitoring (TDM). To support TDM, a selective and precise high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method was developed and validated for the determination of sorafenib in human plasma. Methods: After protein precipitation with acetonitrile, sorafenib and lapatinib (internal standard) were separated using isocratic elution on a Kromasil C18 column using a mobile phase of acetonitrile and 20 mmol/L ammonium acetate in a proportion 53:47 (vol/vol) pumped at a constant flow rate of 1.2 mL/min. Quantification was performed at 260 nm. Validation experiments were carried out after the guidelines for Bioanalytical Method Validation published by the Food and Drug Administration and the European Medicines Agency. Results: Calibration curves were linear over the range 0.1–20 mcg/mL. Inter- and intra-day coefficients of variation were <3%. The limit of detection and the lower limit of quantification were 0.06 and 0.1 mcg/mL, respectively. Recoveries of sorafenib from plasma were >99% in all cases. Conclusions: This method was successfully applied to the determination of the drug in the plasma of 2 patients with cancer receiving sorafenib 200 and 400 mg orally twice daily, respectively, and could be useful for TDM of sorafenib in routine clinical practice.

Pharmacokinetic and Pharmacodynamic Analysis of Hyperthermic Intraperitoneal Oxaliplatin-Induced Neutropenia in Subjects with Peritoneal Carcinomatosis

The objective of this study was to characterize the pharmacokinetics and the time course of the neutropenia-induced by hyperthermic intraperitoneal oxaliplatin (HIO) after cytoreductive surgery in cancer patients with peritoneal carcinomatosis. Data from 30 patients who received 360xa0mg/m2 of HIO following cytoreductive surgery were used for pharmacokinetic–pharmacodynamic (PK/PD) analysis. The oxaliplatin plasma concentrations were characterized by an open two-compartment pharmacokinetic model after first-order absorption from peritoneum to plasma. An oxaliplatin-sensitive progenitor cell compartment was used to describe the absolute neutrophil counts in blood. The reduction of the proliferation rate of the progenitor cells was modeled by a linear function of the oxaliplatin plasma concentrations. The typical values of oxaliplatin absorption and terminal half-lives were estimated to be 2.2 and 40xa0h, with moderate interindividual variability. Oxaliplatin reduced the proliferation rate of the progenitor cells by 18.2% per mg/L. No patient’s covariates were related to oxaliplatin PK/PD parameters. Bootstrap and visual predictive check evidenced the model was deemed appropriate to describe oxaliplatin pharmacokinetics and the incidence and severity of neutropenia. A peritoneum oxaliplatin exposure of 65 and 120xa0mg·L/h was associated with a 20% and 33% incidence of neutropenia grade 4. The time course of neutropenia following HIO administration was well described by the semiphysiological PK/PD model. The maximum tolerated peritoneum oxaliplatin exposure is 120xa0mgxa0L/h and higher exposures should be avoided in future studies. We suggest the prophylactic use of granulocyte colony stimulating factor for patients treated with HIO exposure higher than 65xa0mgxa0L/h.