Time above threshold plasma concentrations as pharmacokinetic parameter in the comparison of oral and intravenous docetaxel treatment of breast cancer tumors.

BACKGROUND: Prolonging the time which plasma concentrations of antimitotic drugs, such as the taxanes, exceed cytotoxic threshold levels may be beneficial for their efficacy. Orally administered docetaxel offers an undemanding approach to optimize such time above threshold plasma concentrations (t C>threshold ). METHODS: A nonsystematic literature screen was performed to identify studies reporting in-vitro half-maximal inhibitory concentration (IC 50 ) values for docetaxel. Pharmacokinetics of intravenously (i.v.) docetaxel (75 mg/m 2 ) and orally administered docetaxel (ModraDoc006) co-administered with ritonavir (r) given twice daily (30 + 20 mg concomitant with 100 mg ritonavir bis in die) were simulated using previously developed population models. T C>threshold was calculated for a range of relevant thresholds in terms of in-vitro cytotoxicity and plasma concentrations achieved after i.v. and oral administration of docetaxel. A published tumor growth inhibition model for i.v. docetaxel was adapted to predict the effect of attainment of time above threshold levels on tumor dynamics. RESULTS: Identified studies reported a wide range of in vitro IC 50 values [median 0.04 µmol/L, interquartile range (IQR): 0.0046-0.62]. At cytotoxic thresholds <0.078 µmol/L oral docetaxel shows up to ~7.5-fold longer t C>threshold within each 3-week cycle for a median patient compared to i.v.. Simulations of tumor dynamics showed the increased relative potential of oral docetaxel for inhibition of tumor growth at thresholds of 0.075, 0.05 and 0.005 µmol/L. CONCLUSION: ModraDoc006/r is superior to i.v. docetaxel 75 mg/m 2 in terms of median time above cytotoxic threshold levels <0.078 µmol/L. This may indicate superior cytotoxicity and inhibition of tumor growth compared to i.v. administration for relatively docetaxel-sensitive tumors.

The influence of docetaxel schedule on treatment tolerability and efficacy in patients with metastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Administration of single-agent docetaxel in a weekly schedule may offer similar efficacy, with a more favorable toxicity profile, compared to a three-weekly schedule in patients with metastatic breast cancer. METHODS: The original search of Medline, Embase, and Scopus was performed in September 2018 and references were updated with additional searches up to January 2021. Two reviewers independently screened the identified literature based on a predefined set of criteria. Randomized controlled trials investigating the use of weekly versus three-weekly docetaxel in metastatic breast cancer patients were included. RESULTS: Four randomized controlled trials (N = 459 patients) were included in the final analyses. No significant differences were found in terms of objective response rate (risk ratio (RR) 0.75, 95% confidence interval (CI): 0.54 - 1.05), progression-free survival (hazard ratio (HR) 0.95, 95% CI: 0.71 - 1.26) or overall survival (HR 0.95, 95% CI: 0.70 - 1.29) between weekly and three-weekly docetaxel, respectively. Weekly docetaxel was associated with a significantly lower risk of grade 3/4 neutropenia (RR 0.16, 95% CI: 0.10 - 0.27), febrile neutropenia (RR 0.21, 95% CI: 0.08 - 0.55), and neuropathy (RR 0.29, 95% CI: 0.11 - 0.78). Although the risk of epiphora (≥ grade 3/leading to treatment withdrawal, RR 3.62, 95% CI: 1.07-12.22) and onycholysis (≥ grade 2/leading to treatment withdrawal, RR 3.90, 95% CI: 1.34 - 11.32) was increased. CONCLUSIONS: Weekly docetaxel is associated with a lower risk of neutropenia, febrile neutropenia and neuropathy than the three-weekly docetaxel schedule in metastatic breast cancer patients. However, the risk of onycholysis, epiphora, and treatment discontinuation seems increased with weekly administration. No significant differences in efficacy outcomes were found. Weekly docetaxel might be an alternative for patients at risk for developing neutropenia.

Investigating the influence of relevant pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of orally administered docetaxel combined with ritonavir.

