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• We report the development of the first adjustable-dose gene therapy system. • The vector is non-antigenic and produces durable and adjustable gene expression. • The system is localized to the subQ injection site and is specific for adipocytes. • Delivered DNA cassettes enable gene expression of secreted therapeutic proteins. • Exenatide, delivered in vivo , achieves clinically relevant levels in circulation. Despite significant potential, gene therapy has been relegated to the treatment of rare diseases, due in part to an inability to adjust dosage following initial administration. Other significant constraints include cost, specificity, antigenicity, and systemic toxicity of current generation technologies. To overcome these challenges, we developed a first-in-class adjustable-dose gene therapy system, with optimized biocompatibility, localization, durability, and cost. A lipid nanoparticle (LNP) delivery system was developed and characterized by dynamic light scattering for size, zeta potential, and polydispersity. Cytocompatibility and transfection efficiency were optimized in vitro using primary human adipocytes and preadipocytes. Durability, immunogenicity, and adjustment of expression were evaluated in C57BL/6 and B6 albino mice using in vivo bioluminescence imaging. Biodistribution was assessed by qPCR and immunohistochemistry; therapeutic protein expression was quantified by ELISA. Following LNP optimization, in vitro transfection efficiency of primary human adipocytes reached 81.3 % ± 8.3 % without compromising cytocompatibility. Critical physico-chemical properties of the system (size, zeta potential, polydispersity) remained stable over a broad range of genetic cassette sizes (1,871–6,203 bp). Durable expression was observed in vivo over 6 months, localizing to subcutaneous adipose tissues at the injection site with no detectable transgene in the liver, heart, spleen, or kidney. Gene expression was adjustable using several physical and pharmacological approaches, including cryolipolysis, focused ultrasound, and pharmacologically inducible apoptosis. The ability of transfected adipocytes to express therapeutic transgenes ranging from peptides to antibodies, at potentially clinically relevant levels, was confirmed in vitro and in vivo. We report the development of a novel, low-cost therapeutic platform, designed to enable the replacement of subcutaneously administered protein treatments with a single-injection, adjustable-dose gene therapy. [ABSTRACT FROM AUTHOR]

Paclitaxel, one of the most frequently used anticancer drugs, is dosed by body surface area, which leads to substantial inter-individual variability in systemic drug exposure. We evaluated clinical evidence regarding the scientific rationale and clinical benefit of individualized paclitaxel dosing based on measured systemic concentrations, known as therapeutic drug monitoring (TDM). In retrospective studies, higher systemic exposure is associated with greater toxicity and efficacy of paclitaxel treatment across several disease types and dosing regimens. In prospective trials, TDM reduces variability in systemic exposure, and has been demonstrated to reduce toxicity while retaining treatment efficacy for 3-weekly dosing in patients with advanced non-small cell lung cancer. Despite the demonstrated benefits of paclitaxel TDM, clinical adoption has been limited due to the challenges with sample collection and analysis. Based on our review, we strongly recommend TDM for patients receiving every 3-week paclitaxel in combination with a platinum agent for advanced NSCLC, due to the prospectively demonstrated clinical benefits, and find moderate evidence to recommend TDM for paclitaxel 3-hour infusions for other tumor types and preliminary evidence suggesting potential usefulness for paclitaxel administered by 1-hour infusions. • BSA-based dosing does not meaningfully reduce inter-patient variability in exposure. • Significant correlations exist between paclitaxel exposure and toxicity. • Significant correlations exist between paclitaxel exposure and activity. • In randomized trials, TDM lowers paclitaxel exposure variability and improves safety. • We strongly recommend TDM for NSCLC patients receiving Q3W paclitaxel. [ABSTRACT FROM AUTHOR]

Pregabalin (PGB) is widely used clinically; however, its pharmacokinetics (PK) has not been studied in pediatric patients with renal impairment (RI). To design optimized PGB regimens for pediatric patients with varying degrees of RI and predict exposure to PGB, physiologically based pharmacokinetic (PBPK) models of PGB were developed and verified, and its disposition was simulated in the healthy population and adults with RI. The simulated results from the PBPK models after single-dose and multi-dose administrations of PGB were consistent with the corresponding observed data based on the fold error values of less than 2. The area under curve ratios were 1.23 ± 0.06, 2.02 ± 0.10, 3.86 ± 0.21, and 9.92 ± 0.79 in pediatric patients with mild, moderate, severe, and end-stage RI, respectively. Based on the predictions for pediatric patients with moderate, severe, and end-stage RI, the maximum dose should not exceed 7, 3.5, and 1.4 mg/kg/day, respectively, among those weighing < 30 kg, and it should not exceed 5, 2.5, and 1 mg/kg/day, respectively, among those weighing > 30 kg. In conclusion, the developed PBPK model is a valuable tool for predicting PGB dosage for pediatric patients with RI. [ABSTRACT FROM AUTHOR]

