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BACKGROUND: Critically ill patients commonly suffer from infections that require antimicrobial therapy. In previous studies, liver dysfunction was shown to have an essential impact on the dose selection in these patients. This pilot study aims to assess the influence of liver dysfunction, measured by the novel LiMAx test, on clinical outcomes in critically ill patients treated with linezolid. METHODS: Twenty-nine critically ill patients were included and treated with linezolid. Indications for linezolid therapy were secondary or tertiary peritonitis (46.7%), bloodstream infection (6.7%) and 46.7% were other infections with gram-positive bacteria. Linezolid Cmin, maximal liver function capacity (LiMAx test) and plasma samples were collected while linezolid therapy was in a steady-state condition. Furthermore, potential factors for the clinical outcome were investigated using logistic regression analysis. Clinical cure was defined as the resolution or significant improvement of clinical symptoms without using additional antibiotic therapy or intervention. RESULTS: Cured patients presented lower median linezolid Cmin yet a significantly higher mean LiMAx-value compared to the clinical failure group (1.9 mg/L vs. 5.1 mg/L) (349 μg/kg/h vs. 131 μg/kg/h). In the logistic regression model, LiMAx < 178 μg/kg/h was the only independent predictor of clinical failure with a sensitivity of 77% and specificity of 93%. CONCLUSIONS: The LiMAx test predicts clinical failure more precisely than linezolid trough levels in critically ill surgical patients. Therefore liver failure may have a stronger impact on the outcome of critically ill surgical patients than low linezolid Cmin. While linezolid Cmin failed to predict patient’s outcome, LiMAx results were the only independent predictor of clinical failure.

Introduction Because of its lower risk of renal toxicity than vancomycin, teicoplanin is the preferred treatment for methicillin-resistant Staphylococcus aureus infection in patients undergoing continuous venovenous haemodiafiltration (CVVHDF) in whom renal function is expected to recover. The dosing regimen for achieving a trough concentration (Cmin) of ≥20 μg/mL remains unclear in patients on CVVHDF using the low flow rate adopted in Japan. Methods The study was conducted in patients undergoing CVVHDF with a flow rate of Results Overall, 60 patients were eligible for study inclusion. The proportion of patients achieving the Cmin target was significantly higher for the enhanced regimen than for the high-dose regimen (52.9% versus 8.3%, p = 0.003). In multivariate analysis, the enhanced regimen (odds ratio [OR] = 39.93, 95% confidence interval [CI] = 5.03–317.17) and hypoalbuminaemia (OR = 0.04, 95% CI = 0.01–0.44) were independent predictors of the achievement of Cmin ≥ 20 μg/mL. Conclusions An enhanced teicoplanin regimen was proposed to treat complicated or invasive infections by methicillin-resistant Staphylococcus aureus in patients receiving CVVHDF even with a low flow rate.

Palbociclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 used in the treatment of locally advanced and metastatic breast cancer, and is extensively metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). A pharmacokinetic/pharmacodynamic relationship between palbociclib exposure and neutropenia is well known. This study aimed to investigate the effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib. We performed a randomized crossover trial comparing the pharmacokinetics of palbociclib monotherapy 125 mg once daily (q.d.) with palbociclib 125 mg q.d. plus oral erythromycin 500 mg three times daily for seven days. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. Eleven evaluable patients have been enrolled. For palbociclib monotherapy, geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0–24h), maximum plasma concentration (Cmax), and minimum plasma concentration (Cmin) were 1.46 × 103 ng•h/mL (coefficient of variation (CV) 45.0%), 80.5 ng/mL (CV 48.5%), and 48.4 ng/mL (CV 38.8%), respectively, compared with 2.09 × 103 ng•h/mL (CV 49.3%, P = 0.000977), 115 ng/mL (CV 53.7%, P = 0.00562), and 70.7 ng/mL (CV 47.5%, P = 0.000488) when palbociclib was administered concomitantly with erythromycin. Geometric mean ratios (90% confidence intervals) of AUC0–24h, Cmax, and Cmin for palbociclib plus erythromycin vs. palbociclib monotherapy were 1.43 (1.24–1.66), 1.43 (1.20–1.69), and 1.46 (1.30–1.63). Minor differences in adverse events were observed, and only one grade ≥ 3 toxicity was observed in this short period of time. To conclude, concomitant intake of palbociclib with the moderate CYP3A4 inhibitor erythromycin resulted in an increase in palbociclib AUC0–24h and Cmax of both 43%. Therefore, a dose reduction of palbociclib to 75 mg q.d. is rational, when palbociclib and moderate CYP3A4 inhibitors are used concomitantly.

Contains fulltext : 249093.pdf (Publisher’s version ) (Open Access) Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 μg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured C(min) at steady-state. The geometric mean (GM) C(min) at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM C(min) at the start dose was 1456 μg/L (95% CI: 1185-1789) vs 682 μg/L (95% CI: 572-812) (P

ObjectivesLong-acting reversible contraceptives are effective contraceptives for women with HIV, but there are limited data on etonogestrel implant and antiretroviral therapy pharmacokinetic drug-drug interactions. We evaluated etonogestrel/antiretroviral therapy drug-drug interactions, and the effects of etonogestrel on ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, and efavirenz pharmacokinetics.Study designWe enrolled postpartum women using etonogestrel implants and receiving ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, or efavirenz-based regimens between 2012 and 2015. Etonogestrel implants were inserted 2 to 12 weeks postpartum. We performed pharmacokinetic sampling pre-etonogestrel insertion and 6 to 7 weeks postinsertion. We measured antiretroviral concentrations pre and postetonogestrel insertion, and compared etonogestrelconcentrations between antiretroviral regimens. We considered a minimum serum etonogestrelconcentration of90 pg/mLadequate for ovulation suppression.ResultsWe collected pharmacokinetic data for 74 postpartum women, 22 on ritonavir-boosted-atazanavir, 26 on ritonavir-boosted-lopinavir, and 26 on efavirenz. The median serum concentrations of etonogestrel when co-administered were highest with etonogestrel/ritonavir-boosted-atazanavir (604 pg/mL) and etonogestrel/ritonavir-boosted-lopinavir (428 pg/mL), and lowest with etonogestrel/efavirenz (125 pg/mL); p < 0.001. Minimum concentration (Cmin) of ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were lower after etonogestrel implant insertion, but overall exposure, predose concentrations, clearance, and half-lives were unchanged. We found no significant change in efavirenz exposure after etonogestrel insertion.ConclusionsUnlike efavirenz, ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were not associated with significant decreases in etonogestrel concentrations. Efavirenz was associated with a significant decrease in etonogestrel concentrations.ImplicationsThe findings demonstrate no interactions between etonogestrel and ritonavir-boosted-lopinavir or ritonavir-boosted-atazanavir, but confirm the decreased efficacy of etonogestrel with efavirenz-based antiretrovirals. This information should be used to counsel women with HIV who desire long-acting reversible contraceptives.

