Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study.

BACKGROUND: FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. METHODS: The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. FINDINGS: Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6-23·9), an objective response was observed in 64 (30% [95% CI 24-36]) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 [12%]), palmar-plantar erythrodysaesthesia syndrome (12 [6%]), and hyperphosphataemia (11 [5%]). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths. INTERPRETATION: RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours. FUNDING: Janssen Research & Development.

Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with FGFR alterations. METHODS: In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified FGFR alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. Prior immunotherapy was allowed. We initially randomly assigned the patients to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen (selected-regimen group), with provision for a pharmacodynamically guided dose escalation to 9 mg. The primary end point was the objective response rate. Key secondary end points included progression-free survival, duration of response, and overall survival. RESULTS: A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths. CONCLUSIONS: The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations. Treatment-related grade 3 or higher adverse events were reported in nearly half the patients. (Funded by Janssen Research and Development; BLC2001 ClinicalTrials.gov number, NCT02365597.).

Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation. WHAT THIS STUDY ADDS: • This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290). The PK and PK-PD relationship of rivaroxaban in patients with ACS were similar to those in other patient populations. In addition, model-based simulations showed that the influence of renal function and age on the exposure to rivaroxaban in the ACS population were similar to the findings from Phase 1 special population studies. These findings suggest that rivaroxaban has highly predictable PK-PD and may provide a consistent anticoagulant effect across the studied patient populations, which allows an accurate prediction of the dose to control anticoagulation optimally. AIMS: The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated. RESULTS: The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h(-1) (interindividual variability, 139%), 6.48 l h(-1) (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients. CONCLUSIONS: The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure-prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied.

Erdafitinib's effect on serum phosphate justifies its pharmacodynamically guided dosing in patients with cancer.

A population pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK-PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once-daily oral continuous (0.5-12 mg) and intermittent (10-12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib-related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23-mediated signaling. PK-PD model-based simulations were performed to assess the approved PD-guided dosing algorithm of erdafitinib (8 mg once-daily continuous dosing, with up-titration to 9 mg based on phosphate levels [<5.5 mg/dl] and tolerability at 14-21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8-fold increase in drug-related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of >95% maximal serum phosphate concentration. The peak-to-trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68-5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate-parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8-mg with up-titration to 9-mg on Days 14-21 maximized the number of patients within the target serum phosphate concentrations (5.5-7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK-PD model provided a detailed understanding of the erdafitinib concentration-related phosphate changes over time, which supports erdafitinib's dosing algorithm.

A quantitative systems pharmacology model for acute viral hepatitis B.

Hepatitis B liver infection is caused by hepatitis B virus (HBV) and represents a major global disease problem when it becomes chronic, as is the case for 80-90% of vertical or early life infections. However, in the vast majority (>95%) of adult exposures, the infected individuals are capable of mounting an effective immune response leading to infection resolution. A good understanding of HBV dynamics and the interaction between the virus and immune system during acute infection represents an essential step to characterize and understand the key biological processes involved in disease resolution, which may help to identify potential interventions to prevent chronic hepatitis B. In this work, a quantitative systems pharmacology model for acute hepatitis B characterizing viral dynamics and the main components of the innate, adaptive, and tolerant immune response has been successfully developed. To do so, information from multiple sources and across different organization levels has been integrated in a common mechanistic framework. The final model adequately describes the chronology and plausibility of an HBV-triggered immune response, as well as clinical data from acute patients reported in the literature. Given the holistic nature of the framework, the model can be used to illustrate the relevance of the different immune pathways and biological processes to ultimate response, observing the negligible contribution of the innate response and the key contribution of the cellular response on viral clearance. More specifically, moderate reductions of the proliferation of activated cytotoxic CD8+ lymphocytes or increased immunoregulatory effects can drive the system towards chronicity.

Population Pharmacokinetics of Total and Free Erdafitinib in Adult Healthy Volunteers and Cancer Patients: Analysis of Phase 1 and Phase 2 Studies.

