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Therapeutic monoclonal antibodies (mAbs) are increasingly used to treat a variety of conditions. The sources of their interindividual pharmacokinetic (PK) variability have been extensively studied, but few data on their intraindividual PK variability are available. In this article, we reviewed the published population compartmental models used to describe the time-varying PK of mAbs in clinical settings. Of 189 publications, 13 report the use of time-varying parameters and 30 describe the effects of antidrug antibody (ADA) development. Currently published time-varying models mainly describe fast decreases in clearance due to target-mediated elimination or slow decreases in clearance owing to cachexia reduction. Immunogenicity models mostly describe 'on-off' increases of clearance due to a rapid elimination of mAbs-ADA complexes. Some more sophisticated models attempted to decipher the time course of immunogenic response, notably by accounting for the time of onset and progressive increase in ADA production. Currently available time-varying and immunogenicity models are empirical approximations of the complex mAb disposition, but they emphasize the necessity to account for the temporal variations of mAb PK in model building. The clinical implications of the time-varying PK of mAbs are not fully understood, but some publications reported a link between clearance decrease and disease improvement. The future perspectives offered by this knowledge include the possibility to adapt the regimen to the disease and the patients' state, and also to immune status, and to monitor their evolution by monitoring PK variations. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors are a new class of monoclonal antibodies that amplify T-cell-mediated immune responses against cancer cells. The introduction of these new drugs, first anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and then anti-programmed death-1 (anti-PD1), was a major improvement in the treatment of advanced or metastatic melanoma, a highly immunogenic tumour. The development strategy for immune checkpoint immunotherapies differed from that traditionally used for cytotoxic therapies in oncology. The choices of doses at which to conduct clinical trials, and subsequently the choice of doses at which to use these new therapies, were not based on the identification of a maximum tolerated dose from dose-escalation studies; thus, pharmacokinetic and pharmacokinetic-pharmacodynamic modelling was essential. The studies conducted have shown that the pharmacokinetics of ipilimumab were linear and not time-dependent. In addition, there was a correlation between the trough concentrations of ipilimumab and its therapeutic efficacy. On the contrary, the anti-PD1 immunotherapies nivolumab and pembrolizumab had time-dependent pharmacokinetics. Their therapeutic efficacy was not related to their trough concentration, but there was a correlation between the clearance of anti-PD1 and the survival of melanoma patients. This review highlights the complexity of interpreting the exposure-response relationships of these agents. Further studies are needed to assess the value of therapeutic drug monitoring of immune checkpoint inhibitors in the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Membrane transporters play an essential role in the pharmacokinetics of drugs as they mediate exchanges between biological compartments. Tacrolimus is characterized by wide interpatient variability in terms of its pharmacokinetics that may in part be due to genetic factors. The pharmacogenetics of drug transporters is therefore a promising area to explore in the clinical pharmacology of tacrolimus. The aim of this review is to provide an overview of currently available data regarding the pharmacogenetics of membrane transporters that may be involved in the interindividual variability of the response to tacrolimus. Several genetic variants in genes coding for influx or efflux membrane transporters (e.g. ABCB1, ABCC2, ABCC8, SLC30A8, SLCO1B1/3, SLC28A1, SLC22A11, and SLC28A3) have been associated with tacrolimus pharmacokinetics variability or the occurrence of toxicity; however, there is still a degree of controversy as to the impact of these variants in vivo and further investigations are needed to confirm these results in larger cohorts and to validate the relevance of such genetic biomarkers for personalization of immunosuppressive therapy in solid organ transplantations. The relationship between transporter polymorphisms and the intracellular concentration of tacrolimus should also be further investigated. Finally, the main challenge could be elucidation of the interplay of biological mechanisms underlying genetic variations that alter the drug concentration or its clinical effect. [ABSTRACT FROM AUTHOR]

This study aimed at describing the pharmacokinetics and the concentration-effect relationships of fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug. A one-compartment model was used to describe fludrocortisone and hydrocortisone pharmacokinetics. Mean plasma half-life was 1.40 h (95%CI [0.80;2.10]) for fludrocortisone and 2.10 h (95%CI [1.78;2.40]) for hydrocortisone. Clearance was 40.8 L/h (95%CI [33.6;48]) for fludrocortisone and 30 L/h (95%CI [25.3;34.7]) for hydrocortisone. An indirect response model was used to describe effects on urinary sodium/potassium ratio. Fludrocortisone plasma concentrations showed a wider inter-individual dispersion than hydrocortisone plasma concentrations. Urinary sodium/potassium ratio variability was also higher with fludrocortisone as compared to hydrocortisone. The plasma concentration of drug producing 50% of maximal inhibition of urinary sodium/potassium (IC) was about 200 times lower for fludrocortisone (0.08 μg/L, 95%CI [0.035;0.125]) than for hydrocortisone (16.7 μg/L, 95%CI [10.5;22.9]). Simulations showed that a 4-time per day administration regimen allow to achieve steady fludrocortisone plasma concentrations with stable decrease in urinary sodium/potassium ratio after the second administration of fludrocortisone. Fludrocortisone and hydrocortisone have short and similar plasma elimination half-lives in healthy subjects. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. The administration regimen of fludrocortisone should be reconsidered. [ABSTRACT FROM AUTHOR]