Introduction:Dosage Optimization of gentamicin in hemodialysis is essential to ensure its antibacterial efficacy. The objective of this study was to evaluate the use of gentamicin in hemodialysis patients.Materials and methods:This is a single-center study; a retrospective, descriptive; Observational and analytical study that was carried out at the Pharmacovigilance Department of the University and Hospital Establishment (UHE) of Oran in Algeria, from November 2021 to June 2022. Patient data was collected from the patient information sheet accompanying the sample for the gentamicin assay. The maximum (Cmax) and residual (Cmin) concentrations of gentamicin were measured by immunoenzymatic method.Results:Our study was included 74 patients; which 44 patients were male (59%) and 30 patients were female (41%) with a mean age of 47 years. The gentamicin‘s administration mode of was 4 hours before the dialysis session in 63.9% of patients. The mean doses used were higher in patients who received gentamicin pre-dialysis (group 1), i.e. 2.49 mg/kg versus 1.38 mg/kg for those who received gentamicin post-dialysis (group 2). The target Cmax was reached in all patients treated for bacterial endocarditis in group 1 versus 20% for group 2. In addition, only 28.10% of patients in group 2 had reached the target Cmin after a first session of dialysis, thus delaying the administration of the next dose administration.Conclusion:This study showed that the administration strategy of gentamicin in predialysis has the advantage of reaching the therapeutic target values; however, a clinical evaluation of the effectiveness of this approach in terms of healing speed and time needs to be established.

Objective In AIDS Clinical Trials Group study A5338, concomitant rifampicin, isoniazid, and efavirenz was associated with more rapid plasma medroxyprogesterone acetate (MPA) clearance compared to historical controls without tuberculosis or HIV therapy. We characterized the pharmacogenetics of this interaction. Methods In A5338, women receiving efavirenz-based HIV therapy and rifampicin plus isoniazid for tuberculosis underwent pharmacokinetic evaluations over 12 weeks following a 150-mg intramuscular injection of depot MPA. Data were interpreted with nonlinear mixed-effects modelling. Associations between individual pharmacokinetic parameters and polymorphisms relevant to rifampicin, isoniazid, efavirenz, and MPA were assessed. Results Of 62 A5338 participants in four African countries, 44 were evaluable for pharmacokinetic associations, with 17 CYP2B6 normal, 21 intermediate, and 6 poor metabolizers, and 5 NAT2 rapid, 20 intermediate, and 19 slow acetylators. There were no associations between either CYP2B6 or NAT2 genotype and MPA Cmin at week 12, apparent clearance, Cmax, area under the concentration-time curve (AUC) or half-life, or unexplained interindividual variability in clearance, and uptake rate constant or mean transit time of the slow-release fraction (P > 0.05 for each). In exploratory analyses, none of 28 polymorphisms in 14 genes were consistently associated with MPA pharmacokinetic parameters, and none withstood correction for multiple testing. Conclusions Study A5338 suggested that more frequent depot MPA dosing may be appropriate for women receiving rifampicin, isoniazid, and efavirenz. The present results suggest that knowledge of CYP2B6 metabolizer or NAT2 acetylator status does not inform individualized DMPA dosing in this setting.

Objectives: The aim of this study was to explore the relationship between cefiderocol pharmacokinetic/pharmacodynamic (PK/PD) target attainment and microbiological outcome in critically ill patients affected by extensively drug-resistant Acinetobacter baumannii (XDR-AB) bloodstream infection (BSI) and/or ventilator-associated pneumonia (VAP). Methods: Patients who received compassionate use of cefiderocol to treat documented XDR-AB infections at the intensive care unit of the IRCCS Azienda Ospedaliero–Universitaria of Bologna and who underwent therapeutic drug monitoring (TDM) from 15 March 2021 to 30 April 2021 were retrospectively assessed. Cefiderocol trough concentration (Cmin) was determined at steady-state, and the free fraction (fCmin) was calculated according to a plasma protein binding of 58%. The fCmin/MIC ratio was selected as a pharmacodynamic parameter of cefiderocol efficacy and was defined as optimal if ≥4, quasi-optimal if between 1 and 4, and suboptimal if

STUDY OBJECTIVES This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. DESIGN Prospective pharmacokinetics study. SETTING The intensive care unit in a tertiary-care medical center. PATIENTS A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. METHODS Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.

Patient ethnicity may influence the pharmacokinetics (PK) of tacrolimus. Because the Canadian First Nations (FN) constitute a large and increasing segment of the liver transplant population, we undertook to determine whether PK differences exist for a once-daily, extended release formulation of tacrolimus (Advagraf) in FN compared to Caucasian (CAUC) liver transplant recipients. Following achievement of a steady state with Advagraf, blood samples were drawn at 0, 1, 2, 4, 6, 8 and 24 hours for whole blood tacrolimus levels by commercial immunoassay and CYP3A4 and CYP3A5 allele analyses were performed by polymerase chain reactions. Nineteen subjects participated in the study (7 FN and 12 CAUC). The FN cohort had significantly higher AUC (214 ± 48 versus 168 ± 25, P

AIMS Data regarding clinical pharmacokinetic/toxicodynamic (PK/TD) of polymyxin B is short of direct quantitative data. This study aims to investigate the risk factors of polymyxin B associated acute kidney injury (AKI) and to assess the relationship between polymyxin B plasma levels and its nephrotoxicity. METHODS A retrospective study was performed in adult patients treated with polymyxin B. Risk factors associated with AKI and plasma trough concentrations of polymyxin B were identified via medical record review. A multivariate logistic regression model was established and the risk of polymyxin B-associated AKI were predicted by a receiver operating characteristic curve, with maximal Youden index used to identify safety thresholds among the study population. RESULTS Fifty-four adult patients were included in the study. AKI was detected in 14 patients during polymyxin B treatment (25.9%, 14 out of 54). Cmin (odds ratio [OR] 2.071; 95% confidence interval [CI] 1.235-3.472) and baseline serum creatinine (OR 1.024; 95% CI 1.005-1.043) were significant independent risk factors for developing AKI. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was at maximum, the optimal cut-off point was 6.678 of the ROC curve. When Cmin ≥ 3.13 mg/L, the probability of AKI was more than 50%. CONCLUSION In this study, when the calculated combined predictor value was >6.678, there was an increased risk of AKI. Maintaining a polymyxin B Cmin level below 3.13 mg/L may be helpful in reducing the incidence of polymyxin B associated nephrotoxicity.

Investigations of carbon dynamics of Eucalyptus and Phragmites feedstock’s made biochar amendments require laboratory soil incubations that provide controlled conditions. The aim was to evaluate the effects of two different biochar amendments on carbon mineralization potential of two different soils. Biochars were produced at 550 °C from the Eucalyptus and Phragmites feedstock materials and at 0, 10, 20, and 40 t ha−1 of doses were mixed with silty loam texture Balcali and clay texture, Kiziltapir soils. The soil + biochar amendments were incubated under constant temperature (28 °C) and moisture (80% of soil field capacity) conditions for 48 days. In both treatments, the biochar doses significantly increased CO2 emission After 48 days, both biochars increased cumulative carbon mineralization (Cmin) by more than 20% in Balcali soil (P

The excessive prescription of benzodiazepines is putting more people at risk of dependence on these drugs and is exacerbating the fatal overdose toll of opioids. A rapid and sensitive SERS method has been developed for trace detection of select benzodiazepines in low-dosage suspect counterfeit tablets, capsules, and injectable solutions using two different portable handheld Raman spectrometers equipped with either a 785-nm laser or a 1064-nm laser. A total of 169 samples and blanks were examined using five handheld Raman spectrometers, which provided data set of 729 examinations. The extraction/SERS procedures yielded true positive rates above 90% for alprazolam, diazepam, and midazolam using the 1064-nm device and yielded true positive rates above 95% for alprazolam, clonazepam, diazepam, estazolam, midazolam, and temazepam using the 785-nm device; however, the extraction/SERS procedures yielded true positive rates below 60% for lorazepam and triazolam. The minimum concentration (Cmin ) of the benzodiazepine standards that reproducibly yielded a positive match ranged from 1 to 10 μg/ml using the 1064-nm laser device and from 0.5 to 50 μg/ml using the 785-nm laser device. For the analysis of authentic and suspect counterfeit tablets containing these benzodiazepines, the measured Cmin ranged between 10 and 15 µg per tablet or capsule for 1064-nm laser device and 1-100 µg per tablet or capsule for 785-nm laser device. The developed methods are simple, rapid, and ideal for screening suspect benzodiazepine-containing pharmaceutical products at satellite laboratories located within or near international mail facilities and express courier hubs.