A population pharmacokinetic (PK) model was developed using data pooled from 6 clinical studies (3 in healthy volunteers and 3 in cancer patients) to characterize total and free plasma concentrations of erdafitinib following single- and multiple-dose administration, to understand clinically relevant covariates, and to quantify the inter- and intraindividual variability in erdafitinib PK. An open, linear, 3-compartment disposition model with first-order absorption and a lag time was used to describe the PK profile of total and free erdafitinib plasma concentrations. The PK of erdafitinib were linear and time independent. After oral administration, erdafitinib was rapidly absorbed, with a time to maximum concentration between 2 and 4 hours. In patients, erdafitinib total apparent oral clearance was 0.200 L/h (median free fraction = 0.24%), and the effective terminal half-life of total drug was 76.4 hours. Interindividual variability in PK parameters was moderate for oral clearance and central volume of distribution, and large for absorption rate and peripheral volume of distribution. Sex and renal function were significant covariates on free oral clearance, while weight, sex, and α1 -acid-glycoprotein were significant on oral central volume of distribution. Age, race, and mild hepatic impairment were not significant covariates of erdafitinib exposure. Given that the magnitude of the covariate effects were within 25% of reference values and that the recommended dosing regimen of erdafitinib comprises individual dose up-titrations and reductions based on presence or absence of toxicities, the clinical relevance of the investigated covariates is expected to be limited, and no dose adjustments are warranted.

Immune network for viral hepatitis B: Topological representation.

The liver is a well-known immunotolerogenic environment, which provides the adequate setting for liver infectious pathogens persistence such as the hepatitis B virus (HBV). Consequently, HBV infection can derive in the development of chronic disease in a proportion of the patients. If this situation persists in time, chronic hepatitis B (CHB) would end in cirrhosis, hepatocellular carcinoma and eventually, the death of the patient. It is thought that this immunotolerogenic environment is the result of complex interactions between different elements of the immune system and the viral biology. Therefore, the purpose of this work is to unravel the mechanisms implied in the development of CHB and to design a tool able to help in the study of adequate therapies. Firstly, a conceptual framework with the main components of the immune system and viral dynamics was constructed providing an overall insight on the pathways and interactions implied in this disease. Secondly, a review of the literature was performed in a modular fashion: (i) viral dynamics, (ii) innate immune response, (iii) humoral and (iv) cellular adaptive immune responses and (v) tolerogenic aspects. Finally, the information collected was integrated into a single topological representation that could serve as the plan for the systems pharmacology model architecture. This representation can be considered as the previous unavoidable step to the construction of a quantitative model that could assist in biomarker and target identification, drug design and development, dosing optimization and disease progression analysis.

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

PURPOSE: Reversible 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 METHODS: Trabectedin was administered to 711 patients as monotherapy (dose range: 0.024-1.8 mg/m(2)) as 1-, 3-, or 24-h infusions every 21 days; 1- or 3-h infusions on days 1, 8, and 15 every 28 days; or 1-h infusions daily for five consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), ECOG performance status scores (89.7% pts or=3 toxicity by 13 and 39% following two and four cycles of therapy, respectively. CONCLUSIONS: A 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.

Population pharmacokinetic meta-analysis of trabectedin (ET-743, Yondelis) in cancer patients.

OBJECTIVE: To characterise the population pharmacokinetics of trabectedin (ET-743, Yondelis(R)) in cancer patients. METHODS: A total of 603 patients (945 cycles) receiving intravenous trabectedin as monotherapy at doses ranging from 0.024 to 1.8 mg/m(2) 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 goodness-of-fit plots and relative error measurements for the test dataset. Simulations were undertaken to evaluate covariate effects on trabectedin pharmacokinetics. RESULTS: The 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. CONCLUSIONS: The integration of trabectedin pharmacokinetic data demonstrated linear elimination, dose-proportionality up to 1.8 mg/m(2) 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.

Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND AND OBJECTIVES: Recent analysis revealed strong associations between prostate-specific antigen (PSA) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) and supported PSA dynamics as bridging surrogacy endpoints for clinical benefit from treatment with abiraterone acetate plus prednisone. This analysis aimed to investigate the abiraterone exposure-PSA dynamics relationship in mCRPC. METHODS: Abiraterone pharmacokinetics-PSA models were constructed using data from the COU-AA-301 (chemotherapy-pretreated) and COU-AA-302 (chemotherapy-naïve) trials comparing abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily with prednisone alone in mCRPC. The drug effect-PSA dynamics relationship was modeled as a function of selected pharmacokinetic measures. The influences of baseline demographic variables, laboratory values, and disease status on PSA dynamics were assessed. RESULTS: A tumor growth inhibition model best described PSA dynamics post-treatment with abiraterone acetate. Abiraterone acetate treatment in chemotherapy-pretreated and chemotherapy-naïve patients increased the PSA decay rate (k dec) to the same extent (1.28-fold, 95 % confidence interval [CI] 0.58-1.98; and 0.93-fold, 95 % CI 0.6-1.27, respectively). Lower baseline lactate dehydrogenase and higher baseline testosterone significantly increased k dec. Findings from our analysis suggest a maximum-effect relationship between abiraterone trough concentration and PSA dynamics in both patient populations. The majority of patients had a steady-state trough concentration greater than the estimated half maximal effective concentration. CONCLUSION: The model appropriately described the exposure-response relationship between abiraterone and PSA dynamics in chemotherapy-pretreated and chemotherapy-naïve patients following oral administration of abiraterone acetate.

Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate-Treated Castration-Resistant Prostate Cancer Patients.

PURPOSE: We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA). EXPERIMENTAL DESIGN: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy pretreated, n = 1,184) and COU-AA-302 (chemotherapy naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model. RESULTS: The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naïve and -pretreated patients. PSA kinetics [e.g., PSA nadir, PSA response rate (≥30%, 50%, and 90%), time to PSA progression, PSA doubling time (PSADT)] were highly associated with OS in both populations. The model-based posttreatment PSADT had the strongest association with OS (HR ∼0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic endpoints, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic endpoints. A strong correlation was also observed between PSA and radiographic progression-free survival. CONCLUSIONS: The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naïve patients, thereby providing a rationale to consider PSA kinetics as surrogacy endpoints to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment.

Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors.

PURPOSE: JNJ-42756493 is an orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. This first-in-human study evaluates the safety, pharmacokinetics, and pharmacodynamics and defines the recommended phase II dose (RP2D) of JNJ-42756493. PATIENTS AND METHODS: Eligible patients with advanced solid tumors received escalating doses of JNJ-42756493 from 0.5 to 12 mg administered continuously daily or JNJ-42756493 10 or 12 mg administered intermittently (7 days on/7 days off). RESULTS: Sixty-five patients were enrolled. The most common treatment-emergent adverse events included hyperphosphatemia (65%), asthenia (55%), dry mouth (45%), nail toxicity (35%), constipation (34%), decreased appetite (32%), and dysgeusia (31%). Twenty-seven patients (42%) experienced grade ≥ 3 treatment-emergent adverse events, and one dose-limiting toxicity of grade 3 ALT elevation was observed at 12 mg daily. Maximum-tolerated dose was not defined. Nine milligrams daily was considered as the initial RP2D; however, tolerability was improved with intermittent schedules, and 10 mg administered on a 7-days-on/7-days-off schedule was considered the final RP2D. Pharmacokinetics were linear, dose proportional, and predictable, with a half-life of 50 to 60 hours. Dose-dependent elevations in serum phosphate, a manifestation of pharmacodynamic effect, occurred in all patients starting at 4 mg daily. Among 23 response-evaluable patients with tumor FGFR pathway alterations, four confirmed responses and one unconfirmed partial response were observed in patients with glioblastoma and urothelial and endometrial cancer (all with FGFR2 or FGFR3 translocations); 16 patients had stable disease. CONCLUSION: JNJ-42756493 administered at 10 mg on a 7-days-on/7-days-off schedule achieved exposures at which clinical responses were observed, demonstrated pharmacodynamic biomarker activity, and had a manageable safety profile.

The association between body composition and toxicities from the combination of Doxil and trabectedin in patients with advanced relapsed ovarian cancer.

