Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.

A meropenem pharmacokinetics model in patients with haematological malignancies.

BACKGROUND: Optimal dosing of antibiotics is critical in immunocompromised patients suspected to have an infection. Data on pharmacokinetics (PK) of meropenem in patients with haematological malignancies are scarce. OBJECTIVES: To optimize dosing regimens, we aimed to develop a PK population model for meropenem in this population. METHODS: Patients aged ≥18 years, hospitalized in the haematology department of our 1500 bed university hospital for a malignant haematological disease and who had received at least one dose of meropenem were eligible. Meropenem was quantified by HPLC. PK were described using a non-linear mixed-effect model and external validation performed on a distinct database. Monte Carlo simulations estimated the PTA, depending on renal function, duration of infusion and MIC. Target for free trough concentration was set at >4× MIC. RESULTS: Overall, 88 patients (181 samples) were included, 66 patients (75%) were in aplasia and median Modification of Diet in Renal Disease (MDRD) CLCR was 117 mL/min/1.73 m2 (range: 35-359). Initial meropenem dosing regimen ranged from 1 g q8h to 2 g q8h over 30 to 60 min. A one-compartment model with first-order elimination adequately described the data. Only MDRD CLCR was found to be significantly associated with CL. Only continuous infusion achieved a PTA of 100% whatever the MIC and MDRD CLCR. Short duration of infusion (<60 min) failed to reach an acceptable PTA, except for bacteria with MIC < 0.25 mg/L in patients with MDRD CLCR below 90 mL/min/1.73 m2. CONCLUSIONS: In patients with malignant haematological diseases, meropenem should be administered at high dose (6 g/day) and on continuous infusion to reach acceptable trough concentrations.

Guidelines of the French Society of Otorhinolaryngology (SFORL): Nonsteroidal anti-inflammatory drugs (NSAIDs) and pediatric ENT infections. Short version.

OBJECTIVES: To present the guidelines of the French Society of Otolaryngology-Head and Neck Surgery concerning the use of non-steroidal anti-inflammatory drugs (NSAIDs) in pediatric ENT infections. METHODS: Based on a critical analysis of the medical literature up to November 2016, a multidisciplinary workgroup of 11 practitioners wrote clinical practice guidelines. Levels of evidence were classified according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system: GRADE A, B, C or "expert opinion". The first version of the text was reworked by the workgroup following comments by the 22 members of the reading group. RESULTS: The main recommendations are: NSAIDs are indicated at analgesic doses (e.g. 20-30 mg/kg/day for ibuprofen) in combination with paracetamol (acetaminophen) in uncomplicated pediatric ENT infections (acute otitis media, tonsillitis, upper respiratory infections, and maxillary sinusitis) if: o pain is of medium intensity (visual analogue scale (VAS) score 3-5 or "Evaluation Enfant Douleur" (EVENDOL) child pain score 4-7) and insufficiently relieved by first-line paracetamol (residual VAS≥3 or EVENDOL≥4); o pain is moderate to intense (VAS 5-7 or EVENDOL 7-10). When combined, paracetamol and ibuprofen are ideally taken simultaneously every 6h. It is recommended: (1) o not to prescribe NSAIDs in severe or complicated pediatric ENT infections; (2) o to suspend NSAIDs treatment in case of unusual clinical presentation of the infection (duration or symptoms); (3) o not to prescribe NSAIDs for more than 72h.

Addition of droperidol to prophylactic ondansetron and dexamethasone in children at high risk for postoperative vomiting. A randomized, controlled, double-blind study.