Remdesivir is one of the most encouraging treatments against SARS‐CoV‐2 infection. After intravenous infusion, RDV is rapidly metabolized (T1/2 1h) within the cells to its active adenosine triphosphate analogue form (GS‐443902) and, then, it can be found in plasma in its nucleoside analogue form (GS‐441524). In this real life study we describe the Remdesivir and GS‐441524 concentrations at 3 time points in nine ICU patients, through a validated UHPLC‐MS/MS method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half‐life of GS‐441524. The mean C min, C max, AUC0–24, were < 0.24 ng/mL and 122.3 ng/ml, 2637,3 ng/mL and 157,8 ng/ml, 5171.2 ng*h/mL and 3676.5 ng*h/ml respectively for RDV and GS‐441524. Three out of nine patients achieved a C max> 2610 ng/mL and 140 ng/mL and AUC0–24 > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS‐441524, respectively. The mean T1/2 value for GS‐441524 was 26.3 h. Although the low number of patients, these data can represent an interesting preliminary report of the variability of RDV and GS‐441524 concentrations in real‐life ICU setting.

The pharmacokinetics of enflicoxib were evaluated in both a bioavailability study and a multi-dose safety study in Beagle dogs. When administered at 8 mg/kg, the oral bioavailability (F) of enflicoxib was 44.1% in fasted dogs, but F increased to 63.4% under post prandial conditions. Enflicoxib is rapidly metabolised. After the first 48 h, the plasma levels of its pyrazol metabolite were much higher and persistent than those of the parent compound. Following intravenous administration, the total body plasma clearance of enflicoxib was of 140 ml/h/kg and the volume of distribution based on the terminal phase was 4 L/kg. Plasma protein binding for both compounds was approximately 99%. The blood to plasma ratio for the pyrazol metabolite showed saturable kinetics with higher blood cell affinity at lower total blood concentrations which ranged from 2.49 to 0.95 for concentrations from 1 to 15 µg/ml. Enflicoxib and its pyrazol metabolite exhibited dose-proportional pharmacokinetics for single oral doses of 8-40 mg⁄kg and for multiple oral doses of 4-20 mg⁄kg. After 7 months of repeated weekly administrations, pre-dose plasma concentrations (Cmin,ss ) remained constant throughout the study, with no trend to any significant over-accumulation. The mean terminal elimination half-life (t½ ) was 20 h for enflicoxib and 17 days for the pyrazol metabolite. The pharmacokinetic profile of enflicoxib and its pyrazol metabolite in dogs supports the proposed dosing regimen in which doses are separated by 1 week.

BACKGROUND Voriconazole primary metabolism is catalysed by CYP2C19. A large variability of trough concentrations in patients with invasive fungal infection treated with voriconazole has been observed in clinical practice. It remains controversial whether the CYP2C19 polymorphisms are responsible for voriconazole metabolism in the individual variation. OBJECTIVES The primary aim of this study was to assess the effect of CYP2C19 polymorphisms on voriconazole trough concentrations. METHODS Following a systematic literature review, we performed a meta-analysis for mean differences (MD) of voriconazole trough concentrations (Cmin ), voriconazole dosage adjusted trough concentrations (Cmin /D) and for risk ratio (RR) of the proportion of patients in the target therapeutic range between pairwise comparisons of CYP2C19 phenotypes. RESULTS Compared with normal metabolisers (NMs), intermediate metabolisers (IMs) (MD: 0.82, 95% CI: 0.57 to 1.07, I2 = 44%, p

It is shown that there are two basic types of design of roller leveling machines (RLM) according to the principle of adjustment of the gap between the rollers, namely, with parallel and inclined arrangement of the rollers. We present the dependences for the numerical analyses of the curvature of reverse bend and the adjustment gap for the RLM both with horizontal and inclined positions of the rollers. It is demonstrated that, in the case of straightening performed in an RLM with horizontal arrangement of the rollers, the gap decreases from 38.8 to 7.8 mm as the thickness of the sheet made of 10KhSND steel decreases from 40 to 12 mm. For the sheet made of 10G2S1D steel, it decreases from 38.6 to 7.2 mm and for the sheet made of 14Kh2GMR steel from 38.6 to 6.2 mm. In the case of straightening carried out in an RLM with inclined arrangement of the rollers for a sheet made of 10KhSND steel with a thickness of 20 mm, the minimal gap constitutes Cmin = 19.6 mm, while the maximal gap Cmax = 20.0 mm. Moreover, for 10G2S1D steel, we get Cmin = 19.5 mm and Cmax = 20.0 mm. Finally, for 12G2MFT steel, we find Cmin = 19.3 mm and Cmax = 19.9 mm. We performed the experimental straightening of sheets of 10 steel 16 mm in thickness and 2400 mm in width on a seven-roller RLM (produced by Severstal’). The comparison of the experimental value of gap Cexp = 13.1 with its theoretical value Ccalc = 12.8 mm shows that difference between these values is equal to 4.5%.

Background Barriers to lifelong HIV-1 suppression by antiretrovirals include poor adherence and drug resistance; regimens with higher tolerance to missed doses (forgiveness) would be beneficial to patients. To model short term non-adherence, in vitro experiments monitoring viral breakthrough (VB) and resistance development were conducted. Methods HIV breakthrough experiments simulated drug exposures at full adherence or suboptimal adherence to bictegravir+emtricitabine+tenofovir alafenamide (BIC+FTC+TAF) or dolutegravir+lamivudine (DTG+3TC). MT-2 cells were infected with wild-type or low frequency M184V HIV-1, exposed to drug combinations, monitored for VB, and rebound virus was deep sequenced. Drug concentrations were determined using human plasma-free adjusted clinical trough concentrations (Cmin), at simulated Cmin after missing 1 to 3 consecutive doses (Cmin-1, Cmin-2, and Cmin-3) based on drug or active metabolite half-lives. Results Cultures infected with wild-type or low frequency M184V HIV-1 showed no viral breakthrough with BIC+FTC+TAF at drug concentrations corresponding to Cmin, Cmin-1, or Cmin-2 but breakthrough did occur in 26/36 cultures at Cmin-3 where the M184V variant emerged in one culture only. Experiments using DTG+3TC prevented most breakthroughat Cmin concentrations (9/60 had breakthrough) but showed more breakthroughs as drug concentrations decreased (up to 36/36) and variants associated with resistance to both drugs emerged in some cases. Conclusions These in vitro viral breakthrough results suggest that the high potency, long half-lives, and antiviral synergy provided by the BIC/FTC/TAF triple therapy regimen may protect from viral rebound and resistance development after short term lapses in drug adherence.