Background: In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, patients with atrial fibrillation and ≥2 dose-adjustment criteria (age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dl [133 μmol/l]) were randomized to receive apixaban 2.5 mg twice daily or warfarin.Objectives: The purpose of this study was to describe the effects of apixaban dose adjustment on clinical and pharmacological outcomes.Methods: Patients receiving the correct dose of study drug were included (n = 18,073). The effect of apixaban 2.5 mg twice daily versus warfarin on population pharmacokinetics, D-dimer, prothrombin fragment 1 + 2 (PF1+2), and clinical outcomes was compared with the standard dose (5 mg twice daily).Results: Patients receiving apixaban 2.5 mg twice daily exhibited lower apixaban exposure (median area under the concentration time curve at a steady state 2,720 ng/ml vs. 3,599 ng/ml; p < 0.0001) than those receiving the standard dose. In patients with ≥2 dose-adjustment criteria, reductions in D-dimers (p interaction = 0.20) and PF1+2 (p interaction = 0.55) were consistent with those observed in the standard-dose population. Patients with ≥2 dose-adjustment criteria (n = 751) were at higher risk for stroke/systemic embolism, major bleeding, and all-cause death than the standard-dose population (0 or 1 dose-adjustment criterion, n = 17,322). The effect of apixaban 2.5 mg twice daily versus warfarin in the ≥2 dose-adjustment criteria population was consistent with the standard dose in the reductions in stroke or systemic embolism (p interaction = 0.26), major bleeding (p interaction = 0.25), and death (p interaction = 0.72).Conclusions: Apixaban drug concentrations were lower in patients receiving 2.5 mg twice daily compared with 5 mg twice daily. However, the effects of apixaban dose adjustment to 2.5 mg versus warfarin were consistent for coagulation biomarkers and clinical outcomes, providing reassuring data on efficacy and safety. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984). [ABSTRACT FROM AUTHOR]

This retrospective chart review examined dose reductions and discontinuations of concomitant antiseizure medications (ASMs) following cenobamate initiation and maintenance in patients with epilepsy treated at MetroHealth (Cleveland, OH) between 9/1/2020–9/26/2022. Concomitant ASM dose adjustments and treatment-emergent adverse events (TEAEs) were assessed. Efficacy (100 % seizure reduction) was examined among patients who received cenobamate for ≥ 3 months at data cutoff (including titration). As of 9/26/2022, 95 patients received cenobamate (mean age, 45.9 years; 48.4 % female, median exposure 7.5 months). Five patients (5.3 %) discontinued (n = 1 withdrawal by patient; n = 1 noncompliance; n = 3 adverse event). Among the 90 patients taking cenobamate at data cutoff, 50 % (45/90) discontinued ≥ 1 concomitant ASM, most commonly clobazam (n = 18), levetiracetam (n = 10), and phenytoin (n = 7); 21 patients (23.3 %) had additional concomitant ASM dose reductions, most commonly phenytoin (n = 6) and clobazam (n = 4). Sixteen patients received cenobamate monotherapy. Among 79 patients who received cenobamate for ≥ 3 months at data cutoff, 51.9 % (41/79) were seizure-free for ≥ 3 months. Of the 41 seizure-free patients, 58.5 % (24/41) were taking 100 mg/day of cenobamate. Sixteen of the 95 cenobamate-treated patients (16.8 %) reported 22 TEAEs. The most common TEAE was fatigue (n = 7). These data suggest that cenobamate therapy may allow reduction or elimination of polytherapy in some patients. • Retrospective chart review examined medication changes after initiating cenobamate. • 73.3 % of patients (66/90) had concomitant ASM dose reduction or discontinuation. • 16 of the 90 patients (17.8 %) received cenobamate monotherapy during the study. • Seizure control was maintained or improved in most patients (87/90, 96.7 %). • Rate of cenobamate discontinuation was low (5.4 %, 5/90). [ABSTRACT FROM AUTHOR]

Immunoglobulin (IG) replacement therapy in patients with primary immunodeficiency diseases (PID) can be administered daily to every 2 weeks subcutaneously (SCIG) or every 3 or 4 weeks intravenously (IVIG). Develop a population pharmacokinetic (PK) model simulating IG exposure with Ig20Gly, a 20% SCIG; determine the dose adjustment factor for Ig20Gly relative to IVIG. Data from patients with PID treated with Ig20Gly and IVIG 10% were used to characterize IG population PK by nonlinear mixed-effects modeling and validated using data splitting and a visual predictive check. IG profiles were simulated for 1000 patients/interval treated with Ig20Gly (daily, every 2 days, every 3 days, twice weekly, weekly, every 2 weeks). An Ig20Gly adjustment factor of 130% was used to simulate Ig20Gly to IVIG AUC ratios for weekly or every 2 weeks Ig20Gly dosing intervals and a monthly IVIG dosing interval. A 1-compartment model, using weight as a covariate on clearance, derived from an index modeling dataset (n = 81) demonstrated predictability for a validation dataset (n = 21). The model estimate of bioavailability was 73.9%. Simulations for 6 dosing intervals showed similar mean profiles with overlapping prediction intervals. Mean AUC ratios of Ig20Gly to IVIG with a dose adjustment factor of 1.30:1 were 98.7% for weekly and 97.7% for twice-weekly administration demonstrating comparable exposure. Ig20Gly exposures from daily to up to every 2 weeks appeared equivalent. A 1.30 conversion factor provided coverage comparable to IVIG when Ig20Gly is administered daily to every 2 weeks. • A population PK model was derived from Ig20Gly and IVIG PK data from PID patients • Ig20Gly, a 20% subcutaneous IG therapy, model estimate of bioavailability was 73.9% • Ig20Gly exposure for varying dosing intervals (daily to every 2 weeks) was similar • A dose adjustment factor of 1.30 for Ig20Gly achieved exposure comparable to IVIG [ABSTRACT FROM AUTHOR]