BACKGROUND: : The combination of dexamethasone (DEX), ondansetron (OND) and droperidol (DRO) is efficacious in preventing postoperative nausea and vomiting in adults, but has not been well assessed in children. METHODS: : Children undergoing elective surgery under general anaesthesia and considered at high risk for postoperative vomiting (POV) were randomly assigned to receive a combination of DEX, OND and placebo (Group A) or a combination of DEX, OND and DRO (Group B). The primary outcome was the incidence of POV during the first 24 hours after surgery. We hypothesized that the addition of DRO to the standard antiemetic prophylaxis would provide a further 15% reduction in the residual risk for POV. The secondary outcome considered was any adverse event occurring during the study. RESULTS: : One hundred and fifty-three children, aged three to 16 years, were randomized to Group A and 162 to Group B. The overall incidence of POV did not differ significantly between the two groups, with 16 patients in Group A (10.5%) and 18 in Group B (11.1%) presenting with one or more episodes of POV, P =0.86. Fewer patients presented with adverse events in Group A (2%) compared with Group B (8%), P =0.01. Drowsiness and headache were the principal adverse events reported. CONCLUSIONS: : The addition of DRO to a combination of OND and DEX did not decrease POV frequency below that obtained with the two-drug combination in children at high risk of POV, but increased the risk of drowsiness. The combination of DEX and OND should be recommended in children with a high risk of POV. CLINICAL TRIAL REGISTRATION.: NCT01739985.

How to replace codeine after tonsillectomy in children under 12 years of age? Guidelines of the French Oto-Rhino-Laryngology--Head and Neck Surgery Society (SFORL).

The authors present the guidelines of the French Oto-rhino-laryngology--Head and Neck Surgery Society (SFORL) regarding pain management in children and adults following tonsillectomy. A multidisciplinary work group was entrusted with a literature review. Guidelines were drawn up based on the articles retrieved and the group members' experience. They were read over by an editorial group independent of the work group. A coordination meeting drew up the final version. Guidelines were graded A, B or C or as professional agreement in decreasing order of level of evidence. At home, non-steroid anti-inflammatory drugs (NSAIDs) are recommended in association with paracetamol in elevated respiratory risk and especially obstructive sleep apnea syndrome; in elevated hemorrhagic risk (hemostasis disorder, surgical problems, etc.), tramadol is recommended. Two other treatment schedules (modified NSAIDs and corticosteroids) have not undergone dedicated study and should be assessed. Management of post-tonsillectomy pain in children is founded on individual risk/benefit analysis.

Guidelines (short version) of the French Oto-Rhino-Laryngology--Head and Neck Surgery Society (SFORL) for the management of post-tonsillectomy pain in adults.

OBJECTIVES: The present clinical practice guidelines cover the entire field of management of post-tonsillectomy pain. Given the French and European regulatory restrictions on the use of codeine, an update appears necessary to clarify the management of post-tonsillectomy pain in adults. METHOD: A work group approached the issue of pain management, following the chronological pathway from initial consultation to postoperative period. As exhaustive a study of the literature as possible assessed the pain impact of the various surgical techniques and the efficacy of the various analgesia schedules. RESULTS: Guidelines on the management of post-tonsillectomy pain in adults were drawn up and graded, based on the levels of evidence of selected articles and on work group consensus. The guidelines stress the importance of patient information and seek to harmonize practice, reduce the risk of postoperative complications and above all improve control of post-tonsillectomy pain in adults.

Pregnancy-associated breast cancer is as chemosensitive as non-pregnancy-associated breast cancer in the neoadjuvant setting.

BACKGROUND: The aim of this study was to determine the chemosensitivity of pregnancy-associated breast cancer (PABC) in the neoadjuvant setting by comparing the observed pathological complete response (pCR) rate with the rate predicted by a validated nomogram. METHODS: Data from 48 PABC patients who received neoadjuvant chemotherapy (NACT) were collected. To predict the response rate to chemotherapy, we used well-calibrated logistic regression-based nomograms to calculate individual probability of pCR. RESULTS: Observed rates of pCR were concordant with predictions in the whole sample and in the analyzed subgroups. For the whole sample, the area under the receiver-operated curve (AUC) was 0.77 (95% CI 0.66-0.87). The calibration of predicted and observed probabilities was excellent. In the subgroup analyses (NACT initiated during pregnancy or postpartum, NACT with only anthracycline or both anthracycline and taxanes), discriminations assessed by AUC were significantly above 0.5, except for patients treated with anthracycline only. The interpretation was limited by a lack of power. CONCLUSION: Through the use of nomograms, our study demonstrates that PABC is as chemosensitive as non-PABC and suggests that taxanes should be part of the NACT regimen for PABC. Further studies are warranted to increase the power of the presented data.

