Highly Variable Paracetamol Pharmacokinetics After Multiple Oral Dosing in Frail Older People: A Population Pharmacokinetic Analysis.

INTRODUCTION: Paracetamol pharmacokinetics (PK) is highly variable in older fit adults after intravenous administration. Frailty and oral administration likely result in additional variability. The aim was to determine oral paracetamol PK and variability in geriatric inpatients. METHODS: A population PK analysis, using NONMEM 7.2, was performed on 245 paracetamol samples in 40 geriatric inpatients (median age 87 [range 80-95] years, bodyweight 66.4 [49.3-110] kg, 92.5% frail [Edmonton Frail Scale]). All subjects received paracetamol 1000 mg as tablet (72.5%) or granulate (27.5%) three times daily. Simulations of dosing regimens (1000 mg every 6 hours [q6h] or q8h) were performed to determine target attainment, using mean steady-state concentration (Css-mean) of 10 mg/L as target. RESULTS: A one-compartment model with first order absorption and lag time best described the data. The inter-individual variability was high, with absorption rate constant containing the highest variability. The inter-individual variability could not be explained by covariates. Simulations of 1000 mg q6h and q8h resulted in a Css-mean of 10.8 [25-75th percentiles 8.2-12.7] and 8.13 [6.3-9.6] mg/L, respectively, for the average geriatric inpatient. The majority of the population remained off-target (22.2% [q6h] and 52.2% [q8h] <8 mg/L; 31.3 [q6h] and 7.6% [q8h] >12 mg/L). CONCLUSION: A population of average geriatric inpatients achieved target Css-mean with paracetamol 1000 mg q6h, while q8h resulted in underexposure for the majority of them. Due to high unexplained variability, a relevant proportion remained either above or below the target concentration of 10 mg/L. Research focusing on PK, efficacy and safety is needed to recommend dosing regimens.

Development of clinical pharmacy in Belgian hospitals through pilot projects funded by the government.

Objectives The goal is to develop clinical pharmacy in the Belgian hospitals to improve drug efficacy and to reduce drug-related problems. Methods From 2007 to 2014, financial support was provided by the Belgian federal government for the development of clinical pharmacy in Belgian hospitals. This project was guided by a national Advisory Working Group. Each funded hospital was obliged to describe yearly its clinical pharmacy activities. Results In 2007, 20 pharmacists were funded in 28 pilot hospitals; this number was doubled in 2009 to 40 pharmacists over 54 institutions, representing more than half of all acute Belgian hospitals. Most projects (72%) considered patient-related activities, whereas some projects (28%) had a hospital-wide approach. The projects targeted patients at admission (30%), during hospital stay (52%) or at discharge (18%). During hospital stay, actions were mainly focused on geriatric patients (20%), surgical patients (15%), and oncology patients (9%). Experiences, methods, and tools were shared during meetings and workshops. Structure, process, and outcome indicators were reported and strengths, weaknesses, opportunities, and threats were described. The yearly reports revealed that the hospital board was engaged in the project in 87% of the cases, and developed a vision on clinical pharmacy in 75% of the hospitals. In 2014, the pilot phase was replaced by structural financing for clinical pharmacy in all acute Belgian hospitals. Conclusion The pilot projects in clinical pharmacy funded by the federal government provided a unique opportunity to launch clinical pharmacy activities on a broad scale in Belgium. The results of the pilot projects showed clear implementation through case reports, time registrations, and indicators. Tools for clinical pharmacy activities were developed to overcome identified barriers. The engagement of hospital boards and the results of clinical pharmacy activities persuaded the government to start structural financing of clinical pharmacy.

Population pharmacokinetic modelling of intravenous paracetamol in fit older people displays extensive unexplained variability.