Emerging research suggests that body composition can predict toxicity of certain chemotherapeutic agents. We used data from a clinical study to investigate associations between body composition and combined DOXIL (pegylated liposomal doxorubicin; PLD) and trabectedin (Yondelis) treatment, an effective treatment for ovarian cancer that shows high interpatient variation in toxicity profile. Patients (n = 74) participating in a phase III randomized trial of relapsed advanced ovarian cancer receiving PLD (30 mg/m(2)) and trabectedin (1.1 mg/m(2)) were included. Muscle tissue was measured by analysis of computerized tomography images, and an extrapolation of muscle and adipose tissue to lean body mass (LBM) and fat mass (FM) were employed. Toxicity profile after cycle 1 was used and graded according to the National Cancer Institute Common Toxicity Criteria (version 3). Patients presented with a wide range of body composition. In overweight and obese patients (body mass index (BMI) ≥ 25 kg/m(2), n = 48) toxicity was more prevalent in those with lower BMI (p = 0.028) and a lower FM (n = 43, p = 0.034). Although LBM alone was not predictive of toxicity, a lower FM/LBM ratio was the most powerful variable associated with toxicity (p = 0.006). A different pattern emerged among normal weight patients (n = 26) where toxicity was rare among patients with smaller BMI (<21 kg/m(2)). A clear association between both FM and LBM (primarily driven by FM) in explaining PLD plus trabectedin toxicity emerged, but only in individuals with excess body weight, with a lower ratio predicting higher exposure and risk for toxicity.

Population pharmacokinetic analysis of abiraterone in chemotherapy-naïve and docetaxel-treated patients with metastatic castration-resistant prostate cancer.

BACKGROUND AND OBJECTIVES: Abiraterone acetate, an androgen biosynthesis inhibitor, prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the pre- and post-chemotherapy setting as demonstrated by the pivotal phase III studies COU-AA-301 and COU-AA-302. We performed population pharmacokinetic analyses to estimate pharmacokinetic parameters after oral administration of 1,000 mg/day of abiraterone acetate in patients with mCRPC, with or without prior chemotherapy, and after a single 1,000 mg dose in healthy volunteers. The study objectives were to determine consistency between patient populations and to characterize factors that may influence abiraterone pharmacokinetics. METHODS: Studies in this analysis included COU-AA-302 (chemotherapy naïve); COU-AA-301 and COU-AA-006 (chemotherapy pretreated); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 359 subjects (62 healthy volunteers, 297 patients) were analyzed using non-linear mixed-effects modeling. RESULTS: An Erlang-type absorption model with first-order elimination and three-transit compartments following sequential zero- and first-order processes was used to characterize abiraterone pharmacokinetics. Absorption-related parameters were affected by food intake. Abiraterone pharmacokinetics were characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1,550 L/h) versus healthy subjects (2,240 L/h), and by large apparent central (5,620 L) and peripheral (17,400 L) volumes of distribution. Abiraterone pharmacokinetics were similar in chemotherapy-pretreated and -naïve patients and were characterized by a high between- and within-subject variability [e.g., between-subject coefficient of variation (CV%) for relative bioavailability for the modified fasting state was 61.1% and the CV% for within-subject variability was 71.3%]. The fat content of food taken with abiraterone acetate affected the bioavailability of abiraterone. No factors beyond food intake and health status (healthy vs. mCRPC) impacted abiraterone pharmacokinetics. CONCLUSIONS: Based on the pharmacokinetics model, the recommended 1,000 mg/day of abiraterone acetate resulted in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy. The fat content of food affected relative bioavailability of abiraterone, though the extent of this effect is dependent on health status.

Modeling the effectiveness of paliperidone ER and olanzapine in schizophrenia: meta-analysis of 3 randomized, controlled clinical trials.

The time course of Positive and Negative Syndrome Scale (PANSS) scores in adult schizophrenia patients was modeled, and the effectiveness of paliperidone extended-release tablets (paliperidone ER) and olanzapine was quantified. Data from 3 randomized, double-blind phase III studies were used. Patients received paliperidone ER (3, 6, 9, 12, or 15 mg), olanzapine 10 mg, or matched placebo once daily for 6 consecutive weeks. An indirect response model implemented using a nonlinear mixed effects approach described the time course of the PANSS. Deterioration rate was modeled as a function of baseline PANSS score, placebo, and drug effects, and the dropout effect. An exponential decrease of the placebo response was also implemented. Paliperidone ER and olanzapine treatment were characterized by a long-lasting drug effect (13%), with a larger but short-lasting placebo effect (40%) and a notable dropout rate. The covariate exploration failed to identify any clinically relevant factors. The nonparametric bootstrap analysis confirmed the acceptable precision of parameter estimates. The visual predictive check supported the model's adequacy to reproduce observed PANSS time courses. The population model describes the time course of PANSS scores in schizophrenia patients and is appropriate for use in clinical trial simulation activities.

Population pharmacokinetics of tapentadol immediate release (IR) in healthy subjects and patients with moderate or severe pain.