Parental comprehension and satisfaction in informed consent in paediatric clinical trials: a prospective study on childhood leukaemia.

OBJECTIVE: To evaluate the extent to which parents are satisfied with and understand the information they are given when their consent is sought for their child to participate in a phase III randomised clinical trial and the reasons for their decision. PATIENTS AND METHOD: The authors carried out a prospective study. The authors included all parents whose consent was sought for their child to participate in the FRALLE 2000A protocol (acute lymphoblastic leukaemia) at two centres. The parents were questioned twice by a qualified psychologist using a semidirected interview, 1 and 6 months after consent was sought. RESULTS: 43 first interviews were carried out. All the parents declared they were satisfied with the explanations provided by the physician. 35 (81%) parents felt that the information provided with the request for consent was appropriate. Eight (19%) parents did not realise that their child had been included in a research protocol. 16 (39%) parents did not understand the concept of randomisation. Half the parents could explain neither the aim of the clinical trial nor the potential benefit of inclusion to their child. Only one third of the parents were aware that they had an alternative. The principal factor underlying their decision, as stated by 29 parents (67%), was confidence in the medical team. CONCLUSIONS: The parents signed consent forms without having fully understood all the elements specific to the experimental protocol. Rather, the parents based their decision on their confidence in the medical team, even when their child's life was at risk.

Relationship between GSTP1 Ile(105)Val polymorphism and docetaxel-induced peripheral neuropathy: clinical evidence of a role of oxidative stress in taxane toxicity.

BACKGROUND: Glutathione-S-transferases (GST) regulate the cellular response to oxidative stress. We previously highlighted the importance of oxidative stress in taxane toxicity and therefore investigated the relationship between the GST isoforms M1, T1 and P1 gene polymorphisms and docetaxel (Taxotere)-induced peripheral neuropathy (DIPN). PATIENTS AND METHODS: The GSTM1 (null), GSTT1 (null) and GSTP1 (Ile(105)Val and Ala(114)Val) polymorphisms were determined in a cohort of cancer patients treated with docetaxel and entered in a clinical trial database. The relationship between GST polymorphisms and grade > or = 2 DIPN as primary end point was studied. RESULTS: Fifty-eight patients (median age 61 years) received a total of 261 cycles of docetaxel given as single agent. Patients with GSTP1 (105)Ile/(105)Ile genotype had a higher risk of developing a grade > or = 2 DIPN than did those with other GSTP1 genotypes (8 of 27 versus 2 of 31, respectively, odds ratio 6.11; 95% confidence interval 1.17-31.94; P = 0.03). In multivariate analysis, grade > or = 2 DIPN was strongly correlated with GSTP1 (105)Ile/(105)Ile genotype (P = 0.01) and the number of cycles (P = 0.03). CONCLUSION: We found a significant correlation between GSTP1 (105)Ile/(105)Ile genotype and the development of grade > or = 2 DIPN. This finding strongly suggests a role of oxidative stress in the pathophysiology of DIPN.

Emerging therapeutic options for breast cancer chemotherapy during pregnancy.