The anticancer drug docetaxel exhibits large interpatient pharmacokinetic and pharmacodynamic variability. In this study, we aimed to assess the functional significance of 14 polymorphisms in the CYP3A, CYP1B1, ABCB1, ABCC2, and SLCO1B3 genes for the pharmacokinetics and pharmacodynamics of oral docetaxel, co-administered with ritonavir. None of the tested CYP3A, ABCB1, ABCC2, and SLCO1B3 genotypes and diplotypes showed a significant relation with an altered bioavailability or clearance of either docetaxel or ritonavir. Similarly, no clear effect of CYP1B1 genotype on clinical outcomes was observed in a subgroup of non-small cell lung cancer (NSCLC) patients. Our post hoc power analysis indicated that our pharmacogenetic-pharmacokinetic analysis was only powered for relatively high effect sizes, which were to be expected given the high interpatient variability. This makes it unlikely that future studies will explain the high observed interpatient variability in oral docetaxel pharmacokinetics as a result of any of these separate polymorphisms and diplotypes.

Intraoperative dexamethasone and delirium after cardiac surgery: a randomized clinical trial.

BACKGROUND: Delirium is common after cardiac surgery and may be partly related to the systemic inflammatory response triggered by the surgery and the use of cardiopulmonary bypass. We hypothesized that intraoperative administration of high-dose dexamethasone, a drug with potent anti-inflammatory effects, would reduce the incidence of delirium at any time point during the first 4 postoperative days after cardiac surgery. METHODS: This was a single-center substudy within a larger, multicenter placebo-controlled randomized clinical trial, the Dexamethasone for Cardiac Surgery (DECS) trial that randomized patients ≥18 years, undergoing cardiac surgery with cardiopulmonary bypass, to receive, in a double-blind fashion, either dexamethasone 1 mg/kg or placebo at the induction of anesthesia. Over the first 4 postoperative days, we compared between groups the incidence of delirium (based on the Confusion Assessment Method adapted for the intensive care unit, or after intensive care unit discharge, by the Confusion Assessment Method, accompanied by chart review), restraint use, and administered haloperidol, benzodiazepines, and opioids. Data were analyzed according to the intention-to-treat principle. The proportion of patients with delirium in the dexamethasone versus the placebo group was compared using the odds ratio (OR) with a 95% confidence interval (CI). The proportion also was compared using logistic regression to adjust for common baseline variables that might confound the presence of delirium between the 2 groups. RESULTS: Of 768 eligible patients, 737 subjects (96.0%) had complete data. The incidence of delirium was similar between the dexamethasone (14.2%) and placebo (14.9%) groups (crude OR = 0.95, 95% CI, 0.63-1.43; adjusted OR = 0.85, 95% CI, 0.55-1.31). Among patients who developed delirium, the median (interquartile range) duration of delirium was similar between the dexamethasone and placebo groups (2 [1-3] vs 2 [1-2] days, respectively, P = 0.45; WMWodds 0.98, 95% CI, 0.83-1.17). Restraint use and the administration of haloperidol, benzodiazepines, and opioids were also similar between the 2 groups. CONCLUSIONS: The intraoperative administration of dexamethasone did not reduce the incidence or duration of delirium in the first 4 days after cardiac surgery.

Routine use of the confusion assessment method for the intensive care unit: a multicenter study.

RATIONALE: Delirium is often unrecognized in ICU patients and associated with poor outcome. Screening for ICU delirium is recommended by several medical organizations to improve early diagnosis and treatment. The Confusion Assessment Method for the ICU (CAM-ICU) has high sensitivity and specificity for delirium when administered by research nurses. However, test characteristics of the CAM-ICU as performed in routine practice are unclear. OBJECTIVES: To investigate the diagnostic value of the CAM-ICU in daily practice. METHODS: Teams of three delirium experts including psychiatrists, geriatricians, and neurologists visited 10 ICUs twice. Based on cognitive examination, inspection of medical files, and Diagnostic and Statistic Manual of Mental Disorders, 4th edition, Text Revision criteria for delirium, the expert teams classified patients as awake and not delirious, delirious, or comatose. This served as a gold standard to which the CAM-ICU as performed by the bedside ICU-nurses was compared. Assessors were unaware of each other's conclusions. MEASUREMENTS AND MAIN RESULTS: Fifteen delirium experts assessed 282 patients of whom 101 (36%) were comatose and excluded. In the remaining 181 (64%) patients, the CAM-ICU had a sensitivity of 47% (95% confidence interval [CI], 35%-58%); specificity of 98% (95% CI, 93%-100%); positive predictive value of 95% (95% CI, 80%-99%); and negative predictive value of 72% (95% CI, 64%-79%). The positive likelihood ratio was 24.7 (95% CI, 6.1-100) and the negative likelihood ratio was 0.5 (95% CI, 0.4-0.8). CONCLUSIONS: Specificity of the CAM-ICU as performed in routine practice seems to be high but sensitivity is low. This hampers early detection of delirium by the CAM-ICU.