Abstract The pharmacokinetics (PK) and pharmacodynamics of many oral antidepressants (OADs) vary substantially among different genders and ethnicities. Likewise is their therapeutic effectiveness, time to response and the incidence of adverse drug events. The aim of this study is to compare the PK of four OADs (desvenlafaxine; DSV, venlafaxine; VLX, escitalopram; ESP, and agomelatine; AGT) among Egyptian males and females. In this study, LC-MS/MS methods were developed and validated for determining the four OADs in human plasma. Samples were prepared by liquid-liquid extraction. Chromatographic separation was performed on reversed-phase C 18 columns followed by positive-ion electrospray ionization and MS/MS detection. The assays were applied for the assessment of PK parameters in human volunteers (n = 95). The developed methods were linear, accurate, and precise for the determination of DSV, VLX, ESP and AGT with extraction recovery of 90 ± 2.0, 98 ± 1.0, 90 ± 1.3 and 87 ± 4.3%, respectively. OADs levels were successfully measured in subjects' plasma and PK parameters were calculated. A prevalent inter-individual variation in PK of the studied OAD was observed. The PK profile of DSV, VLX or ESP did not vary significantly between male and female subjects (p = 0.07–0.98; confidence level (CL) = 95) while the PK of AGT exhibited a significant gender-based variation in both the C max and the AUC ∞ (p = 0.047 and 0.0015; CL = 95). Our results highlight the significance of therapeutic drug monitoring of OADs. Further, it indicates the dose adjustment based on gender difference may not be relevant for DSV, VLX and ESP while it may be considered for AGT. Graphical abstract Unlabelled Image Highlights • Fast LC-MS/MS methods were developed for analysis of oral antidepressants (OADs). • The pharmacokinetic profiles of OADs were compared between men and women. • A significant inter-individual variation was observed for the analyzed OADs. • The pharmacokinetic profile of agomelatine was significantly different among men and women. [ABSTRACT FROM AUTHOR]

Background ODYSSEY OLE (NCT01954394) was an open-label extension (OLE) study for patients with heterozygous familial hypercholesterolemia (HeFH) who had completed previous phase 3 clinical trials with alirocumab. Alirocumab dose could be increased or decreased as per physician judgment. Objective To assess how the alirocumab dosing strategy was used by physicians during OLE. Methods Patients who entered OLE on a starting dose of alirocumab 75 mg every 2 weeks (Q2W) were included in the analysis (those from FH I, FH II, and LONG TERM trials). Those who completed LONG TERM entered an 8-week washout period before receiving alirocumab 75 mg Q2W at the start of OLE. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible, based on the physician's clinical judgment. Results In total, 909 patients with HeFH completed the 3 parent studies and were treated during OLE for a duration of up to 40 months. Most patients (56.7%) were maintained on 75 mg Q2W throughout OLE, whereas 43.3% of patients had their dose increased to 150 mg Q2W. The dose was subsequently decreased in 7.4% of the patients in whom alirocumab was initially uptitrated. Overall, treatment-emergent adverse events were similar between those who had received placebo or alirocumab in the parent studies. Conclusions In the opinion of physicians, alirocumab 75 mg Q2W enabled over half of patients with HeFH to achieve sufficient low-density lipoprotein cholesterol lowering. Graphical abstract Highlights • In total, 909 patients with heterozygous familial hypercholesterolemia received alirocumab (median duration 2.5 years). • Alirocumab dose received (75 or 150 milligrams) based on clinical judgment of physician. • Seventy-five milligram dose considered enough for low-density lipoprotein cholesterol control for 56.7% of patients by physicians. • During open-label extension, 5.9% of patients reported local injection-site reaction adverse events. • Physician's decision to increase alirocumab dose was primarily due to high low-density lipoprotein cholesterol. [ABSTRACT FROM AUTHOR]

Abstract Objective To examine the laboratory anticoagulant effect of two thromboprophylactic low-molecular weight heparin (LMWH) regimens in post-cesarean obese patients. Methods A prospective cohort study, performed during 2017–2018 at a university hospital, of post-cesarean obese (>90 kg) patients receiving 40 mg/day (n = 30) or 60 mg/day (n = 30) enoxaparin, and a control group of non-obese (n = 30) post-cesarean patients receiving 40 mg/day enoxaparin. Thrombin generation and anti-Xa were measured twice on the third postoperative day: prior to and 3.5–4 h following the third LMWH dose. Results Age, parity, weight and body mass index were comparable between the obese study groups. Compared to the control non-obese group, the 40 mg obese and 60 mg obese groups showed increased baseline thrombin generation: medians 491, 581, 571 nM, respectively (P = 0.001 and P = 0.04, respectively). At peak LMWH activity, thrombin generation was higher in the 40 mg than in the 60 mg obese and control groups: medians 2599, 2391, 2229 nM, respectively (P = 0.01 and P < 0.0001, respectively); and thrombin generation was comparable between the 60 mg obese and the control groups (P = 0.58). Similarly, a significantly lower proportion of patients in the 40 mg obese group (10%) had anti-Xa levels within the recommended prophylactic range (0.2–0.5 IU/mL) than in the other groups (P < 0.0001 for both comparisons). Conclusion As determined by thrombin generation and anti-Xa testing, post-cesarean obese patients have an increased procoagulant potential, which was diminished only in those receiving higher dosages of LMWH. These findings support the need for clinical evaluation of LMWH dose adjustment in this setting. Highlights • A prospective study of 2 LMWH regimens in post-cesarean obese women. • Thrombin generation and anti-Xa levels were assessed. • Procoagulant potential was higher in post-cesarean obese women than in controls. • This was diminished only in those receiving higher LMWH dosage (60 vs. 40 mg/day). • Clinical evaluation of LMWH dose adjustment in postpartum obese patients is needed. [ABSTRACT FROM AUTHOR]