Background Despite high HIV co-infection prevalence in Ethiopian visceral leishmaniasis (VL) patients, the adequacy of antileishmanial drug exposure in this population and effect of HIV-VL co-morbidity on pharmacokinetics of antileishmanial and antiretroviral (ARV) drugs is still unknown. Methods HIV-VL co-infected patients received the recommended liposomal amphotericin B (LAmB) monotherapy (total dose 40 mg/kg over 24 days) or combination therapy of LAmB (total dose 30 mg/kg over 11 days) plus 28 days 100 mg/day miltefosine, with possibility to extend treatment for another cycle. Miltefosine, total amphotericin B and ARV concentrations were determined in dried blood spots or plasma using LC–MS/MS. Results Median (IQR) amphotericin B Cmax on Day 1 was 24.6 μg/mL (17.0–34.9 μg/mL), which increased to 40.9 (25.4–53.1) and 33.2 (29.0–46.6) μg/mL on the last day of combination and monotherapy, respectively. Day 28 miltefosine concentration was 18.7 (15.4–22.5) μg/mL. Miltefosine exposure correlated with amphotericin B accumulation. ARV concentrations were generally stable during antileishmanial treatment, although efavirenz Cmin was below the 1 μg/mL therapeutic target for many patients. Conclusions This study demonstrates that antileishmanial drug exposure was low in this cohort of HIV co-infected VL patients. Amphotericin B Cmax was 2-fold lower than previously observed in non-VL patients. Miltefosine exposure in HIV-VL co-infected patients was 35% lower compared with adult VL patients in Eastern Africa, only partially explained by a 19% lower dose, possibly warranting a dose adjustment. Adequate drug exposure in these HIV-VL co-infected patients is especially important given the high proportion of relapses.

Background While aminoglycosides (AG) have been used for decades, debate remains on their optimal dosing strategy. We investigated the international practices of AG usage specifically regarding dosing and therapeutic drug monitoring (TDM) in critically ill patients. We conducted a prospective, multicentre, observational, cohort study in 59 intensive-care units (ICUs) in 5 countries enrolling all ICU patients receiving AG therapy for septic shock. Results We enrolled 931 septic ICU patients [mean ± standard deviation, age 63 ± 15 years, female 364 (39%), median (IQR) SAPS II 51 (38–65)] receiving AG as part of empirical (761, 84%) or directed (147, 16%) therapy. The AG used was amikacin in 614 (66%), gentamicin in 303 (33%), and tobramycin in 14 (1%) patients. The median (IQR) duration of therapy was 2 (1–3) days, the number of doses was 2 (1–2), the median dose was 25 ± 6, 6 ± 2, and 6 ± 2 mg/kg for amikacin, gentamicin, and tobramycin respectively, and the median dosing interval was 26 (23.5–43.5) h. TDM of Cmax and Cmin was performed in 437 (47%) and 501 (57%) patients, respectively, after the first dose with 295 (68%) patients achieving a Cmax/MIC > 8 and 353 (71%) having concentrations above Cmin recommended thresholds. The ICU mortality rate was 27% with multivariable analysis showing no correlation between AG dosing or pharmacokinetic/pharmacodynamic target attainment and clinical outcomes. Conclusion Short courses of high AG doses are mainly used in ICU patients with septic shock, although wide variability in AG usage is reported. We could show no correlation between PK/PD target attainment and clinical outcome. Efforts to optimize the first AG dose remain necessary. Trial registration Clinical Trials, NCT02850029, registered on 29th July 2016, retrospectively registered, https://www.clinicaltrials.gov

The inhibitor of anaplastic lymphoma kinase (ALK) crizotinib significantly increases survival in patients with ALK-positive non-small cell lung cancer (NSCLC). When evaluating crizotinib pharmacokinetics (PKs) in patients taking the standard flat oral dose of 250 mg b.i.d., interindividual PK variability is substantial and patient survival is lower in the quartile with the lowest steady-state trough plasma concentrations (Cmin,ss ), suggesting that concentrations should be monitored and doses individualized. We investigated whether the CYP3A inhibitor cobicistat increases Cmin,ss of the CYP3A substrate crizotinib in patients with low exposure. Patients with ALK-positive NSCLC of our outpatient clinic treated with crizotinib were enrolled in a phase I trial (EudraCT 2016-002187-14, DRKS00012360) if crizotinib Cmin,ss was below 310 ng/mL and treated with cobicistat for 14 days. Crizotinib plasma concentration profiles were established before and after a 14-day co-administration of cobicistat to construct the area under the plasma concentration-time curve in the dosing interval from zero to 12 hours (AUC0-12 ). Patients were also monitored for adverse events by physical examination, laboratory tests, and 12-lead echocardiogram. Enrolment was prematurely stopped because of the approval of alectinib, a next-generation ALK-inhibitor with superior efficacy. In the only patient enrolled, cobicistat increased Cmin,ss from 158 ng/mL (before cobicistat) to 308 ng/mL (day 8) and 417 ng/mL (day 14 on cobicistat), concurrently the AUC0-12 increased by 78% from 2,210 ng/mL*h to 3,925 ng/mL*h. Neither safety signals nor serious adverse events occurred. Pharmacoenhancement with cobicistat as an alternative for dose individualisation for patients with NSCLC with low crizotinib exposure appears to be safe and is cost-effective and feasible.

Background: Mylan trastuzumab (MYL-1401O) is a biosimilar to trastuzumab (Herceptin®). A multicenter, double blind, randomized, phase III study (HERITAGE) compared the efficacy, safety, Pop PK and immunogenicity of MYL-1401O and trastuzumab in patients with HER2-positive mBC. Patients were randomized 1:1 to receive either MYL-1401O or Herceptin®, in combination with taxane Q3W for 24 weeks followed by monotherapy until unacceptable toxicity, disease progression or early discontinuation.Objectives: The objectives of the Pop PK analysis were to compare the Pop PK derived AUC, Cmax, clearance, Vd, and T1/2 profiles of MYL1401O and Herceptin® and to perform an exploratory assessment of the impact of shed extracellular domain (ECD) fragments of the HER2 receptor (HER2/ ECD) on PK parameters.Methods: One end of infusion PK sample was collected at Cycle 1 and Cycle 6, and 1 trough sample per cycle from all patients; additional samples were taken in a Pop PK subset (MYL-1401O: 45; Herceptin®: 37) in the first dosing interval and at subsequent times. Pop PK modeling was performed using NONMEM. Individual patient empiric Bayesian parameter estimates were used to estimate PK measures. The impact of HER2/ECD presence on PK levels was evaluated in the primary covariate analysis. Results: Two hundred forty-five (245) patients in the PK population received MYL-1401O, while 240 received Herceptin® of which 482 were included in the base model Pop PK analysis. 3170 concentration records with sufficient information were included in the Pop PK analysis. There were no notable demographic differences between the treatment groups. Bayesian parameter based exposure estimates at or near steady-state dosing were comparable between treatments, confirming similar PK (Table 1). Treatment was not a significant covariate of clearance (p=0.177) or volume of the central compartment (p=0.584) using the likelihood ratio Chi-square test.The test-to reference mean ratios of Cmin for Cycle 1 and Cycle 6 (end of cycle) were 103.11(90% CI = 90.61, 117.33) and 104.16 (90% CI = 94.00, 115.42), respectively.The HER2/ECD concentrations were a significant covariate of trastuzumab clearance. Conclusion: Pop PK profiles of MYL-1401O vs. Herceptin® were similar in patients with HER2positive mBC. Model-based exposure measures were similar between treatments. HER2/ECD concentrations were a strong determinant of trastuzumab clearance, and clearance was similar between treatments. The observed trough concentrations were similar between treatments at the end of Cycle 1 and at Cycle 6.Clinical trial identification: EudraCT Number: 2011-001965-42Legal entity responsible for the study: Mylan GmbHFunding: Mylan GmbH Table 1:Bayesian Parameter Based Exposure Estimates at Cycle 6MYL-1401O (N=245)Herceptin®(N=240)Total(N=485)Parametern*213202415Dose (mg)Mean (SD)420.70 (90.46)421.25 (97.67)420.97 (93.92)Clearance (L/day)0.27 (0.10)0.28 (0.08)0.27 (0.09)Volume of Central Compartment (L)3.16 (0.60)3.20 (0.60)3.18 (0.60)Volume at Steady State (L)6.36 (1.19)6.32 (1.14)6.34 (1.16)AUC (ug*day/mL)40501.40 (13037.04)38816.90 (11966.26)39681.40 (12540.58)Dose-normalized AUC (ug*day/mL/mg)98.50 (30.56)94.41 (28.90)96.51 (29.80)Cmax,ss (ug/mL)177.00 (37.76)171.52 (34.61)174.33 (36.32)Dose-normalized Cmax,ss (ug/mL/mg)0.43 (0.10)0.42 (0.09)0.43 (0.10)Half-life (day)Median (SD)25.12 (7.50)24.34 (6.89)24.74 (7.21)*concentrations below lower limit of quantification and samples before first dose with values >zero were excluded from Pop PK analysis, as were some patients with incomplete information for covariates significant in the final model. Citation Format: Joel Owen, Russell Rackley, Mark Liu, Adolfo Fuentes-Alburo, Tazeen Idris, Subramanian Loganathan, Abhijit Barve, Cornelius F. Waller, Hope S. Rugo. Population pharmacokinetics (Pop PK) of MYL-1401O (a trastuzumab biosimilar) and reference trastuzumab (Herceptin®) in patients with HER2-positive metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-23.

