Infraorbital and infratrochlear nerve blocks combined with general anaesthesia for outpatient rhinoseptoplasty: A prospective randomised, double-blind, placebo-controlled study.

INTRODUCTION: We conducted a study to determine the efficacy of bilateral extraoral infraorbital and infratrochlear nerve blocks during outpatient rhinoseptoplasty under general anaesthesia. PATIENTS AND METHODS: In this prospective, double-blind, randomised, controlled trial, 40 adult patients undergoing outpatient rhinoseptoplasty under general anaesthesia were assigned to receive bilateral infraorbital and infratrochlear nerve blocks with either 10mL of 0.25% levobupivacaine (Group LB) or isotonic saline (control group). Patients in Group LB received 0.1mL/kg of isotonic saline as a placebo and patients in the control group received 0.1mL/kg of morphine. The primary endpoint was total perioperative morphine consumption (intraoperative and in the post-anaesthesia care unit). The secondary endpoints were pain scores, time spent in the post-anaesthesia care unit and the outpatient ward, block-related complications and patient satisfaction. RESULTS: The total dose of perioperative morphine was lower in Group LB than in the control group (2.5±2.8mg versus 9.5±3.5mg, respectively, P<0.001). The mean±SD or median [IQR] times spent in the post-anaesthesia care unit (60±10min and 78±33min, respectively, P<0.03) and in the outpatient ward (210 [178-223] min versus 275 [250-300] min, respectively, P<0.001) were lower in Group LB than in the control group. There were no differences between groups for other endpoints. CONCLUSION: Bilateral extraoral infraorbital and infratrochlear nerve blocks performed with 0.25% levobupivacaine during general anaesthesia combining remifentanil and desflurane reduce the perioperative dose of morphine and the time spent in the post-anaesthesia care unit and the outpatient ward in adult patients undergoing outpatient rhinoseptoplasty.

Determination of the most influential sources of variability in tacrolimus trough blood concentrations in adult liver transplant recipients: a bottom-up approach.

Tacrolimus, an immunosuppressant drug, presents a narrow therapeutic window and a large pharmacokinetic variability with poor correlation between drug dosing regimen and blood concentration. The objective was to identify predictive factors influencing tacrolimus trough concentrations (C0) using a bottom-up approach. A physiologically based pharmacokinetic (PBPK) model of tacrolimus was proposed, taking into account the body weight, the proportion of fat (P(fat)), hematocrit, lipid fraction of organs, typical intrinsic clearance (CLi(typ)), CYP3A5 genotype of liver donor, plasma unbound fraction of tacrolimus (fu(p)), and concomitant drugs (CYP3A4 inhibitors). For the evaluation of the PBPK model, mean C0 and concentrations 2 h after oral dose of tacrolimus were compared with those from 66 liver transplant recipients included in a multicentric pharmacokinetic study and were found very close. Tacrolimus concentration profiles were simulated in a virtual population defined by a set of covariate values similar to those from the real population. The sensitivity of tacrolimus C0 with respect to each covariate has been tested to identify the most influential ones. With the range of covariate values tested, the impact of each covariate on tacrolimus C0 may be ranked as follows: fu(p), CLi(typ), bioavailability, body weight, hematocrit, CYP3A5 polymorphism, P(fat), and CYP3A4 inhibitory drug-drug interactions. Values for initial dosing regimen of tacrolimus in order to reach a C0 of 10 ng/ml at day 5 (assuming a constant dosing schedule) as a function of CYP3A5 donor genotype and patient's hematocrit and body weight are proposed.

Links between cyclosporin exposure in tissues and graft-versus-host disease in pediatric bone marrow transplantation: analysis by a PBPK model.