Background: Different methods have been proposed to analyze adverse events (AEs) associated with targeted therapies. While these AEs lead to dose adjustments for many patients, conventional reporting methods do not take drug administration into consideration. This paper underlines the importance of jointly reporting AEs and drug administration using prevalence, and proposes a complementary approach to reporting. Patients and methods: The prevalence method estimates the probability of progression-free patients being in a particular health state (state 1: AEs with full dose; state 2: AEs with reduced dose; state 3: no AEs with reduced dose) at different time points. To take into account the impact of dose adjustments on efficacy, the weighted prevalence method can be used by assigning utility weights to the different health states. The benefit of these methods was illustrated using data from a phase II trial of regorafenib. Results: Only 4.6% of progression-free patients developed mucositis/stomatitis (grade≤2) at 3 months. The prevalence of patients not experiencing this AE but whose dose was reduced or treatment interrupted was 58.1%. The weighted prevalence of the regorafenib toxicity profile and dose reduction was higher in the control arm. Conclusion: This case study confirms the importance of jointly analyzing AEs and drug administration. The weighted prevalence approach is an average score that incorporates the dimension of drug administration into AE assessment. This can be helpful for regulatory agencies as well as for clinicians to evaluate the benefit-risk ratio of therapies in their treatment choice. [ABSTRACT FROM AUTHOR]

Objectives Impaired renal function is a risk factor for cefepime (CFPM)-induced encephalopathy (CFPMIE) in patients treated with CFPM; dose-titration to renal function is recommended to prevent CFPMIE. However, available evidence on the incidence of CFPMIE or preventive efficacy of dose adjustment against CFPMIE in end-stage renal disease (ESRD) patients is limited. Methods Single-centre, retrospective observational study. We reviewed consecutive in-hospital adult patients treated with adjusted-dose of CFPM in the period between September 2012 and September 2016, and assessed the CFPMIE in ESRD patients treated with adjusted-dose of CFPM. Results Out of 422 eligible patients, 6 patients (1.4%) were diagnosed with CFPMIE. The incidence of CFPMIE in ESRD patients was 7.5% (5/67). Among ESRD patients, pre-existing central nervous system (CNS) morbidity was significantly associated with the risk of CFPMIE. CFPMIE occurred in ESRD patients regardless of daily dose, and even with 0.5 g/day of CFPM. Conclusions Pre-existing CNS morbidity may be associated with an increased risk of CFPMIE in ESRD patients. No significant association was observed between CFPM dose and incidence of CFPMIE in ESRD patients, and future investigation on the safer dose-adjustment strategy in ESRD patients is required for achieving balance between successful infectious treatment and reducing CFPMIE. [ABSTRACT FROM AUTHOR]

Background: In routine clinical practice, chemotherapy doses are frequently capped at a body surface area (BSA) of 2.0 m2 or adjusted to an ideal weight for obese patients due to safety reasons. Materials and methods: Between August 2004 and July 2008, a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense (dd) regimen [epirubicin, docetaxel and cyclophosphamide (iddETC) versus epirubicin and cyclophosphamide (EC) followed by docetaxel (T) plus capecitabine (X)]. We retrospectively evaluated a total of 555 patients with a BMI of =30 for safety and outcome. Results: Eighteen percent of all patients were obese: 31% of those received chemotherapy according to an unadjusted BSA. For the remaining patients, BSA was adjusted to ideal weight or was capped at 2.0 m2. A total of 15% of obese patients receiving full (unadjusted) dose of chemotherapy versus 6% of obese patients with an adjusted BSA experienced febrile neutropenia (P = 0.003) and 9% versus 3% high-grade thrombopenia (P = 0.002). Overall, 17% versus 10% had a thromboembolic event (P = 0.017), which was high grade in 13% versus 6%, respectively (P = 0.019), and 3% versus 0.3% high-grade hot flushes (P = 0.013). Dizziness (5% versus 11%; P = 0.016), diarrhea (19% versus 27%; P = 0.033) and an increase in serum creatinine (7% versus 14%; P = 0.019) were higher in the adjusted group. However, no differences in disease-free survival (DFS) and overall survival (OS) were observed between non-obese patients, obese patients receiving full-dose chemotherapy or according to an adjusted BSA [5-year DFS 81% (confidence interval 79% to 83%) versus 82% (75% to 87%) versus 81% (76% to 84%); P = 0.761; 5-year OS 90% (88% to 91%) versus 86% (80% to 91%) versus 88% (84% to 91%); P = 0.143]. Conclusion: Obese patients receiving dd chemotherapy according to their real BSA have a higher risk of developing severe toxicities without influencing survival. Therefore, a dose adjustment of intense dd chemotherapy should be carried out to avoid life-threatening complications. [ABSTRACT FROM AUTHOR]

Patients with Crohn's disease (CD) treated with ustekinumab who experience inadequate response, or loss of response after standard induction and/or maintenance dosing may benefit from dose escalation. We conducted a systematic review and meta-analysis examining the effectiveness of reinduction and/or dose interval shortening of ustekinumab in patients with active CD despite standard induction and maintenance. Through a systematic literature search through March 31, 2021, we identified 15 cohort studies in 925 adults with CD with inadequate response or loss of response to standard dose ustekinumab, underwent dose escalation (reinduction and/or dose interval shortening to <8 weeks), and reported rates of achieving clinical response, corticosteroid-free clinical remission, endoscopic response, and/or remission. We calculated pooled rates (with 95% confidence intervals) using random effects meta-analysis and examined factors associated with response to dose escalation through qualitative synthesis of individual studies. On meta-analysis, 55% of patients (95% confidence interval, 52%–58%) with inadequate response or loss of response who underwent ustekinumab dose escalation achieved clinical response, with moderate heterogeneity (I2 = 57%). Approximately 61% of patients were able to achieve endoscopic response, including 29% who achieved endoscopic remission. Dose interval shortening alone recaptured response in 57% patients. No consistent factors associated with response to dose escalation were identified on qualitative synthesis. In real word settings, ustekinumab dose escalation was effective in achieving response in patients with CD with inadequate response, or loss of response to standard dose induction and/or maintenance therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Integrated analysis of all plasma concentration data obtained from phase 1 studies in Japanese subjects, including a high dose study and special population studies, was conducted to thoroughly re-investigate the pharmacokinetics of doripenem by means of a population approach. Dose adjustments for patients with renal impairment were assessed by Monte-Carlo pharmacokinetics/pharmacodynamics simulation. The population pharmacokinetics of doripenem was evaluated using 921 plasma concentration data from 92 subjects from eight phase 1 studies in Japan. The two-compartment model could well describe the plasma concentration profile of doripenem after intravenous infusion. Creatinine clearance and age were found to be covariates of doripenem clearance, and creatinine clearance was the most important factor influencing the pharmacokinetics of doripenem, which is consistent with the fact that doripenem is mainly excreted via the urine. Simulations suggest that exposures (AUC) to 1 g every 8 h for patients with normal renal function would be similar to those expected at 1 g every 12 h, 0.5 g every 8 h and 0.25 g every 8 h for patients with mild, moderate and severe renal impairment, respectively. These dosing regimens also provide sufficient exposure to doripenem from the viewpoint of the percentage of time above the minimum inhibitory concentration. [ABSTRACT FROM AUTHOR]