Objectives Abiraterone acetate is registered for the treatment of metastatic castration-sensitive and resistant prostate cancer (mCRPC). Treatment outcome is associated with plasma trough concentrations (Cmin) of abiraterone. Patients with a plasma Cmin below the target of 8.4 ng/mL may benefit from treatment optimization by dose increase or concomitant intake with food. This study aims to investigate the cost-effectiveness of monitoring abiraterone Cmin in patients with mCRPC. Methods A Markov model was built with health states progression-free survival, progressed disease, and death. The benefits of monitoring abiraterone Cmin followed by a dose increase or food intervention were modeled via a difference in the percentage of patients achieving adequate Cmin taking a healthcare payer perspective. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainties and their impac to the incremental cost-effectiveness ratio (ICER). Results Monitoring abiraterone followed by a dose increase resulted in 0.149 incremental quality-adjusted life-years (QALYs) with €22 145 incremental costs and an ICER of €177 821/QALY. The food intervention assumed equal effects and estimated incremental costs of €7599, resulting in an ICER of €61 019/QALY. The likelihoods of therapeutic drug monitoring (TDM) with a dose increase or food intervention being cost-effective were 8.04%and 81.9%, respectively. Conclusions Monitoring abiraterone followed by a dose increase is not cost-effective in patients with mCRPC from a healthcare payer perspective. Monitoring in combination with a food intervention is likely to be cost-effective. This cost-effectiveness assessment may assist decision making in future integration of abiraterone TDM followed by a food intervention into standard abiraterone acetate treatment practices of mCRPC patients.

Diabetes mellitus is a global health problem causing premature death and economic burden. The study aimed to investigate an application of the protection motivation theory (PMT) model to explain the intention of healthy eating behaviors and physical activity among healthy Thais.This study was a part of a large case control focused only on the control group without noncommunicable diseases. Nine hundred ninety-seven subjects were drawn from eleven provinces of Thailand. A self-administered questionnaire was constructed based on the PMT model to gather information on predictive factors on eating behaviors and physical activity. Path analysis was used to determine whether the empirical data fit the PMT structure as well as to assess the strength of association among PMT constructed factors predicting behavioral intention.The findings demonstrated that empirical data of eating behaviors (CMIN χ2 p-value = 0.462; CMIN/df = 0.901; NFI = 0.997; CFI = 1; RMSEA0.001) and physical activity (CMIN χ2 p-value = 0.053; CMIN/df = 2.187; NFI = 0.987; CFI = 0.993; RMSEA = 0.035) fit the PMT. The strongest predictive factor of behavioral intention on eating behaviors was response efficacy (β = 0.146), while self-efficacy was found to be the strongest factor for physical activity (β = 0.11). Knowledge had the only indirect effect on behavior intention through perceived susceptibility and perceived severity.In conclusion, information on susceptibility and severity should be incorporated in intervention strategies to enhance response efficacy and self-efficacy to prevent diabetes.

Background To mitigate increased risk of premature cardiovascular disease in antiretroviral therapy (ART) suppressed adults living with HIV (PWH), low-dose methotrexate (LDMTX) was evaluated in a multicenter randomized placebo controlled clinical trial of 176 PWH taking various ART regimens (ACTG A5314). Given shared methotrexate (MTX) and tenofovir (TFV) pharmacokinetic (PK) pathways, a substudy was conducted to investigate whether LDMTX alters TFV exposure. Methods Adults virally suppressed on ART for >24 weeks were randomized to LDMTX or placebo. The first 66 participants taking a tenofovir disoproxil fumarate-containing regimen underwent intensive PK sampling over 24 hours after the second dose of LDMTX 10 mg or placebo. TFV and MTX levels were quantified using validated mass spectrometry methods. TFV PK between LDMTX and placebo groups were compared and MTX PK was characterized. Results Forty-eight participants completed this substudy (n = 20 on LDMTX and 28 on placebo). Baseline characteristics were balanced except for protease inhibitor (PI)-use (25% in LDMTX and 43% in placebo groups). For TFV, AUC6 (primary endpoint), and AUC24,imputed, Cmax, and Cmin (secondary endpoints) were on average 22%, and 24%, 27%, and 31% less in the LDMTX versus placebo groups, with reductions in secondary endpoints reaching statistical significance. Additional analyses suggested a greater reduction in the absence of PI although not significant. Conclusion Lower TFV AUC24,imputed and Cmax indicates that LDMTX reduces TFV exposure in PWH. However, this change was modest, not warranting a change in TFV dosing at this time. Further studies of TFV PK with LDMTX, especially without PI co-administration, are warranted.

AIMS Cytochrome 2C19 genotype-directed dosing of voriconazole (VRC) reduces the incidence of insufficient VRC trough concentrations (Cmin ) but does not account for CYP3A polymorphisms, also involved in VRC metabolism. This prospective observational study aimed to evaluate the utility of a genetic score combining CYP2C19 and CYP3A genotypes to predict insufficient initial VRC Cmin (

The root assessments and nutrient uptake kinetics parameters, i.e. Vmax, Km and Cmin, are useful to characterize the efficiency of nutrients uptake, but it is generally studied for a unique nutrien...

We study and optimize the conditions for the cloud-point extraction (CPE) preconcentration of Cu(II) in the form of its complex with 6,7-dihydroxy-4-methyl-2-phenylbenzopyrylium chloride in the micellar phase of the nonionic surfactant Triton X-100. The introduction of ammonium benzoate into the system until a pH of 4.5 is reached at a Triton X-100 concentration of 0.4 vol % leads to the initiation of the formation of a micellar phase at room temperature. We develop a procedure for the atomic absorption determination of Cu(II) after its CPE preconcentration. The calibration dependence is linear in the concentration range of 5.0 to 213 μg/L, and the detection (cmin) and determination (clim) limits are, respectively, 1.5 and 5.0 μg/L. The proposed procedure is tested in the analysis of natural and drinking waters, and the relative standard deviation (RSD) does not exceed 4%.