Development of a population pharmacokinetic/pharmacodynamic model for various oral paclitaxel formulations co-administered with ritonavir and thrombospondin-1 based on data from early phase clinical studies.

PURPOSE: Orally administered paclitaxel offers increased patient convenience while providing a method to prolong exposure without long continuous, or repeated, intravenous infusions. The oral bioavailability of paclitaxel is improved through co-administration with ritonavir and application of a suitable pharmaceutical formulation, which addresses the dissolution-limited absorption of paclitaxel. We aimed to characterize the pharmacokinetics of different paclitaxel formulations, co-administered with ritonavir, and to investigate a pharmacodynamic relationship between low-dose metronomic (LDM) treatment with oral paclitaxel and the anti-angiogenic marker thrombospondin-1 (TSP-1). METHODS: Fifty-eight patients treated with different oral paclitaxel formulations were included for pharmacokinetic analysis. Pharmacodynamic data was available for 36 patients. All population pharmacokinetic/pharmacodynamic modelling was performed using non-linear mixed-effects modelling. RESULTS: A pharmacokinetic model consisting of gut, liver, central, and peripheral compartments was developed for paclitaxel. The gastrointestinal absorption rate was modelled with a Weibull function. Relative gut bioavailabilities of the tablet and capsule formulations, as fractions of the gut bioavailability of the drinking solution, were estimated to be 0.97 (95%CI: 0.67-1.33) and 0.46 (95%CI: 0.34-0.61), respectively. The pharmacokinetic/pharmacodynamic relationship between paclitaxel and TSP-1 was modelled using a turnover model with paclitaxel plasma concentrations driving an increase in TSP-1 formation rate following an Emax relationship with an EC50 of 284 ng/mL (95%CI: 122-724). CONCLUSION: The developed pharmacokinetic model adequately described the paclitaxel plasma concentrations for the different oral formulations co-administered with ritonavir. This model, and the established pharmacokinetic/pharmacodynamic relationship with TSP-1, may facilitate future development of oral paclitaxel.

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin.

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.

Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial.

BACKGROUND: Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. METHODS: Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT00704301. FINDINGS: Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7-14·2) than in the placebo group (3·0 days, IQR 1·0-9·3; p=0·06). INTERPRETATION: Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. FUNDING: ZonMw, the Netherlands Brain Foundation, and Novartis.

ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients: A phase Ib study.

BACKGROUND: ModraDoc006 is an oral formulation of docetaxel, which is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration-resistant prostate cancer (mCRPC). AIM: We assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC. METHODS: mCRPC patients, treatment naïve or following abiraterone or enzalutamide treatment, were included. Dose-escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate-specific antigen (PSA) and radiological evaluation. RESULTS: Cohort 1 (n = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/100-100). The mean docetaxel area under the plasma concentration-time curve (mAUC0-inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (n = 6, ModraDoc006/r 30-20/200-200), the mAUC0-inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (n = 6, ModraDoc006/r 30-20/200-100), the mAUC0-inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B (n = 3, ModraDoc006/r 20-20/200-100), the mAUC0-inf was 558 ng/mL × h without DLTs. The mAUC0-inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of >50% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed. CONCLUSION: The RP2D was established at weekly ModraDoc006/r 30-20/200-100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3-weekly IV docetaxel in patients with mCRPC.

Comparison of delirium assessment tools in a mixed intensive care unit.