Oral methadone may be prescribed to detainees with the aim of minimising the risk of fatal opioid poisoning on release. To study the circumstances under which methadone-related deaths can occur in detention, we audited reports of 17 [14 male, 3 female; median (range) age 34 (22-52) years] such deaths, July 2010-December 2011. The median (range) methadone dose was 40 (10-110) mg/d (N = 16). The median (range) post-mortem blood methadone concentration was 0.42 (0.16-1.40) mg/L. Those who died within 7 days of the commencement of methadone treatment were significantly younger (Mann-Whitney U 102.5, p < 0.05), were prescribed a significantly lower dose (U = 80.0, p < 0.05) and had significantly lower blood methadone concentrations at death (U = 106.5, p < 0.02) than in those given methadone long-term. In 8 reports the prisoner had been recorded as either 'sleepy' (N = 7), or 'unwell' in the hours before death. In 13 deaths, the prisoner was either found dead first thing in the morning, or in one instance could not be roused ('snoring heavily'). Pneumonia, tracheobronchitis, end-stage cirrhosis, and ischaemic heart disease/coronary artery atherosclerosis were cited as associated factors in four patients, all of whom were on long term stable methadone treatment. Attention to warning signs of likely methadone toxicity (daytime or excessive drowsiness, snoring, nausea/vomiting) and associated risk factors (use of drugs such as benzodiazepines and gabapentinoids, the presence of respiratory infection, liver or renal disease) could help minimise the risk of unexpected death in patients given methadone. [ABSTRACT FROM AUTHOR]

Abstract: Background: CYP2D6 is a key enzyme in tamoxifen metabolism, transforming it into its main active metabolite, endoxifen. Poor CYP2D6 metabolizers (PM) have lower endoxifen plasma concentrations and possibly benefit less from treatment with tamoxifen. We evaluated tamoxifen dose adjustment in CYP2D6 PM patients in order to obtain plasma concentrations of endoxifen comparable to patients with extensive CYP2D6 metabolism (EM). Patients and methods: Comprehensive CYP2D6 genotyping and plasma tamoxifen metabolite concentrations were performed among 249 breast cancer patients in adjuvant treatment with tamoxifen. Tamoxifen dose was increased in PM patients to 40 mg and to 60 mg daily for a 4-month period each, repeating tamoxifen metabolite measurements on completion of each dose increase. We compared the endoxifen levels between EM and PM patients, and among the PM patients at each dose level of tamoxifen (20, 40 and 60 mg). Results: Eleven PM patients (4.7%) were identified. The mean baseline endoxifen concentration in EM patients (11.30 ng/ml) was higher compared to the PM patients (2.33 ng/ml; p < 0.001). In relation to the 20 mg dose, increasing the tamoxifen dose to 40 and 60 mg in PM patients significantly raised the endoxifen concentration to 8.38 ng/ml (OR 3.59; p = 0.013) and to 9.30 ng/ml (OR 3.99; p = 0.007), respectively. These concentrations were comparable to those observed in EM patients receiving 20 mg of tamoxifen (p = 0.13 and p = 0.64, respectively). Conclusion: In CYP2D6 PM patients, increasing the standard tamoxifen dose two-fold or three-fold raises endoxifen concentrations to levels similar to those of patients with EM phenotype. [Copyright &y& Elsevier]

Abstract: The aim of the present study was to evaluate the efficacy of dose modification based on the risk factor for linezolid-induced thrombocytopenia. A multivariate logistic regression analysis performed in the observational study showed that low body weight of <55 kg (odds ratio [OR]: 33.2, 95% confidence interval [CI]: 2.16–510.1, P = 0.012) and the baseline platelet count of <200 × 103/mm3 (OR: 24.9, 95% CI: 1.53–404.7, P = 0.024) were found to be risk factors for linezolid-induced thrombocytopenia. In the subsequent intervention study, in which daily dose of linezolid was set to 20 mg/kg in patients with either one of the risk factors or 1200 mg in those without any risk factor, the onset of thrombocytopenia was significantly prolonged in the intervention study group (P = 0.043), without reducing clinical efficacy. These findings suggest that dose adjustment of linezolid is effective in preventing thrombocytopenia without reducing its clinical efficacy in patients having risk factors. [Copyright &y& Elsevier]