Halei M., Dzubanovskyi I., Marchuk I. Analysis of visualization index using technique of simultaneous laparoscopic operations. Journal of Education, Health and Sport. 2020;10(10):174-182. eISSN 2391-8306. DOI http://dx.doi.org/10.12775/JEHS.2020.10.10.015 https://apcz.umk.pl/czasopisma/index.php/JEHS/article/view/JEHS.2020.10.10.015 https://zenodo.org/record/4265125 The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019. © The Authors 2020; This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 12.10.2020. Revised: 16.10.2020. Accepted: 30.10.2020. Analysis of visualization index using technique of simultaneous laparoscopic operations M. Halei1, I. Dzubanovskyi 2, I. Marchuk2 1Department of Surgery by Educational and Scientific Institute of Postgraduate Education, I. Horbachevsky Ternopil National Medical University, Ternopil 2Volyn Regional Clinical Hospital, Lutsk Abstract Fatigue is a temporary decrease in the efficiency of an organism or organ due to intensive or long-term work, which is manifested in a decrease in quantitative and qualitative indicators of work and deterioration of coordination of work functions. Groups of simultaneous operations (411 patients) and group of single operations (746 patients) were formed. In both groups these changes were insignificant in most cases (except for marginal values in obese patients III, there were 6 such cases in the first group and 8 in the second), corrections of the port administration scheme were performed when performing vertical gastrectomy in both groups. After the calculation, the average deviations were 1.2 cm in the first group and 1.4 cm in the second. When using a laparoscope with a viewing angle of 0 o, the approach distance of the laparoscope with its own method of access on average during normal surgery is (6.92 ± 0.306) cm and is slightly smaller than standard methods, the average value of the studied parameter in the control group is - (6.98 ± 0.258) cm (p Key words: visualization; laparoscopy; simultaneous; surgery

OBJECTIVE The aim of this study was to analyze the pharmacokinetics/pharmacodynamics (PK/PD) of higher-dose tigecycline (100 mg q12h) in severely infected intensive care unit (ICU) patients receiving continuous renal replacement therapy (CRRT). MATERIALS AND METHODS In this prospective single-center observational study, severely infected patients receiving intravenous tigecycline were enrolled. They were divided into a CRRT group (7 cases) and a non-CRRT group (9 cases). The blood samples and CRRT ultrafiltrate were collected. The drug concentration in each sample was determined by a HPLC-UV method. The pharmacokinetic parameters were simulated and calculated with DAS 2.0. The PK/PD parameters were evaluated according to published data. The registration number of this study is NCT02931526 in ClinicalTrials.gov. RESULTS In the non-CRRT group, Cmax, Cmin, and AUC0-24 were 1.00 ± 0.66 µg×mL-1, 0.20 ± 0.12 µg×mL-1, and 22.12 ± 14.46 µg×h×mL-1, respectively. The clinical efficiency was 55.6%, and the bacterial clearance rate was 77.8%. In the CRRT group, Cmax, Cmin, and AUC0-24 were 0.96 ± 0.31 µg×mL-1, 0.22 ± 0.12 µg×mL-1, and 19.90 ± 8.14 µg×h×mL-1, respectively. The clinical efficiency was 28.6%, and the bacterial clearance rate was 28.6%. The individual differences of tigecycline plasma concentrations in our study were widely variable, and the differences of the two groups' PK/PD parameters had no statistical significance (p

Introduction Vulvar and vaginal atrophy (VVA) affects up to two thirds of postmenopausal women, with symptoms of vaginal dryness, dyspareunia, and vulvar/vaginal irritation. Despite the availability of various treatments, women express dissatisfaction with their options. An estradiol (E2; 4-µg and 10-µg) softgel vaginal insert was approved by the Food and Drug Administration (FDA) to treat moderate to severe dyspareunia, a symptom of VVA, due to menopause. These inserts were designed to treat VVA effectively and safely while avoiding some of the drawbacks of other administration methods. Areas covered This article reviews the physical characteristics and pharmacokinetic data of the E2 softgel vaginal insert. Primary and secondary efficacy endpoints and safety data are reviewed from the pivotal REJOICE trial (NCT02253173), and substudies that explore response rates, changes in vaginal epithelium by visual assessment, efficacy in patient subgroups, effects on sexual function, and patient satisfaction compared with other treatments. Expert opinion The E2 insert shows that vaginal drug delivery is an optimal route of administration for locally treating VVA. This E2 softgel vaginal insert is a safe and effective treatment for symptoms of postmenopausal VVA. The E2 insert's pharmacokinetic characteristics are related to its unique formulation, rapid dissolution, and minimal systemic absorption. Abbreviations AE: adverse event; AUC: area under the concentration-time curve; BMI: body mass index; Cavg: average concentration; CI: confidence interval; Cmax: maximum concentration; Cmin: minimum concentration; E2: estradiol; FDA: Food and Drug Administration; FSFI: Female Sexual Function Index; GSM: genitourinary symptoms of menopause: MBS: most bothersome symptom; NAMS: North American Menopause Society; OR: odds ratio; PI: pulsatility index; PK: pharmacokinetic; REVIVE: Real Women's Views of treatment options for menopausal Vaginal changEs; RI: resistance index; ROC: receiver operating characteristic; TEAE: treatment-emergent adverse event; tmax: time to maximum concentration; VVA: vulvar and vaginal atrophy.

Purpose We conducted exposure-response modeling and simulations to compare the predicted efficacy of extended-release oxcarbazepine (OXC-XR), an oral once-daily (qd) antiepileptic drug, with that of immediate-release (IR) OXC twice-daily (bid) when the agents are used as monotherapy or adjunctive therapy in patients with epilepsy characterized by partial-onset seizures (POS). Methods Modeling assessed percent change from baseline 28-day seizure frequency (PCH) as a function of minimum concentration (Cmin) of monohydroxy derivative (MHD), the clinically relevant metabolite of OXC. For OXC-IR, the model used historical data; values for OXC-XR were derived from observed data. The model was simulated (N=100) to predict PCH at MHD Cmin concentrations achieved with 1200 and 2400 mg/day in adults and children receiving OXC-XR qd or OXC-IR bid. Mean PCH and 95% confidence intervals (CIs) were generated and compared. Results Predicted efficacy was not different (ie, 95% CI of mean PCH overlapped) for OXC-XR qd vs OXC-IR bid at mean MHD Cmin concentrations achieved with 1200 and 2400 mg/day adjunctive OXC-XR (47.4 and 76.4 µmol/L) and at target MHD Cmin concentrations for OXC-IR monotherapy (59.1 and 112 µmol/L) in adults. Predicted efficacy in adults vs children was not different between formulations. Depending on MHD Cmin, the predicted mean PCH in adults ranged from -51.4% to -73.4% with OXC-XR qd and -53.2% to -78.5% with OXC-IR bid. In children, the predicted mean PCH ranged from -48.4% to -58.1% (OXC-XR qd) and -32.5% to -70.4% (OXC-IR bid). Conclusion This model-based analysis predicted comparable efficacy for OXC-XR qd vs OXC-IR bid at MHD Cmin concentrations corresponding to 1200 and 2400 mg/day as monotherapy or adjunctive therapy. Based on this analysis, the US Food & Drug Administration approved OXC-XR for use as monotherapy in adults and children ≥6 years of age with POS.

