European Journal of Clinical Pharmacology

Blanco, José-Ramón; Morillo, Ramón; Abril, Vicente; Escobar, Ismael; Bernal, Enrique; Folguera, Carlos; Brañas, Fátima; Gimeno, Mercedes; Ibarra, Olatz; Iribarren, José-Antonio; Lázaro, Alicia; Mariño, Ana; Martín, María-Teresa; Martinez, Esteban; Ortega, Luis; Olalla, Julian; Robustillo, Aguas; Sanchez-Conde, Matilde; Rodriguez, Miguel-Angel; de la Torre, Javier; Sanchez-Rubio, Javier; Tuset, Montse; ,

doi: 10.1007/s00228-019-02785-zpmid: 31865412

PurposeIn recent decades, the life expectancy of HIV-infected patients has increased considerably, to the extent that the disease can now be considered chronic. In this context of progressive aging, HIV-infected persons have a greater prevalence of comorbid conditions. Consequently, they usually take more non-antiretroviral drugs, and their drug therapy are more complex. This supposes a greater risk of drug interactions, of hospitalization, falls, and death. In the last years, deprescribing has gained attention as a means to rationalize medication use.MethodsReview of the different therapeutic approach that includes optimization of polypharmacy and control and reduction of potentially inappropriate prescription.ResultsThere are several protocols for systematizing the deprescribing process. The most widely used tool is the Medication Regimen Complexity Index, an index validated in HIV-infected persons. Anticholinergic medications are the agents that have been most associated with major adverse effects so, various scales have been employed to measure it. Other tools should be employed to detect and prevent the use of potentially inappropriate drugs. Prioritization of candidates should be based, among others, on drugs that should always be avoided and drugs with no justified indication.ConclusionsThe deprescribing process shared by professionals and patients definitively would improve management of treatment in this population. Because polypharmacy in HIV-infected patients show that a considerable percentage of patients could be candidates for deprescribing, we must understand the importance of deprescribing and that HIV-infected persons should be a priority group. This process would be highly feasible and effective in HIV-infected persons.

Ali, Sheraz; Peterson, Gregory M.; Bereznicki, Luke R.; Salahudeen, Mohammed S.

doi: 10.1007/s00228-019-02795-xpmid: 31832732

PurposeThe purpose of the study is to conduct a systematic review of studies examining the association between anticholinergic burden and mortality in older individuals.MethodsA literature search was performed to identify relevant studies, using MEDLINE, EMBASE, PsycINFO and CENTRAL, from January 1990 to December 2018. We included studies of patients with a mean age of 65 years or older where the anticholinergic burden was estimated using anticholinergic risk assessment tools, and associations between anticholinergic load and mortality were investigated. The primary outcome of interest was the association between anticholinergic burden and mortality.ResultsTwenty-seven studies were included. These were three cross-sectional, one nested case-control and 23 prospective or retrospective cohort studies. Most studies were determined to be of good quality. A total of 15 studies reported a positive correlation between anticholinergic burden and mortality, while the remaining 10 studies did not report a significant association. Eighteen out of 27 studies (80%) had a short follow-up period of 1 year or less. Among the five high-quality studies that met all the domains of the quality assessment criteria, four showed a positive association.ConclusionThe variation in results could relate to the quality of the studies, follow-up period, anticholinergic risk assessment tool used and the study setting. Sixty-three percent (n = 17) of all the included studies, but almost all of the high-quality studies with an extended follow-up, reported a positive correlation between anticholinergic burden and mortality. Further high-quality research, using standardized measures and with adequate follow-up periods, is required to confirm the relationship between anticholinergic burden and mortality.

Puumalainen, Emmi; Airaksinen, Marja; Jalava, Sanni E.; Chen, Timothy F.; Dimitrow, Maarit

doi: 10.1007/s00228-019-02796-wpmid: 31822957

PurposeThis study aims to systematically review studies describing screening tools that assess the risk for drug-related problems (DRPs) in older adults (≥ 60 years). The focus of the review is to compare DRP risks listed in different tools and describe their development methods and validation.MethodsThe systematic search was conducted using evidence-based medicine, Medline Ovid, Scopus, and Web of Science databases from January 1, 1985, to April 7, 2016. Publications describing general DRP risk assessment tools for older adults written in English were included. Disease, therapy, and drug-specific tools were excluded. Outcome measures included an assessment tool’s content, development methods, and validation assessment.ResultsThe search produced 15 publications describing 11 DRP risk assessment tools. Three major categories of risks for DRPs included (1) patient or caregiver related risks; (2) pharmacotherapy-related risks; and (3) medication use process-related risks. Of all the risks included in the tools only 8 criteria appeared in at least 4 of the tools, problems remembering to take the medication being the most common (n=7). Validation assessments varied and content validation was the most commonly conducted (n = 9). Reliability assessment was conducted for 6 tools, most commonly by calculating internal consistency (n = 3) and inter-rater reliability (n = 2).ConclusionsThe considerable variety between the contents of the tools indicates that there is no consensus on the risk factors for DRPs that should be screened in older adults taking multiple medicines. Further research is needed to improve the accuracy and timeliness of the DRP risk assessment tools.