Abstract: Background: The objective of the study was to investigate vancomycin dose adjustment in pediatric burn patients by evaluating trough drug concentrations and the pharmacokinetic and pharmacodynamic (PK/PD) correlation. Methods: Study subjects included 13 patients who were 6.0 years old, 25kg (median). with normal renal function. These had at least a 30% total burn surface area and inhalation injury were present in 7/13 patients. The patients were investigated prospectively. Plasma monitoring and PK assessments were performed by serial blood sample collections (30 sets). Only 0.2mL of each plasma sample was required for our plasma measurements, which were made by high performance liquid chromatography. The vancomycin PK/PD target was set at . Results: Trough values less than 10μg/mL were obtained in 16/30 sets (53%) as a consequence of increased plasma clearance and the apparent volume of distribution. The daily dose was subsequently increased from 43.4±9.0mg/kg (mean±SD) to 98.0±17.9mg/kg, p <0.05. The PK/PD target was reached for pathogens with 0.5mg/L, 1mg/L, 2mg/L and 4mg/L MIC in 93.3% (28/30), 66.7% (20/30), 33.3% (10/30) and 3.3% (1/30) of the sets, respectively. Conclusions: To more rapidly achieve the PK/PD targets in pediatric burn patients with normal renal function, an initial dose of approximately 90–100mg/kg/day is recommended; however, this higher dosage regimen should be further evaluated in this population in terms of efficacy and toxicity as well as in terms of achieving pharmacodynamic goals. [Copyright &y& Elsevier]

Abstract: Objective: To determine whether appropriate dose adjustment was taken into account or not by the physicians when prescribing drugs in patients with renal impairment. Design: A retrospective chart review was performed and included 98 adult in-patients, diagnosed with renal impairment based on clinical evaluation and laboratory data, in King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia, who was admitted to the hospital from September 2005 to January 2011. Data of the patients were noted and recorded including baseline demographics, clinical data, laboratory data, renal state, treatment data and medications. Results: The initial number of the patients was reduced to 80 where a total of 502 drugs were investigated in the present study with an average of six drugs per patient. Of these 502 studied drugs, 196 (39%) required dose adjustment where 92 (46.9%) were adjusted and 104 (53.1%) were not adjusted. It was found also that most of the drugs requiring dose adjustment were antibiotics (39.8%). Conclusion: The current study confirms that physicians still do not take into account sufficiently patients’ renal function when prescribing drugs. Continuous medical education and collaboration with clinical pharmacist should be encouraged for quality improvement in patients with renal impairment. [Copyright &y& Elsevier]

Abstract: Breast cancer is frequently diagnosed in older women, yet treatment standards are based largely on clinical trials conducted in younger women. Survival outcomes for breast cancer in older women are suboptimal, partly because of underuse of appropriate therapy. Capecitabine is an oral fluoropyrimidine with a favorable side effect profile that is an attractive therapeutic option for older breast cancer patients. However, dose adjustments for renal function and careful monitoring of adherence, potential drug interactions, and toxicity are particularly important in this population. The article reviews the safety and efficacy data from studies with capecitabine monotherapy or capecitabine in combination with other therapies for breast cancer, with a particular focus on elderly patients. [ABSTRACT FROM AUTHOR]

The use of glycoprotein IIb/IIIa inhibitors (GPI) reduces ischemic events in patients undergoing percutaneous coronary intervention (PCI). However, the same properties that confer this benefit lead to an increased bleeding risk. Recent studies have shown a less robust net clinical benefit of GPI in the current era of routine thienopyridine and direct thrombin inhibitor use. To optimize the net clinical benefit of GPI, these agents need to be selectively used in patients most likely to benefit from their anti-ischemic effect, namely patients undergoing PCI for non–ST-segment elevation myocardial infarction, select patients undergoing primary PCI, and select patients undergoing PCI without appropriate pre-loading with a thienopyridine. Moreover, strategies to minimize bleeding should be applied in these patients and include shorter GPI infusions (in some patients), dose adjustments of heparin and GPI, careful access site management with more frequent use of the transradial approach, use of smaller sheaths, and identification of patients at high bleeding risk. This review provides an update of the current literature that supports these measures, an insight on the tailored use of GPI, and a potential direction for future research addressing combined antithrombotic therapies. [ABSTRACT FROM AUTHOR]

Abstract: Although being used for decades in the treatment of several types of cancer, either alone or in association, only a few data about the pharmacokinetics of doxorubicin (DOX) in humans are available. DOX is frequently used in association with other anticancer drugs in the management of breast cancer. Pharmacokinetic data available in the literature show that after i.v. administration DOX follows a two-compartment open model, with a fast distribution phase followed by a very slow elimination phase. The objective of this work is to perform a pilot study in order to verify if the usual dose adjustment based on body surface area (BSA) would be producing the same plasma concentration–time profiles in patients with normal (<25) and above normal (>25) body mass index (BMI). In order to assess the pharmacokinetics of DOX after a short-term i.v. infusion of 60mg/m2 of BSA, an experimental design using only five plasma samples of each patient was applied. Samples were collected at 0.00, 0.66 (right after the end of infusion), 1.66, 8.66, and 24.66h. DOX pharmacokinetic profiles were evaluated after quantification of DOX using a new HPLC method developed and validated. Pharmacokinetic parameters (AUC0–24.66 and C max) were analyzed by non-compartmental and compartmental approaches. Significant differences (α =0.05) between overweight and normal weight groups were found with respect to AUC and C max. After adjustment of dose by weight and by BMI, the compartmental model was used to simulate plasma concentrations and new values for C max and AUC0–24.66 were calculated. The new values obtained using both body weight (BW) and BMI were closer to the normal group than those obtained with BSA. According to the simulation, the differences of AUC and C max between the overweight group and the group of patients with normal weight were lower when the dose was adjusted by BW and BMI. These results suggest that more studies must be conducted, with more patients, in order to evaluate the best dose adjustment for DOX in women with breast cancer and overweight. [Copyright &y& Elsevier]