OBJECTIVE: Delirium is a frequent problem in the intensive care unit (ICU) associated with poor prognosis. Delirium in the ICU is underdiagnosed by nursing and medical staff. Several detection methods have been developed for use in ICU patients. The aim of this study was to compare the value of three detection methods (the Confusion Assessment Method for the ICU [CAM-ICU], the Intensive Care Delirium Screening Checklist [ICDSC] and the impression of the ICU physician with the diagnosis of a psychiatrist, neurologist, or geriatrician). DESIGN: Prospective study. SETTING AND PATIENTS: During an 8-month period, 126 patients (mean age 62.4 years, sd 15.0; mean Acute Physiology and Chronic Health Evaluation II score 20.9, sd 7.5) admitted to a 32-bed mixed medical and surgical ICU were studied. MEASUREMENTS: The included patients were assessed independently by trained ICU nurses using either the CAM-ICU or the ICDSC. Furthermore, the ICU physician was asked whether a patient was delirious or not. A psychiatrist, geriatrician, or neurologist serving as reference rater diagnosed delirium using established criteria. MAIN RESULTS: The CAM-ICU showed superior sensitivity and negative predictive value (64% and 83%) compared with the ICDSC (43% and 75%). The ICDSC showed higher specificity and positive predictive value (95% and 82% vs. 88% and 72%). The sensitivity of the physicians view was only 29%. CONCLUSIONS: ICU physicians underdiagnose delirium in the ICU, which underlines the necessity of standard evaluation in all critically ill patients. In our mixed ICU population, the CAM-ICU had a higher sensitivity than the ICDSC.

Cytochrome P450 3A4, 3A5, and 2C8 expression in breast, prostate, lung, endometrial, and ovarian tumors: relevance for resistance to taxanes.

Enzymes of the cytochrome P450 (CYP) subfamily 3A and 2C play a major role in the metabolism of taxane anticancer agents. While their function in hepatic metabolism of taxanes is well established, expression of these enzymes in solid tumors may play a role in the in situ metabolism of drugs as well, potentially affecting the intrinsic taxane susceptibility of these tumors. This article reviews the available literature on intratumoral expression of docetaxel- and paclitaxel-metabolizing enzymes in mammary, prostate, lung, endometrial, and ovarian tumors. Furthermore, the clinical implications of the intratumoral expression of these enzymes are reviewed and the potential of concomitant treatment with protease inhibitors (PIs) as a method to inhibit CYP3A4-mediated metabolism is discussed.

Intensive care delirium monitoring and standardised treatment: a complete survey of Dutch Intensive Care Units.

OBJECTIVE: Delirium is a frequent and serious problem in the Intensive Care Unit (ICU). Several international guidelines recommend daily monitoring for ICU-delirium. The purpose of this article is to give an up-to-date overview of the current status of monitoring and treatment of ICU-delirium in the Netherlands. DESIGN: Nation-wide, telephone-based questionnaire survey. PARTICIPANTS: Head nurse of all ICUs and a random sample of intensivists. RESULTS: Only 14% (n=14) of all Dutch ICUs (n=103) monitored for ICU-delirium. Of these, only half (7%) used a tool that is validated in ICU patients. In 31% of Dutch ICUs, a protocol was used to treat ICU-delirium. Responses were obtained from 100% of ICUs. CONCLUSION: Despite an international guideline, not more than 7% of ICUs in our study routinely evaluated the presence of delirium with a validated instrument. Fewer than one-third of Dutch ICUs use a protocol to treat ICU-delirium.

Intensive care unit environment may affect the course of delirium.

PURPOSE: Delirium is a common disorder in intensive care unit (ICU) patients. It is unclear whether ICU environment affects delirium. We investigated the influence of ICU environment on the number of days with delirium during ICU admission. METHODS: In this prospective before-after study, ICU delirium was compared between a conventional ICU with wards and a single-room ICU with, among others, improved daylight exposure. We included patients admitted for more than 24 h between March and June 2009 (ICU with wards) or between June and September 2010 (single-room ICU). Patients who remained unresponsive throughout ICU admission were excluded. The presence of delirium in the preceding 24 h was assessed daily with the confusion assessment method for the ICU (CAM-ICU) by research physicians combined with evaluation of medical and nursing charts. The number of days with delirium was investigated with Poisson regression analysis. RESULTS: We included 55 patients (449 observation days) in the ICU with wards and 75 patients (468 observation days) in the single-room ICU. After adjusting for confounding, the number of days with delirium decreased by 0.4 days (95 % confidence interval 0.1-0.7) in the single-room ICU (p = 0.005). The incidence of delirium during ICU stay was similar in the ICU with wards (51 %) and in the single-room ICU (45 %, p = 0.53). CONCLUSIONS: This study is the first to show that ICU environment may influence the course of delirium in ICU patients.