BACKGROUND: Breast cancer is the commonest solid tumor observed during pregnancy. Anthracycline-based chemotherapy is feasible during the 2nd and 3rd trimesters of pregnancy, but few data are available on recent and highly active drugs taxanes, vinorelbine and anti-HER-2 agents in this setting. PATIENTS AND METHODS: We carried out a comprehensive review of reports documenting the use of taxanes, vinorelbine, trastuzumab and lapatinib during pregnancy in the English literature, in order to evaluate their safety profile in pregnant patients. RESULTS: Twenty-four pregnancies are described, in which no grade 3-4 maternal toxicity nor malformation in the offspring was reported. Whereas only one report studied the pharmacokinetics of paclitaxel (Taxol) during pregnancy, several preclinical reports indicate that the placental P-glycoprotein could prevent the transplacental transfer of taxanes and vinorelbine. The use of trastuzumab was associated with the occurrence of anhydramnios in three of six cases. CONCLUSION: The administration of recent drugs taxanes and vinorelbine seems feasible during the 2nd and 3rd trimesters of pregnancy, with a favorable toxicity profile. In contrast, anti-HER-2 agents may obscure the normal development of the fetal kidney, and should be avoided during pregnancy.

Clinical pharmacodynamic factors in docetaxel toxicity.

Neutropenia is the main dose-limiting toxicity occurring in docetaxel treatment. The objective of this study was to identify pharmacodynamic (PD) factors responsible for the neutropaenia caused by docetaxel. Data were obtained from 92 patients treated with docetaxel as a monochemotherapy in two different treatment centres. A semiphysiological population pharmacokinetic-pharmacodynamic (PK/PD) model was applied to describe the time course of neutrophils and the neutropaenic effect of docetaxel. The plasma docetaxel concentration was assumed to inhibit the proliferation of neutrophil precursors through a linear model: Drug effect=Slope x Conc. Slope corresponds to the patients' sensitivity to the neutropaenic effect of docetaxel. Covariate analysis was performed by testing the relationship between the patients' characteristics and Slope using the program NONMEM. The neutropaenic effect of docetaxel showed a high interindividual variability. Three significant PD covariates were identified: serum alpha1-acid glycoprotein levels (AAG), level of chemotherapy pretreatment, and treatment centre. Extensive pretreatment was associated with an increase in Slope values meaning a higher haematotoxicity. An increase in AAG was associated with a decrease of both Slope and docetaxel plasma clearance. Patients treated in one centre had both higher Slope and docetaxel clearance. The centre effect (most likely due to a bias in the PK part of the study between the two centres) reveals the robustness of the PK/PD model. Individual dosing of docetaxel should be based on previous chemotherapy but not on the AAG level since it has a similar influence on PD and PK docetaxel parameters. This methodology should be applied to further investigate elderly patients and to identify more precisely the characteristics of previous chemotherapy that contribute to the cumulative myelotoxicity.

Relationship between cytochrome 3A activity, inflammatory status and the risk of docetaxel-induced febrile neutropenia: a prospective study.

BACKGROUND: We hypothesized that cancer-related inflammation might increase the risk of febrile neutropenia (FN) induced by docetaxel (DCX, Taxotere), by both affecting the exposure to DCX and the tissue sensitivity. PATIENTS AND METHODS: Advanced cancer patients with normal liver function, performance status (PS)<3, were included. Cytochrome P450 3A (CYP 3A) activity was estimated before the first cycle of DCX by a single determination of midazolam plasma concentration, 4 hours after 0.015 mg/kg i.v. bolus. Following the first cycle of 75-100 mg/m2 DCX, clearance and area under the concentration versus time curve (AUC) were estimated using a limited sampling strategy. RESULTS: Among 56 assessable patients, 7 FNs occurred after first cycle (13%). In univariate analysis, high midazolam concentration and free DCX AUC were associated with severe neutropenia and FN. In addition to DCX exposure-related parameters, the risk of FN was also correlated with poor PS, baseline lymphopenia and lung cancer, while high ferritin level, indicator of an inflammatory state, reached borderline significance (P=0.07). By multivariate analysis, total DCX AUC and baseline lymphopenia were associated with FN. High midazolam concentration was correlated with elevated ferritin level (r=0.32; P=0.02). CONCLUSION: Inflammatory status and lymphocyte count should be included in the evaluation of the benefice/risk ratio before the initiation of DCX.

Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms.

OBJECTIVE: Patients initiating docetaxel chemotherapy were genotyped for CYP3A4, CYP3A5, MDR1, GSTM1, GSTT1, GSTM3, and GSTP1 to identify variability factors of docetaxel pharmacokinetics and toxicity. METHODS: Genotyping was performed by direct sequencing (CYP3A4), real-time polymerase chain reaction (CYP3A5), and polymerase chain reaction-restriction fragment length polymorphism (MDR1 and GST). The clearance and area under the curve of docetaxel were calculated by use of a Bayesian approach. Absolute neutrophil count was recorded twice weekly. RESULTS: With regard to the pharmacokinetic analysis, 58 patients were included. CYP3A4*1B carriers (*1A/*1B, n=4), who are also CYP3A5*1/*3 carriers, had a significantly higher clearance and lower dose-normalized area under the curve of docetaxel than those with the wild genotype (*1A/*1A, n=53): 55.2+/-13.5 L/h versus 37.3+/-11.7 L/h (P=.01) and 31.4+/-6.2 (microg . h/L)/(mg/m(2)) versus 52.7+/-18.2 (microg . h/L)/(mg/m(2)) (P=.005), respectively. No influence of MDR1 was evidenced. With regard to the pharmacodynamic analysis, febrile neutropenia occurred more frequently in GSTP1*A/*B carriers (31.6% versus 3.7% in *A/*A carriers and 0% in *A/*C, *B/*B, and *B/*C carriers) (P=.037). Grade 3 neutropenia occurred more frequently in 3435TT MDR1 genotype carriers: TT, 100%; CT, 77.3%; and CC, 54.5% (P=.046). No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity. CONCLUSIONS: Patients carrying the CYP3A*1B allele may have enhanced docetaxel clearance and may be underexposed, whereas those carrying GSTP1*A/*B and 3435TT genotypes may have excessive hematologic toxicity. Further studies are warranted to determine the usefulness of genotyping before docetaxel treatment.

Parental consent in paediatric clinical research.

AIMS: To assess parental understanding and memorisation of the information given when seeking for consent to their child's participation to clinical research, and to identify the factors of significant influence on parents' decision making process. METHODS: Sixty eight parents who had been approached for enrolling their child in a clinical oncology or HIV study were asked to complete an interview. Their understanding was measured by a score which included items required to obtain a valid consent according to French legislation. RESULTS: Items that were best understood by parents were the aims of the study (75%), the risks (70%), the potential benefits to their child (83%), the potential benefits to other children (70%), the right to withdraw (73%), and voluntariness (84%). Items that were least understood were the procedures (44%), the possibility of alternative treatments (53%), and the duration of participation (39%). Less than 10% of the parents had understood all these points. Ten parents (15%) did not remember that they had signed up for a research protocol. Thirty three parents (48%) reported no difficulty in making their decision. Twenty four parents (38%) declared that they made their decision together with the investigator; 26 (41%) let the physician decide. Fifty four parents (78%) felt that the level of information given was satisfactory. CONCLUSION: There was an apparent discrepancy between parents' evaluation of the adequacy of the information delivered and evaluation of their understanding and memorisation. The majority of parents preferred that the physician take as much responsibility as possible in the decision making process.

Protective effect of stiripentol on acetaminophen-induced hepatotoxicity in rat.