Background: In patients with kidney impairment, warfarin, a drug metabolized primarily by the cytochrome P-450 system, is initiated at similar doses and managed similarly as in the general medical population. Unfortunately, few data exist to guide dose adjustment in patients with decreased kidney function. Here, we determine the degree of warfarin dose reduction associated with kidney impairment and make recommendations for warfarin dosing. Study Design: Cross-sectional analysis. Setting & Participants: Long-term warfarin users followed up at anticoagulation clinics (n = 980); 708 participants from the University of Alabama (UAB) and 272 participants from the University of Chicago (UIC). Predictor: No/mild (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m²), moderate (eGFR, 30-59 mL/min/1.73 m²), and severe (eGFR <30 mL/min/1.73 m²) kidney impairment; CYP2C9 and VKORC1 genotype; age; race; sex; body mass; sociodemographic factors; smoking status; alcohol; vitamin K intake; comorbid conditions (eg, congestive heart failure); and drug interactions (eg, amiodarone and statins). Outcome & Measurement: Warfarin dose (milligrams per day) was evaluated using linear regression after adjustment for clinical, demographic, and genetic factors. Results: Prevalences of moderate (31.8% and 27.6%) and severe kidney impairment (8.9% and 6.6%) were similar in the UAB and UIC cohorts. Warfarin dose requirements were significantly lower in patients with moderate and severe kidney impairment compared with those with no/mild kidney impairment in the UAB (P < 0.001) and UIC (P < 0.001) cohorts. Compared with patients with no/mild kidney impairment, patients with moderate kidney impairment required 9.5% lower doses (P < 0.001) and patients with severe kidney impairment required 19% lower doses (P < 0.001). Limitations: No measurement of warfarin, serum albumin, vitamin K, and coagulation factors; no evaluation of other markers (eg, cystatin). Conclusion: Moderate and severe kidney impairment were associated with a reduction in warfarin dose requirements. [ABSTRACT FROM AUTHOR]

Abstract: The changes in the shape and size of vines during the growing season require a continuous adjustment of the applied dose to optimize spray application efficiency. Target detection with ultrasonic sensors can be used to adapt the applied dose following the principles of the variable rate technology. A multi-nozzle air-blast sprayer was fitted with three ultrasonic sensors and three electro-valves, to modify the flow rate from the nozzles in real time, in relation to the variability of crop width. A constant application rate of 300lha−1 was compared with a variable rate application using the tree row volume principle at a 0.095lm−3 canopy. The total flow rate sprayed by the nozzles was modified according to the variations of crop width measured by the ultrasonic sensors. On average 58% less liquid was applied compared to the constant rate application, with similar deposition on leaves with both treatments. A detailed analysis of savings indicates differences between the lower, middle and top part of the crop, in accordance with the leaf area distribution with crop height. No significant differences between treatments were detected in uniformity of liquid distribution and capability to reach the inner parts of the crop. This important reduction in spray volume could be followed by an equivalent reduction of plant protection products but further research work is needed to guarantee biological efficacy of a reduced dose. [Copyright &y& Elsevier]

Abstract: The purpose of the study was to adjust the individual maintenance dose of warfarin with a simple approach based on indirect pharmacodynamic model (IDR). Based on the distinct pharmacokinetic and pharmacodynamic features of warfarin, the relationship between the maintenance dose and the steady-state anticoagulation effect was simplified and an approach for the maintenance dose adjustment was proposed. According to the steady-state anticoagulation effect before and after multiple doses (0.1mgkg−1 day−1), the optimal maintenance doses were predicted for the target anticoagulation effect (INRtarget =2.5), then the actual anticoagulation effect (prothrombin times, PT) on the 6th (8pm)\8th (8am)\10th (2pm) day after dose adjustment according the present method was compared with the target effects with a view of determination the feasibility and accuracy of the proposed approach. The proposed method was also used to adjust warfarin maintenance doses in the presence of metabolism inhibitor metronidazole. The results suggested that the proposed approach could appropriately achieve the target international normalized ratio (INRtarget) when warfarin used alone or in combination with metronidazole, the actual INR values of three days were 2.69±0.18 and 2.52±0.22 (mean±S.D.), respectively. The method provided a relatively simple and accurate strategy for warfarin maintenance dose adjustment. [Copyright &y& Elsevier]

Abstract: The use of growth hormone (GH) replacement for GH-deficient adults is now in its 10th year of FDA-approved use in the United States; it has been used for a longer period of time in some European countries. Despite widespread experience, there is still lack of consensus regarding the best approach to GH initiation and titration in adults with growth hormone deficiency. Several factors must be considered prior to dose selection, including patient age, gender, symptoms, and the use and route of estrogen replacement therapy. We retrospectively examined GH dosing practices within our institution over a 5-year period to define GH dose requirements during the initial titration and maintenance phases, the frequency of dose adjustments, and the reasons behind the dose adjustments in young and older adults. Based on this review, we offer practical recommendations for endocrinologists in the management of adults with hypopituitarism and long-term GH treatment. [Copyright &y& Elsevier]

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Abstract: This paper examines some of the consequences of adopting the Leaf-Wall-Area (LWA) method of dose expression for the registration of plant protection products used in commercial orchards. The examination method uses Light Detection And Range (LiDAR) recordings of a wide range of UK pome-fruit orchards and a generalised dosage model to simulate the results of deposit trials with a broadcast air-assisted sprayer. The results are constrained in accordance with the normal practices of pesticide registration (i.e. the recommended LWA dose rate is assumed to be efficacious and safe to use below the maximum dose per unit ground area). The discussion of results examines new regulatory aspirations for improving the efficiency of pesticide use through the introduction of LWA dose expression and considers the needs for additional information to support spray applications with and without dose adjustment. [Copyright &y& Elsevier]