Purpose The updated World Health Organization guidelines recommend efavirenz (EFV) 400 mg as the preferred alternate first-line antiretroviral therapy to dolutegravir, with EFV 600 mg recommended only in special situations. We examined the pharmacokinetic (PK) properties of EFV 600 mg/d during pregnancy and post partum to inform EFV dosing decisions in pregnant women. Methods Ghanaian pregnant women with HIV infection initiating tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg/EFV 600 mg fixed-dose combination tablet once daily were enrolled. Efavirenz concentrations were measured at 4 weeks of antiretroviral therapy initiation during pregnancy and 6 weeks post partum using validated LC-MS/MS assays. Efavirenz PK parameters were calculated using noncompartmental analysis, and within-group parameters between the 2 periods were compared. Findings Of 25 enrolled women, 19 completed PK sampling during pregnancy and post partum. The Cmax, Cmin, AUC0–24h, and CL/F for EFV during pregnancy were similar to values at 6 weeks post partum. The pregnancy/postpartum geometric mean ratios for EFV Cmax, Cmin, AUC0–24, and CL/F were 1.10 (95% CI, 0.93–1.31), 0.88 (95% CI, 0.67–1.17), 0.84 (95% CI, 0.71–0.98), and 1.20 (95% CI, 1.02–1.40), respectively. Viral load suppression (HIV RNA Implications We found that the PK parameters of EFV 600 mg once daily during pregnancy were similar to those in the postpartum period. Our findings suggest that EFV dose adjustment during pregnancy is not necessary in our study population.

Crizotinib and alectinib are anaplastic lymphoma kinase (ALK)-inhibitors indicated for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). At the currently used fixed doses, interindividual variability in exposure is high. The aim of this study was to investigate whether minimum plasma concentrations (Cmin ) of crizotinib and alectinib are related to efficacy and toxicity. An observational study was performed, in which ALK-positive NSCLC patients who were treated with crizotinib and alectinib and from whom pharmacokinetic samples were collected in routine care, were included in the study. Exposure-response analyses were explored using previously proposed Cmin thresholds of 235 ng/mL for crizotinib and 435 ng/mL for alectinib. Forty-eight crizotinib and 52 alectinib patients were included. For crizotinib, median progression-free survival (mPFS) was 5.7 vs. 17.4 months for patients with Cmin

Background For oral anticancer drugs, trough concentration (Cmin) is usually used as a target in therapeutic drug monitoring (TDM). Recording of Cmin is highly challenging in outpatients, in whom there is typically a variability in sample collection time after dosing. Various methods are used to estimate Cmin from the collected samples. This simulation study aimed to evaluate the performance of 3 different methods in estimating the Cmin of 4 oral anticancer drugs for which TDM is regularly performed. Methods Plasma concentrations of abiraterone, dabrafenib, imatinib, and pazopanib at a random time (Ct,sim) and at the end of the dosing interval (Cmin,sim) were simulated from population pharmacokinetic models including 1000 patients, and the values were converted into simulated observed concentrations (Ct,sim,obs and Cmin,sim,obs) by adding a residual error. From Ct, sim,obs, Cmin was predicted (Cmin,pred) by the Bayesian estimation (method 1), taking the ratio of the Ct,sim,obs and typical population concentration and multiplying this ratio with the typical population value of Cmin,sim (method 2), and log-linear extrapolation (method 3). Target attainment was assessed by comparing Cmin,pred with the proposed pharmacokinetic targets related to efficacy and calculating the positive predictive and negative predictive values. Results The mean relative prediction error and root mean squared relative prediction error results showed that method 3 was out-performed by method 1 and 2. Target attainment was adequately predicted by all 3 methods (the respective positive predictive value of method 1, 2, and 3 was 92.1%, 92.5%, and 93.1% for abiraterone; 87.3%, 86.9%, and 99.1% for dabrafenib; 79.3%, 79.3%, and 75.9% for imatinib; and 72.5%, 73.5%, and 67.6% for pazopanib), indicating that dose adjustments were correctly predicted. Conclusions Both method 1 and 2 provided accurate and precise individual Cmin,pred values. However, method 2 was easier to implement than method 1 to guide individual dose adjustments in TDM programs.

OBJECTIVES: Taking advantage of its food-dependent bioavailability, the present study investigated the effect of a reduced dose taken with real-life meals on the pharmacokinetics (PK) of nilotinib in chronic myeloid leukaemia (CML) patients.METHODS: Nilotinib was taken fasted (300 mg BID, days 1-4) or with real-life meals (200 mg BID, days 5-11). Rich sampling (days 1, 3, 8, 11) allowed for non-compartmental PK analysis. Nilotinib exposure (AUC0-12 h -Cmin -Cmax ) and its intra- and interpatient variability were compared between the two regimens. Adverse events were recorded by means of a patient diary and ECG monitoring.RESULTS: Fifteen patients aged 40-74 years participated. Nilotinib PK following 200 mg BID taken with a meal strongly resembled that of 300 mg BID taken fasted (Cmin percentile (P)10-P90: 665-1404 ng/mL and 557-1743 ng/mL, respectively). Meals delayed nilotinib absorption. Intra- and interpatient variability were not increased by intake with meals. Nilotinib with food was well tolerated.CONCLUSION: With support of therapeutic drug monitoring, the use of a reduced 200 mg nilotinib dose with real-life meals seems feasible and safe. Future (confirmatory) studies should further explore the usefulness of nilotinib dosing together with food, including the relationship with treatment efficacy as well as long-term effects on quality of life.CLINICAL TRIAL REGISTRATION: NTR5000 (Netherlands Trial Register, www.trialregister.nl).

Eucalyptus clones are selected according to productivity, wood quality, rooting capacity, and resistance to drought, frost and diseases. However, kinetic and morphological parameters that determine the absorption efficiency of nutrients such as nitrate (NO3−) and ammonium (NH4+) are often not considered in breeding programs. The objective of this study was to evaluate the morphological, physiological and kinetic parameters of nitrogen uptake by clones of Eucalyptus saligna (32,864) and Eucalyptus grandis (GPC 23). Morphological parameters in shoot and root systems, biomass and N concentrations in different organs, photosynthetic pigment concentrations, parameters of chlorophyll a fluorescence and photosynthetic rates were evaluated. Kinetic parameters, maximum absorption velocity (Vmax), Michaelis–Menten constant (Km), minimum concentration (Cmin) and influx (I) were calculated for NO3− and NH4+ in the two clones. E. grandis clone was more efficient in the uptake of NO3− and NH4+, and showed lower Km and Cmin values, allowing for the absorption of nitrogen at low concentrations due to the high affinity of the absorption sites of clone roots to NO3− and NH4+. Higher root lengths, area and volume helped the E. grandis clone in absorption efficiency and consequently, resulted in higher root and shoot biomass. The E. saligna clone had higher Km and Cmin for NO3− and NH4+, indicating adaptation to environments with higher N availability. The results of NO3− and NH4+ kinetic parameters indicate that they can be used in Eucalyptus clone selection and breeding programs as they can predict the ability of clones to absorb NO3− and NH4+ at different concentrations.