AIMS: Paracetamol is the analgesic most used by older people. The physiological changes occurring with ageing influence the pharmacokinetics (PK) of paracetamol and its variability. We performed a population PK-analysis to describe the PK of intravenous (IV) paracetamol in fit older people. Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady-state concentration (Css-mean ) of 10 mg l-1 as target for effective analgesia. METHODS: A population PK-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age 77.3 years, range [61.8-88.5], body weight 79 kg [60-107]). All had received an IV paracetamol dose of 1000 mg (over 15 min) after elective knee surgery. RESULTS: A two-compartment PK-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css of 9.2 mg l-1 and 7.2 mg l-1 , for every 6 h and every 8 h respectively. Variability in paracetamol PK resulted in Css above 5.4 and 4.1 mg l-1 , respectively, in 90% of the population and above 15.5 and 11.7, respectively, in 10% at these dosing regimens. CONCLUSIONS: The target concentration was achieved in the average patient with 1000 mg every 6 h, while every 8 h resulted in underdosing for the majority of the population. Furthermore, due to a large (unexplained) interindividual variability in paracetamol PK a relevant proportion of the fit older people remained either under- or over exposed.

Incidence of medication-related osteonecrosis of the jaw in patients treated with both bone resorption inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: Several case reports and small case series have suggested a higher incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients treated concomitantly with bone resorption inhibitors (BRIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), as compared to patients treated with BRIs alone. We aimed to assess ONJ-incidence in patients exposed concomitantly to BRIs and VEGFR-TKIs. PATIENTS AND METHODS: We reviewed the records of all patients who received VEGFR-TKIs concomitantly with BRIs. Patients, who were treated with BRIs without VEGFR-TKI, served as a control group. Endpoints of the study were total MRONJ-incidence, MRONJ-incidence during the first and second year of exposure, and time-to-ONJ-incidence. RESULTS: Ninety patients were treated concomitantly with BRIs and VEGFR-TKIs with a median BRI-exposure of 5.0 months. Total MRONJ-incidence was 11.1%. During the first year of BRI-exposure (with a median concomitant exposure of 4.0 months), 6 out of 90 patients (6.7%) developed a MRONJ, compared to 1.1% in the control group (odds ratio 5.9; 95%CI 2.0-18.0; p = 0.0035). In Kaplan-Meier estimates, time-to-ONJ-incidence was significantly shorter in patients treated with BRIs and VEGFR-TKIs compared to BRIs alone (hazard ratio 9.5; 95%CI 3.1-29.6; p < 0.0001). MRONJs occurred earlier in patients treated concomitantly compared to patients treated with BRIs only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033). CONCLUSION: With a global MRONJ-incidence of 11%, patients receiving concomitant treatment with VEGFR-TKIs and BRIs have a five to ten times higher risk for development of MRONJ compared to patients treated with BRIs alone.

Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients.

Administration of azole antifungals to tacrolimus-treated solid organ recipients results in a major drug-drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co-treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose-corrected trough concentrations (C/D) between baseline and tacrolimus-azole co-therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0-20.2) for voriconazole and 4.4 ± 2.6 (range 0.9-18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: -43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (-14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus-azole interaction, but these did not permit accurate predictions in individual patients.

Stimulation of the i.v. to oral switch of bioavailable drugs by phone calls in a Belgian tertiary care hospital.

INTRODUCTION: Early switch from intravenous to oral administration of drugs with an almost complete oral bioavailability, can have important benefits. Drugs with almost complete bioavailability, like clindamycin (Dalacin), levofloxacin (Tavanic) and paracetamol (Perfusalgan/Dafalgan), are very suitable for an early intravenous to oral switch in patients whose gastrointestinal absorption is intact. The aim of this study was to investigate the impact of direct phone contact between pharmacist and clinician on the intravenous to oral switch and to evaluate the reasons, mentioned by clinicians, that prevented an early switch. MATERIALS & METHODS: The project was initiated in a Belgian 1900-bed tertiary care hospital with a poster, communicated through the hospital's intranet and spread to every hospital ward. During one month, all prescriptions for intravenous clindamycin, levofloxacin and paracetamol were evaluated. The treating clinician was contacted by phone to evaluate if an intravenous to oral switch was possible. RESULTS: Clinicians were contacted concerning 377 patients. For 58.7% of patients, the switch from intravenous to oral administration was made. In case of refusal, several reasons were mentioned by the clinician, some more appropriate than others. CONCLUSION: Despite several appropriate reasons preventing an early intravenous to oral switch, there are still some aberrant opinions circulating in the hospital environment. Active interventions of pharmacists to stimulate intravenous to oral switch, using phone contact with the treating clinicians, can possibly be an adequate technique to stimulate intravenous to oral switch, but this needs to be further optimized.