Background: Research on how US physicians individualize buprenorphine-naloxone treatment is limited. The current study uses conjoint analysis to examine the importance of current dose, visit frequency, clinical indicators, and payment type on office visit and dose adjustments during buprenorphine-naloxone treatment.Methods: A national random sample of 776 US buprenorphine-prescribing physicians participated in a mailed survey between October 2015 and July 2018. The survey contained 16 patient vignettes describing: (1) current dose, (2) urine drug test (UDT) results and opioid blockade, (3) recent intravenous use, (4) visit attendance, (5) counseling adherence, (6) payment, and (7) visit schedule. Physicians rated how they would adjust office visits (0=definitely decrease to 5=no change to 10=definitely increase) and the dose (0=definitely decrease to 5=no change to 10=definitely increase). Descriptive statistics were calculated for the vignette responses. Conjoint analysis was used to estimate relative importance scores and part-worth utilities.Results: Across the vignettes, the mean response for adjusting office visits was 7.43 (SD = 1.69), indicating a tendency to increase the frequency of visits. UDT results/opioid blockade, intravenous use, and current visit schedule had the greatest importance scores for office visit adjustments. The mean response for adjusting the dose was 5.48 (SD = 1.69), corresponding with a tendency toward not changing dose. Current dose, UDT results/opioid blockade, and intravenous use had the largest importance scores for dose adjustment.Conclusions: Physicians individualized buprenorphine-naloxone treatment in response to hypothetical patient attributes by changing visit frequency and, to a lesser extent, modifying maintenance dose, in a manner generally consistent with current practice guidelines. [ABSTRACT FROM AUTHOR]

Abstract Purpose Nemonoxacin is a novel C-8-methoxy nonfluorinated quinolone that has been approved for the treatment of community-acquired pneumonia (CAP) in adults. The goals of this study were to evaluate the pharmacokinetic (PK) and population PK parameters of nemonoxacin and to provide the appropriate dose adjustment recommendations for patients with hepatic impairment. Methods An open-label, single-dose, parallel group (moderate hepatic impairment group and healthy control group) PK study of nemonoxacin was conducted. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) was performed to detect the unchanged nemonoxacin concentration in blood and urine samples. The nonlinear mixed effects modeling tool NONMEN (version 7.3) was used to conduct the population PK analysis. The paired-t test was conducted to compare the PK parameters of the hepatic impairment group and the healthy control group by SPSS (Version 17.0). Findings Ten subjects for each group were enrolled into the PK study. The PK parameters as well as the plasma concentration-time and logarithmic concentration-time profiles after taking a 500-mg single dose of nemonoxacin showed few differences between the two groups (P > 0.05). The mean areas under the plasma concentration vs. time curve from 0 to 72 h (AUC0-72 h) of the moderate hepatic impairment group and the healthy control group in the nemonoxacin PK study were 58.50 (17.30) mg·h/mL and 49.74 (10.16) mg·h/mL, respectively, giving a mean (SD) AUC0-72 h ratio of 1.15 (0.42) with a 90% CI of 0.91–1.39. A 3- compartment model was considered to be the best model for the data, especially in fitting the plasma point at low drug concentrations. Covariate analysis indicated that weight affected CL/F, V1/F, and V3/F and that eGFR only affected CL/F in the power function model, while gender affected V3/F in the linear model by forward selection and backward deletion. Implications The population PK parameters of nemonoxacin were evaluated in patients with hepatic impairment. The hepatic function did not have a significant impact on the PK parameters of nemonxacin, but renal function was a meaningful covariate that is consistent with its PK characteristics. In this study, nemonoxacin was well tolerated in the patients with moderate hepatic impairment as well as in the healthy subjects. Based on these data, it is not necessary to consider dose adjustment of nemonoxacin in patients with mild or moderate hepatic impairment. ClinicalTrials.gov identifier: NCT02604498. [ABSTRACT FROM AUTHOR]

Purpose In critical burn patients, the pharmacokinetic parameters (absorption, distribution, metabolism, and excretion) of many classes of drugs, including antibiotics, are altered. The aim of this study was to compare 2 groups of burn patients undergoing treatment for health care–associated infections with and without therapeutic drug monitoring. Methods A retrospective analysis of a clinical intervention (ie, a before/after study) was conducted with patients with health care–associated pneumonia, burn infection, bloodstream infection, and urinary tract infection in the burn intensive care unit of a tertiary care hospital. The patients were divided into 2 groups: (1) those admitted from May 2005 to October 2008 who received conventional antimicrobial dose regimens; and (2) those admitted from November 2008 to June 2011 who received antibiotics (imipenem, meropenem, piperacillin, and vancomycin) with doses adjusted according to plasma monitoring and pharmacokinetic modeling. General characteristics of the groups were analyzed, as were clinical outcomes and 14-day and in-hospital mortality. Findings Sixty-three patients formed the conventional treatment group, and 77 comprised the monitored treatment group. The groups were homogeneous, median age was 31 years (range: 1–90) and 66% were male. Improvement occurred in 60% of the patients under monitored treatment (vs 52% with conventional treatment); 14-day mortality was 16% vs 14%; and the in-hospital mortality was similar between groups (39% vs 36%). In the final multivariate models, variables significantly associated with in-hospital mortality were total burn surface area ≥30%, older age, and male sex. Treatment group did not affect the prognosis. Implications Therapeutic drug monitoring of antimicrobial treatment did not alter the prognosis of these burn patients. More trials are needed to support the use of therapeutic drug monitoring to optimize treatment in burn patients. [ABSTRACT FROM AUTHOR]