Das, Shampa; Zhou, Diansong; Nichols, Wright W.; Townsend, Andy; Newell, Paul; Li, Jianguo

doi: 10.1007/s00228-019-02804-zpmid: 31836928

PurposeCeftazidime–avibactam is a novel β-lactam/β-lactamase inhibitor combination recently approved in Europe and the USA for the treatment of adults with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), among other indications. In the phase III REPROVE trial (NCT01808092), ceftazidime–avibactam demonstrated non-inferiority to meropenem for the treatment of patients with nosocomial pneumonia (NP), including VAP. As ceftazidime–avibactam was not studied in patients with NP prior to REPROVE, selecting an appropriate dosage regimen in the “perfect storm” of NP required careful consideration of potential determinants and confounders of response specific to the NP patient population.MethodsThis review describes the series of preclinical studies and pharmacokinetic/pharmacodynamic (PK/PD) analyses that supported ceftazidime–avibactam dosage selection for patients with NP/VAP (2000/500 mg by 2-h intravenous infusion every 8 h, adjusted for renal function). In parallel, important considerations for antibiotic dosage selection in patients with NP are highlighted, including adequate drug penetration into the lungs, the suitability of murine-derived plasma PK/PD targets, evaluation of MIC distributions against clinical bacterial isolates from patients with NP, and consideration of PK in patients with NP, who are often critically ill. These analyses also supported the European approval of ceftazidime–avibactam for adults with HAP, including VAP, before the completion of REPROVE.ConclusionsThis work serves as a successful practical example of dosage design for a new antibacterial drug therapy in the indication of NP, including VAP, where previous drug therapies have failed, possibly as a result of evaluation of too few variables, thereby limiting the accuracy of pharmacodynamic predictions.

Sys, Judith; Van Cleynenbreugel, Simon; Deschodt, Mieke; Van der Linden, Lorenz; Tournoy, Jos

doi: 10.1007/s00228-019-02812-zpmid: 31838549

PurposeInsomnia is highly prevalent in older persons and significantly impacts quality of life, functional abilities, and health status. It is frequently treated with benzodiazepines or Z-drugs. Due to adverse events, an increased use of alternative sedative medications has been observed in older adults. We aimed to study the efficacy and safety of alternative sedative medications for treating insomnia in older people, excluding benzodiazepines and Z-drugs.MethodsWe conducted a systematic search of MEDLINE (PubMed), EMBASE, and the Cochrane Central register of Controlled Trials databases. We included randomized controlled trials and prospective and retrospective quasi-experimental studies, conducted in patients older than 65 years, without psychiatric or neurological comorbidities.ResultsThe systematic search yielded 9483 articles, of which 24 were included in this review, describing nine different sleep medications in total. No clear beneficial impact on sleep could be demonstrated in studies investigating the impact of melatonin (n = 10), paroxetine (n = 1), diphenhydramine (n = 1), tiagabine (n = 2), and valerian (n = 1). Ramelteon slightly improved sleep latency (n = 4), while doxepin was found to provide a sustained sleep improvement with a safety profile that was comparable to placebo (n = 3). Suvorexant showed an improved sleep maintenance with only mild side effects (n = 1). One study detected increased adverse effects of trazodone after 3 months but did not evaluate the effect on sleep.ConclusionsThe overall level of evidence was limited, making it difficult to draw robust conclusions. Preliminary evidence points towards suvorexant, doxepin, and possibly ramelteon as effective and safe pharmacological alternatives for treating insomnia in older adults.

Sheng, Xiao-yan; Liang, Yan; Yang, Xue-yuan; Li, Li-e; Ye, Xia; Zhao, Xia; Cui, Yi-min

doi: 10.1007/s00228-019-02800-3pmid: 31873765

PurposeThe aim of the present study was to evaluate the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of remimazolam besylate following single ascending dose (SAD) and continuous infusion in healthy Chinese volunteers.MethodsThis was a randomized phase I study conducted in two parts. Part I was a double-blind, placebo- and midazolam-controlled, SAD study among healthy Chinese participants with a remimazolam dose of 0.025–0.4 mg/kg. Part II was an open-label, midazolam-controlled, continuous infusion study. Bispectral index (BIS) monitoring and Modified Observers Assessment of Alertness and Sedation (MOAA/S) score assessment were used to assess the PD properties.ResultsThe half-life range of remimazolam was from 34.1 ± 8.1 to 59.8 ± 20.5 min in the SAD study. The sedation function was initially observed at the dose of 0.05 mg/kg remimazolam. Doses of ≥ 0.075 mg/kg exerted a peak sedation effect within 1–2 min after injection, resulting in a deeper and more rapid sedation. In the 2 h continuous infusion, remimazolam showed a deeper sedation and more rapid recovery than midazolam. For general anesthesia, an induction dosage of 0.2 mg/kg/min and a maintenance dosage of 1 mg/kg/h can achieve a satisfactory efficacy effect.ConclusionsRemimazolam was safe and well tolerated in healthy Chinese participants. Based on the phase I clinical study, we suggest that remimazolam besylate demonstrates greater sedation and quicker recovery from sedation than midazolam.