Acetaminophen (APAP) is mainly eliminated at a therapeutic dose through glucuronidation and sulfatation and a small fraction is oxidized by cytochromes P450 (CYP) 2E1, 3A4, and 1A2 to N-acetyl-p-benzoquinone-imine (NAPQI), a highly reactive metabolite further conjugated with glutathione into APAP-GSH, and then metabolized to APAP-cystein and APAP-mercapturate excreted in urine. After APAP overdose, the glucuronidation and sulfatation pathways are saturated and the production of NAPQI increases, causing hepatic injury. Stiripentol (STP); (200 mg/kg), an anticonvulsant drug inhibitor of CYP1A2 and CYP3A4 in vivo in humans was tested against APAP-induced toxicity in rat in comparison with N-acetylcysteine (NAC; 100 mg/kg). The mortality rates 24 h after APAP overdose (2 x 500 mg/kg) were 63% (control), 38% (NAC), 0% (STP), and 4% (STP + NAC). The mean plasma transaminase concentrations 5 and 24 h after overdose were significantly higher in control than in STP and NAC groups. The percentage of rats without microscopic liver necrosis 5 h after APAP overdose was significantly higher in rats receiving STP (100%), NAC (83%), or STP + NAC (83%) than controls (42%). In another experiment, four similar groups were administered 50 mg/kg APAP. Plasma AUC(0-5 h) for APAP-GSH, APAP-cystein, and APAP-mercapturate as well as urine APAP-mercapturate mean amounts were significantly lower in STP animals than in the other groups. STP (200 mg/kg) inhibited NAPQI synthesis through CYP inhibition, thus preventing both liver necrosis and mortality in rats.

Ontogenesis of CYP2C-dependent arachidonic acid metabolism in the human liver: relationship with sudden infant death syndrome.

A modification of the human monooxygenase system have been previously associated with the sudden infant death syndrome (SIDS): the hepatic CYP2C content was markedly enhanced and resulted from an activation of CYP2C gene transcription. To determine the possible consequence of the up-regulation of CYP2C in SIDS, we examined the metabolism of arachidonic acid (AA) an endogenous substrate of CYP2C involved in the physiologic regulation of vascular tone. The overall AA metabolism was extremely low during the fetal period and rose after birth to generate 14,15 epoxyeicosatrienoic acid (EET), 11,12 EET and the sum of 5,6 dihydroxyeicosatrienoic acid (diHETE)+omega/omega-1 hydroxy AA. In SIDS, the accumulation of CYP2C proteins was associated with a significant increase in the formation of 14,15 and 11,12 diHETE, which were shown to be supported by individually expressed CYP2C8 and 2C9 and HETE1 (presumably 15 HETE). This increase was markedly inhibited by addition of sulfaphenazole, a selective inhibitor of CYP2C9. So, we propose that the higher CYP2C content in SIDS stimulates the production of EETs and diHETEs and might have severe pathologic consequences in children.

Drug disposition in cystic fibrosis.

There are many pathological changes in patients with cystic fibrosis (CF) which can lead to alterations in drug disposition. Although, in patients with CF, the extent of drug absorption varies widely and the rate of absorption is slower, bioavailability is not altered. Plasma protein binding for the majority of drugs studied did not differ in patients with CF compared with control groups. The difference in volume of distribution of most drugs between patients with CF and healthy individuals vanished when corrected for lean body mass. Despite hepatic dysfunction, patients with CF have enhanced clearance of many, but not all, drugs. Phase I mixed-function oxidases are selectively affected: cytochrome P450 (CYP) 1A2 and CYP2C8 have enhanced activity, while other CYP isoforms such as CYP2C9 and CYP3A4 are unaffected. Increased phase II activities are also demonstrated: glucuronyl transferase, acetyl transferase (NAT1) and sulfotransferase. The increased hepatic clearance of drugs in the presence of CF may be the consequence of disease-specific changes in both enzyme activity and/or drug transport within the liver. The renal clearance (CLR) of many drugs in patients with CF is enhanced although there has been no pathological abnormality identified which could explain this finding: glomerular filtration rate and tubular secretion appear normal in patients with CF. The precise mechanisms for enhanced drug clearance in patients with CF remain to be elucidated. The optimisation of antibiotic therapy in patients with CF includes increasing the dose of beta-lactams by 20 to 30% and monitoring plasma concentrations of aminoglycosides. The appropriate dosage of quinolones has not been definitively established.