PURPOSE: In hematopoietic stem cell transplantation (HSCT), cyclosporin is used to prevent graft-versus-host disease (GVHD). However, cyclosporin distribution in tissues is not linear, resulting in uncertainty regarding optimal dosing and monitoring. The objective of this study was to link the probability and severity of acute GVHD to cyclosporin exposure in blood, GVHD target organs, and lymphoid organs. METHODS: A physiologically based pharmacokinetic model of cyclosporin disposition and logistic regression models were used. Sixty-one pediatric patients undergoing HSCT were studied. Cyclosporin was administered by intermittent (n = 31) or continuous infusion (n = 30). RESULTS: At steady state (1 day before acute GVHD), exposures in all organs were related with the probability and severity of acute GVHD. Average cyclosporin concentration or, equivalently, its area under the curve (AUC) was the pharmacokinetic index best correlated with the anti-GVHD effect. Cyclosporin AUC in interstitial fluid of lymphoid organs was a superior index than that in blood, but marginally. CONCLUSION: Hence, AUC in blood maybe used as an index of cyclosporin efficacy. Using our model, target AUCs in blood could be defined for malignant and non-malignant diseases, as well as the equivalent target values for C(2) and C(0) concentrations.

Influence of dosing schedule on organ exposure to cyclosporin in pediatric hematopoietic stem cell transplantation: analysis with a PBPK model.

PURPOSE: Cyclosporin is administered by intermittent infusions (II) or continuous infusions (CI) to prevent acute graft-versus-host disease (aGVHD). Because cyclosporin disposition is nonlinear, organ exposure may be higher after II than after CI, but saturation of receptors must be accounted for. The aim of the study was to compare both types of administration using a mechanistic model. METHODS: A physiologically based pharmacokinetic model was developed to estimate cyclosporin exposure and receptor occupancies (RO) in aGVHD target organs and kidneys and to compare these estimations in pediatric patients that received cyclosporin either by II or CI. The relevant biological parameters were based on a clinical study in 2 groups of pediatric patients that received cyclosporin either by II (n = 31) or CI (n = 30). RESULTS: Simulations showed that the exposure to cyclosporin in the interstitial fluid of aGVHD target organs was greater at day 1 after II than after CI. In kidneys, the opposite order was observed. AUC(RO) in all organs was greater after CI than after II. The therapeutic index (the ratio of AUC(RO) in blood to AUC(RO) in kidneys) was greater with CI than with II. CONCLUSIONS: CI may be slightly more favorable than II for aGVHD prevention.

[Amikacin pharmacokinetics in adults: a variability that question the dose calculation based on weight]. / Pharmacocinétique de l'amikacine chez l'adulte : une hétérogénéité qui remet en cause le calcul de la dose basé sur le poids.

The use of amikacin is difficult because of its toxicity and its pharmacokinetic variability. This variability is almost ignored in adult standard dosage regimens since only the weight is used in the dose calculation. Our objective is to test if the pharmacokinetic of amikacin can be regarded as homogenous, and if the method for calculating the dose according to patients' weight is appropriate. From a cohort of 580 patients, five groups of patients were created by statistical data partitioning. A population pharmacokinetic analysis was performed in each group. The adult population is not homogeneous in term of pharmacokinetics. The doses required to achieve a maximum concentration of 60 mg/L are strongly different (585 to 1507 mg) between groups. The exclusive use of the weight to calculate the dose of amikacine appears inappropriate for 80% of the patients, showing the limits of the formulae for calculating doses of aminoglycosides.

[Not Available]. / Pharmacocinétique de l'amikacine chez l'adulte : une hétérogénéité qui remet en cause le calcul de la dose basé sur le poids.

The use of amikacin is difficult because of its toxicity and its pharmacokinetic variability. This variability is almost ignored in adult standard dosage regimens since only the weight is used in the dose calculation. Our objective is to test if the pharmacokinetic of amikacin can be regarded as homogenous, and if the method for calculating the dose according to patients' weight is appropriate. From a cohort of 580 patients, five groups of patients were created by statistical data partitioning. A population pharmacokinetic analysis was performed in each group. The adult population is not homogeneous in term of pharmacokinetics. The doses required to achieve a maximum concentration of 60mg/L are strongly different (585 to 1507mg) between groups. The exclusive use of the weight to calculate the dose of amikacine appears inappropriate for 80% of the patients, showing the limits of the formulae for calculating doses of aminoglycosides.