BACKGROUND: Tapentadol is a new, centrally active analgesic agent with two modes of action--mu opioid receptor agonism and norepinephrine reuptake inhibition--and the immediate-release (IR) formulation is approved in the US for the relief of moderate to severe acute pain. The aims of this analysis were to develop a population pharmacokinetic model to facilitate the understanding of the pharmacokinetics of tapentadol IR in healthy subjects and patients following single and multiple dosing, and to identify covariates that might explain variability in exposure following oral administration. METHODS: The analysis included pooled data from 11,385 serum pharmacokinetic samples from 1827 healthy subjects and patients with moderate to severe pain. Population pharmacokinetic modelling was conducted using nonlinear mixed-effects modelling (NONMEM) software to estimate population pharmacokinetic parameters and the influence of the subjects' demographic characteristics, clinical laboratory chemistry values and disease status on these parameters. Simulations were performed to assess the clinical relevance of the covariate effects on tapentadol exposure. RESULTS: A two-compartment model with zero-order release followed by first-order absorption and first-order elimination best described the pharmacokinetics of tapentadol IR following oral administration. The interindividual variability (coefficient of variation) in apparent oral clearance (CL/F) and the apparent central volume of distribution after oral administration were 30% and 29%, respectively. An additive error model was used to describe the residual variability in the log-transformed data, and the standard deviation values were 0.308 and 0.314 for intensively and sparsely sampled data, respectively. Covariate analysis showed that sex, age, bodyweight, race, body fat, hepatic function (using total bilirubin and total protein as surrogate markers), health status and creatinine clearance were statistically significant factors influencing the pharmacokinetics of tapentadol. Total bilirubin was a particularly important factor that influenced CL/F, which decreased by more than 60% in subjects with total bilirubin greater than 50 micromol/L. CONCLUSIONS: The population pharmacokinetic model for tapentadol IR identified the relationship between pharmacokinetic parameters and a wide range of covariates. The simulations of tapentadol exposure with identified, statistically significant covariates demonstrated that only hepatic function (as characterized by total bilirubin and total protein) may be considered a clinically relevant factor that warrants dose adjustment. None of the other covariates are of clinical relevance, nor do they necessitate dose adjustment.

Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic.

OBJECTIVES: To characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting palmitate ester at various doses and at two different injection sites (deltoid and gluteal muscle). METHODS: The retrospective analysis included pooled data from 1795 subjects from six phase I trials and five phase II and III trials. A total of 18 530 pharmacokinetic samples with valid concentration timepoints were available for this analysis. Nonlinear mixed-effects modelling of the pooled data was conducted using NONMEM software. The full dataset was divided into an index dataset (model development) and a validation dataset. After validation both the index and validation datasets were combined and the final model was re-run on the full dataset. RESULTS: The concentration-time data for paliperidone following intramuscular administration of its palmitate ester were best fitted to a one-compartment model with first-order elimination. The absorption component of the model allowed a fraction of the dose (f(2)) to enter relatively quickly into the central compartment via a zero-order process. After a lag time, the remaining fraction then entered the systemic circulation via a first-order process. Interindividual variability (IIV) in clearance (CL), central volume of distribution (V(d)) and the absorption rate constant (k(a)) were estimated at a 40%, 69% and 59% coefficient of variation (CV), respectively. The IIV on f(2) for paliperidone absorption via the dual-input process was fitted through logit transformation, and its standard deviation (SD) was 0.064. Similarly, the interoccasion variability (IOV) on CL, V(d) and f(2) was 26% CV, 14% CV and 0.07 SD, respectively. An additive-error model with log-transformed data was used to describe the residual variability (RV), and its SD was 0.22. The final covariate model indicated that the following variables had a significant influence on k(a): sex, age, injection volume (IVOL) and injection site (INJS). Similarly, the following variables had a significant influence on f(2): sex, body mass index (BMI), needle length (NDLL), INJS and IVOL. In addition, CL was related to creatinine clearance (CL(CR)), whereas V(d) was related to BMI and sex. CONCLUSIONS: A dual-absorption pharmacokinetic model best described the complex pharmacokinetics of paliperidone after intramuscular administration of its palmitate ester. These results suggest that the pharmacokinetics of paliperidone palmitate are mostly influenced by BMI, CL(CR), INJS, IVOL and NDLL.