Background: We aimed at assessing the benefit-to-risk ratio of activated protein C (drotrecogin-alfa activated, DAA) and corticosteroids, given alone or in combination, in patients with septic shock. Methods: We implemented an investigator-led, publicly funded, multicenter, randomized according to a 2 × 2 factorial design, placebo-controlled, double-blind trial in four parallel groups in which adults with persistent septic shock and no contraindication to DAA were assigned to either DAA alone (24 mg/kg/h for 96 h), or hydrocortisone (50 mg intravenous bolus q6 for 7 days) and fludrocortisone (50 µg once daily through the nasogastric tube for 7 days) alone, or their respective combinations, or their respective placebos. Primary endpoint was 90-day mortality rate. Follow-up duration was 6 months. Statistical analysis was planned to be performed in intent-to-treat once after all participants completed 180-day follow-up and according to the 2 × 2 factorial design. Results: The first patient was recruited in September 2008. The trial was suspended on October 25, 2011, owing to the withdrawal from the market of DAA. At this time, 411 patients had been enrolled. On May 17, 2012, the continuation of the trial on two parallel groups was approved by all legal authorities with the aim of investigating the benefit-to-risk ratio of corticosteroids. On June 30, 2014, the trial was suspended again by the study sponsor upon request of the independent data and safety monitoring board. Recruitment restarted on October 7, 2014, after any safety concern was ruled out. Finally, the trial was completed on June 23, 2015, with the recruitment of 1241 patients. Conclusions: This report details the design, statistical plan and conduct of a randomized controlled trial of hydrocortisone and fludrocortisone in septic shock. Trial registration The trial was registered at ClinicalTrials.gov under NCT00625209 [ABSTRACT FROM AUTHOR]

Purpose: The benefits of low-dose steroids in septic shock remain controversial. We investigated if these low doses were able to induce their expected hormonal effects by analyzing the biological modifications observed during the study, which first demonstrated the survival benefit of low-dose steroids. Methods: This was a multicenter, placebo-controlled, randomized, double-blind study in which 299 septic shock patients received a 7-day treatment with a combination of hydrocortisone (50 mg intravenously four times daily) and fludrocortisone (50 μg orally once daily) or matching placebos. Gluco- and mineralocorticoid biological effects observed during the 7 days of treatment were compared between groups. Results: Steroids significantly decreased eosinophil counts from day 2 to day 7. Steroids significantly increased plasma glucose from day 2 (compared with placebos: +0.8 mmol/l) to day 7 (+1.8 mmol/l) and cholesterol from day 3 (+0.54 mmol/l) to day 7 (+0.39 mmol/l). Steroids significantly increased plasma sodium from day 3 (+2 mmol/l) to day 7 (+5 mmol/l) and significantly decreased plasma potassium on day 7 (−0.2 mmol/l). Steroids significantly decreased urinary sodium/potassium ratio from day 2 (−47 %) to day 7 (−57 %) and sodium fractional excretion from day 3 (−25 %) to day 7 (−66 %). Steroids significantly increased urine output on day 4 and 5 and osmolar clearance from day 4 to day 7, and decreased free-water clearance from day 4 to day 7, this effect being significant on day 4 and 6. Conclusions: In septic shock, low-dose steroids induced both gluco- and mineralocorticoid biological effects and seemed to improve renal function. Most of these effects appeared after 2-3 days of treatment and lasted at least until the end of treatment. [ABSTRACT FROM AUTHOR]

Objective: Illustration of the difficulties in approaching critically ill patients for informed consent for inclusion into a randomized controlled trial and the impact of a waiver of consent from the patient's next of kin in the conduction of such studies.Design: Descriptive survey of the inclusion rates into the Ger-Inf-05 study before and after a waiver of consent from the patient's next of kin.Setting: Nineteen intensive care units in France.Patients: Septic shock patients (n=300) included in a placebo-controlled randomized double-blind study on the efficacy and safety of a 7-day treatment with 50 mg hydrocortisone every 6 h intravenously and 50 microg fludrocortisone every 24 h orally.Intervention: Introduction, 10 months after the beginning of the study, of a waiver of consent from the patient's next of kin if it was not present at the time of the patient's inclusion.Measurements and Results: The mean inclusion rate was four patients per month before the introduction of the waiver of consent and increased to 10 patients per month after the study amendment including the waiver of consent. Informed consent was obtained from the patient himself or herself in 10 patients (3%) and from next of kin in 70 patients (23%). For the 220 other patients (74%), the investigators could not contact the responsible relative within the inclusion period.Conclusions: Recruitment rate in the Ger-Inf-05 study was clearly improved after the waiver of consent from the patient's next of kin. This probably contributed to the successful completion of the study. [ABSTRACT FROM AUTHOR]

OBJECTIVE: One third of subjects who suffer from fecal incontinence are found to have values within the normal range when anal manometry is performed. For these patients, one hypothesis is that impaired rectal adaptation to distension may occur. The aim of our study was to analyze anorectal responses to rectal isobaric distension in this population. METHODS: This was a prospective study conducted in 51 consecutive incontinent patients (45 female, six male) divided into two groups according to their functional anal state: absence (19 patients aged 55 ± 6 yr) or presence of manometric anal weakness (32 patients aged 59 ± 2 yr). The subjects were submitted to two randomized modes of rectal isobaric distension (tonic, phasic) with an electronic barostat. Anal pressures, perception, and volumes of the rectum were recorded at six different preselected pressures. RESULTS: As compared with those having anal weakness, patients with no anal weakness retained higher mean pressures at both upper (36.9 ± 2.2 vs 22.9 ± 1.4 mm Hg: p ± 0.01) lower parts (41.0 ± 2.0 vs 23.3 ± 1.4 mm Hg; p = 0.002) of the anal canal, similar perception scores, but much lower rectal volumes (68.5 ± 5.5 vs 121.8 ± 7.0 ml; p = 0.008) in response to rectal isobaric distension. CONCLUSION: A decrease in rectal adaptation could be involved in fecal leakage in patients with no anal manometric weakness. [ABSTRACT FROM AUTHOR]