Ergotamine-induced pleural and pericardial effusion successfully treated with colchicine.

A 83-year-old woman was admitted to hospital with chest pain, fever, dry cough and palpitations. Chest X-ray revealed a pleural effusion, assumed to be caused by cardiac failure and respiratory infection. Despite treatment with antibiotics and diuretics, the pleural effusion increased on chest X-ray and there were signs of pleural and pericardial effusion on computed tomography (CT) scan. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) was not successful. Meanwhile patients' long-term use of ergotamine for migraine was revealed, which is associated with pleuropulmonary and cardiac fibrotic reactions. Tentative treatment with colchicine was successful, with complete resolution of pleural fluid, fever, cough and inflammatory parameters. This case highlights the importance of establishing an ergot alkaloid use registry in unexplained pleuropericardial effusions and supports the use of colchicine as a potential therapeutic approach.

Drug-related admissions due to interaction with an old drug, lithium.

Lithium is one of the oldest psychotropic drugs with a well-known narrow therapeutic range and the drugs that interact with lithium elimination are well established. However, patients are still admitted to the emergency department with lithium toxicity due to often overlooked interactions with concomitant drugs. We report on two patients, admitted to the emergency department, with lithium toxicity. One patient presented with aphasia and ataxia, showing moderate toxicity. The other was referred due to coma, illustrating severe lithium toxicity. In both cases, a non-steroidal anti-inflammatory drug was the underlying cause. We highlight the mechanism of this drug-drug interaction and underline the need for thoughtful use of other medications in patients taking lithium. Special attention has to be paid for the non-steroidal antiinflammatory drugs due to the low threshold of prescribing them for the control of acute pain and its availability as free over-the-counter drugs.

Selecting an appropriate and reimbursed anti-osteoporotic treatment option: a practical tool in the Belgian setting.

Osteoporosis is a highly prevalent and often undertreated disease in the elderly. Osteoporosis-related fractures are associated with significant morbidity and mortality. Anti-osteoporotic drugs are only reimbursed by the Belgian government if strict conditions are fulfilled. The aim of this paper was to create a practical tool to guide the physician and other health care professionals to make an appropriate choice. Two flowcharts, based on Belgian reimbursement criteria and literature review were developed. Both tools provide an overview of the reimbursed pharmacological agents in the management of osteoporosis in male and female subjects.

Long-term treatment of refractory invasive fungal infection with posaconazole: additive value of therapeutic drug monitoring.

Posaconazole is a recently developed broad-spectrum triazole antifungal with potential for long-term prophylaxis or therapy of invasive fungal infections. This case illustrates the additive value for therapeutic drug monitoring to guide clinical decision-making in high risk patients.

Significance of the isolation of Candida species from airway samples in critically ill patients: a prospective, autopsy study.

PURPOSE: Recovery of Candida from the respiratory tract is common. Large series on the incidence of histologically proven Candida pneumonia in intensive care unit (ICU) patients are lacking. METHODS: A two-year prospective study of all autopsies performed on patients who died in the ICU was conducted. For autopsy-proven cases of Candida pneumonia, we required microscopic demonstration of yeast invasion in lung autopsy specimens that showed inflammation. We looked for differences in incidence in patients with and without respiratory samples positive for Candida species pre-mortem. RESULTS: Of 1,587 patients admitted to the ICU, 301 (19%) died of whom 232 (77%) were autopsied. Of those, 135 patients (58%) had histopathological evidence of pneumonia. A total of 77 cases (57%) with pneumonia at autopsy had positive tracheal aspirate and/or BAL cultures for Candida spp. performed during the preceding two weeks. No cases of Candida pneumonia were identified amongst those 77 cases. In the other 58 patients with autopsy-proven pneumonia and no Candida isolation pre-mortem, no Candida pneumonia was observed either. CONCLUSIONS: Despite frequent isolation of Candida spp. from the airways, over a two-year period no single case of Candida pneumonia was found among the patients with evidence of pneumonia on autopsy. This study indicates that Candida pneumonia is an extremely rare occurrence in ICU patients and provides further evidence against the common use of antifungal therapy triggered by a microbiology report of Candida isolation from the respiratory tract.