Boland, Jason W; Allgar, Victoria; Boland, Elaine G; Bennett, Mike I; Kaasa, Stein; Hjermstad, Marianne Jensen; Johnson, Miriam

doi: 10.1007/s00228-019-02801-2pmid: 31865411

PurposeOpioids reduce cancer-related pain but an association with shorter survival is variably reported. Aim: To investigate the relationship between pain, analgesics, cancer and survival within the European Palliative Care Cancer Symptom (EPCCS) study to help inform clinical decision making.MethodsSecondary analysis of the international prospective, longitudinal EPCCS study which included 1739 adults with advanced, incurable cancer receiving palliative care. In this secondary analysis, for all participants with date of death or last follow up, a multilevel Weibull survival analysis examined whether pain, analgesics, and other relevant variables are associated with time to death.ResultsDate of death or last follow-up was available for 1404 patients (mean age 65.7 [SD:12.3];men 50%). Secondary analysis of this group showed the mean survival from baseline was 46.5 (SD:1.5) weeks (95% CI:43.6–49.3). Pain was reported by 76%; 60% were taking opioids, 51% non-opioid analgesics and 24% co-analgesics. Opioid-use was associated with decreased survival in the multivariable model (HR = 1.59 (95% CI:1.38–1.84), p < 0.001). An exploratory subgroup analysis of those with C-reactive protein (CRP) measures (n = 219) indicated higher CRP was associated with poorer survival (p = 0.001). In this model, the strength of relationship between survival and opioid-use weakened (p = 0.029).ConclusionOpioid-use and survival were associated; this relationship weakened in a small sensitivity-testing subgroup analysis adjusting for CRP. Thus, the observed relationship between survival and opioid-use may partly be due to tumour-related inflammation. Larger studies, measuring disease activity, are needed to confirm this finding to more accurately judge the benefits and risks of opioids in advanced progressive disease.

Batchelder, Nathan; Lutheran, Carrie Faith; Frens, Jeremy

doi: 10.1007/s00228-019-02811-0pmid: 31834422

PurposeThe purpose of this study was to compare therapeutic vancomycin trough levels in obese adults when using an original nomogram (phase I) versus a modified nomogram (phase II).MethodsThis study compared a vancomycin nomogram with a modified vancomycin nomogram for obese adults over 100 kg. The primary endpoint compared the percentage of sub-therapeutic, therapeutic, and supra-therapeutic vancomycin trough concentrations between the nomograms. Patients were included if they were at least 18 years of age, had a total body weight of 100–299 kg, and had an initial vancomycin trough level collected. Patients were excluded if they had end-stage renal disease or were on continuous renal replacement therapy.ResultsTherapeutic trough levels occurred in 85 out of 171 patients (50%) in phase I and 98 out of 149 patients (66%) in phase II. The incidence of both sub-therapeutic and supra-therapeutic troughs was less in phase II (p = 0.013). In the subgroup of adults aged 18 to 49 with a normalized creatinine clearance of greater than 90 mL/min, there was a trend in more therapeutic levels with the modified nomogram and less chance of sub-therapeutic levels (p = 0.088). In the subgroup of adults with a normalized creatinine clearance of 60–90 mL/min, there was significant improvement in therapeutic levels and a decrease in supra-therapeutic levels without increasing the percent of sub-therapeutic levels (p = 0.001).ConclusionThe modified vancomycin nomogram at Cone Health showed significant improvement in therapeutic trough concentrations while reducing the rates of under and over dosing obese adults. The Cone Health–modified vancomycin nomogram could be a useful tool for initial dosing of vancomycin in the obese population.

Facchini, Fabio Alessandro; Di Fusco, Davide; Barresi, Simona; Luraghi, Andrea; Minotti, Alberto; Granucci, Francesca; Monteleone, Giovanni; Peri, Francesco; Monteleone, Ivan

doi: 10.1007/s00228-019-02799-7pmid: 31982922

Karaźniewicz-Łada, Marta; Krzyżańska, Dagmara; Danielak, Dorota; Rzeźniczak, Janusz; Główka, Franciszek; Słomczyński, Marek; Burchardt, Paweł

doi: 10.1007/s00228-019-02822-xpmid: 31897532

PurposeImpaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin.MethodsThe study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n = 25) or rosuvastatin (n = 25) for at least 6 months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay.ResultsThere were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P < 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P < 0.01).ConclusionThe CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.