Administering β-lactam antibiotics via prolonged infusions for critically ill patients is mainly based on preclinical evidence. Preclinical data on this topic have not been systematically reviewed before. The aim of this study was to describe the pharmacokinetic/pharmacodynamic (PK/PD) indices and targets reported in preclinical models and to compare the bactericidal efficacy of intermittent and prolonged infusions of β-lactam antibiotics. The MEDLINE and EMBASE databases were searched. To compare the bactericidal action of β-lactam antibiotics across different modes of infusion, the reported PK/PD outcomes, expressed as the percentage of time (T) that free (f) β-lactam antibiotic concentrations remain above the minimal inhibitory concentration (MIC) (%fT>MIC) or trough concentration (Cmin)/MIC of individual studies, were recomputed relative to the area under the curve of free drug to MIC ratio (fAUC24/MIC). A linear mixed-effects meta-regression was performed to evaluate the impact of the β-lactam class, initial inoculum, Gram stain, in vivo or in vitro experiment and mode of infusion on the reduction of bacterial cells (in colony-forming units/mL). Overall, 33 articles were included for review, 11 of which were eligible for meta-regression. For maximal bactericidal activity, intermittent experiments reported a PK/PD target of 40–70% fT>MIC, while continuous experiments reported a steady-state concentration to MIC ratio of 4–8. The adjusted effect of a prolonged as opposed to intermittent infusion on bacterial killing was small (coefficient 0.66, 95% confidence interval − 0.78 to 2.11). Intermittent and prolonged infusions of β-lactam antibiotics require different PK/PD targets to obtain the same level of bacterial cell kill. The additional effect of a prolonged infusion for enhancing bacterial killing could not be demonstrated.

What is known and objective Anidulafungin, caspofungin and micafungin are three widely used echinocandin drugs licensed for the treatment of invasive fungal infections, and their clinical use is widespread. To evaluate pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients by comparing the differences in pharmacokinetic parameters between critically ill patients and healthy volunteers or general patients. Methods MEDLINE, EMBASE, The Cochrane Library and Pubmed were searched from inception until 6 September 2018. Studies investigating the pharmacokinetic parameters of echinocandins in critically ill patients, healthy volunteers or general patients were included. Our primary outcomes included AUC0‐24 h, Cmax and Cmin (24 hours). Two reviewers independently reviewed all titles, abstracts and text, and extracted data. We applied R software (R 2017) to conduct meta‐analysis. Results and discussion Of 3235 articles screened, 17 studies were included in the data synthesis. Descriptive data from single‐arm studies show that critically ill patients who received caspofungin had more stable AUC0‐24 h than those who received anidulafungin and micafungin. The Cmax of critically ill patients who received caspofungin and micafungin was similar to healthy volunteers. However, the Cmax in critically ill patients who received anidulafungin was lower than in healthy volunteers. The Cmin and T1/2 of critically ill patients who received caspofungin were larger than in healthy volunteers. The Vd and CL of critically ill patients receiving anidulafungin and micafungin were larger than in healthy volunteers. What is new and conclusion This systematic review provides an analysis of the pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients. Based on the limited data available, caspofungin has less pharmacokinetic/pharmacodynamics variability than anidulafungin and micafungin., This systematic review included 17 studies. Descriptive data from single‐arm studies showed that in critical ill patients who received caspofungin has more stable AUC0‐24 h than those who received anidulafungin and micafungin. However, the Cmax in critical ill patients who received anidulafungin was lower than in healthy volunteers.

Introduction Body weight can affect exposure, safety and efficacy of antibody-based therapies; sometimes these effects may not be clinically relevant. Panitumumab is approved for wild-type RAS metastatic colorectal cancer, using a body weight-based dosing regimen. Recently, a report cited fixed-dose usage of panitumumab, rather than approved body weight-based dosing. The current work evaluates optimal dosing regimen scientifically based on clinical data, modeling and simulation. Herein, we assessed the effect of fixed and body weight-based dosing on panitumumab pharmacokinetics to determine which approach resulted in the least interpatient pharmacokinetic variability. Patients and methods From the Vectibix program, 352 patients enrolled in three studies were evaluated; they had received panitumumab (body weight-based dose: 6 mg/kg every 2 weeks) and had pharmacokinetic (maximum serum [Cmax] and trough [Cmin] concentrations) and body weight data available. Additionally, concentration-time profiles at fixed (480 mg) and body weight-based doses (6 mg/kg) were simulated using a population pharmacokinetics model developed from 1200 patients. Results After administration of panitumumab 6 mg/kg, Cmax and Cmin increased with increasing body weight; the mean Cmax and Cmin for patients weighing 88 kg (upper quartile). The simulated area under the concentration-time curve (AUC) data also indicated that overall panitumumab exposure increased with increasing body weight for the body weight-based regimen. When AUC was simulated for a fixed dose (480 mg), the opposite effect was observed. Over the range of body weights, interpatient variability in simulated AUC was lower for the weight-based dose (29%) than for the fixed dose (34%). Conclusion Results demonstrate that the weight-based dose (6 mg/kg) reduced variability in panitumumab exposure across the range of body weights compared with the fixed-dose approach, indicating that a body weight-based approach is the recommended patient dosing strategy.

Background A trough concentration (Cmin) ≥20 μg/mL of teicoplanin is recommended for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. However, sufficient clinical evidence to support the efficacy of this target Cmin has not been obtained. Even though the recommended high Cmin of teicoplanin was associated with better clinical outcome, reaching the target concentration is challenging. Methods Pharmacokinetics and adverse events were evaluated in all eligible patients. For clinical efficacy, patients who had bacteremia/complicated MRSA infections were analyzed. The primary endpoint for clinical efficacy was an early clinical response at 72–96 h after the start of therapy. Five dosed of 12 mg/kg or 10 mg/kg was administered as an enhanced or conventional high loading dose regimen, respectively. The Cmin was obtained at 72 h after the first dose. Results Overall, 512 patients were eligible, and 76 patients were analyzed for treatment efficacy. The proportion of patients achieving the target Cmin range (20–40 μg/mL) by the enhanced regimen was significantly higher than for the conventional regimen (75.2% versus 41.0%, p min ≥ 20 μg/mL was an independent factor for an early clinical response (odds ratio 3.95, 95% confidence interval 1.25–12.53). There was no significant difference in the occurrence of adverse events between patients who did or did not achieve a Cmin ≥ 20 μg/mL. Conclusion A target Cmin ≥ 20 μg/mL might improve early clinical responses during the treatment of difficult MRSA infections using 12 mg/kg teicoplanin for five doses within the initial 3 days.

AIMS A new formulation of posaconazole (PCZ), delayed-release tablets (PCZ-tab), increases PCZ bioavailability and plasma trough concentrations (Cmin ) over those achieved with an oral suspension (PCZ-susp). PCZ is an inhibitor of cytochrome P450 3A4 and P-glycoprotein. We therefore investigated the impact of PCZ-tab treatment on blood Cmin and doses of tacrolimus (TAC) and everolimus (EVR). METHODS Eighteen lung transplant patients receiving TAC (n = 13) or TAC + EVR (n = 5) between June 2015 and March 2016 were retrospectively included. Ten of these patients received both PCZ-tab and PCZ-susp (i.e. switched patients); the other 8 received only PCZ-tab. Plasma Cmin of PCZ (n = 64), blood Cmin of TAC (n = 299) and EVR (n = 80) were determined during routine therapeutic drug monitoring by liquid chromatography-tandem mass spectrometry. RESULTS PCZ Cmin on PCZ-tab treatment (n = 48) was 2.5 times higher than that on PCZ-susp therapy (n = 16), for both PCZ patients (P < .0001) and for switched patients (P = .003). PCZ initiation, regardless of galenic form, increased TAC and EVR Cmin adjusted for dose (D), 3-fold and 3.5-fold, respectively (P < .0001 for both). PCZ-tab treatment was associated with a higher TAC Cmin /D (PCZ-tab vs PCZ-susp: 0.004 ± 0.004 L-1 vs 0.009 ± 0.006 L-1 , P < .0001) and lower TAC daily dose than PCZ-susp (PCZ-tab vs PCZ-susp: 1.08 ± 0.92 vs 2.32 ± 1.62 mg d-1 , P < .0001). EVR Cmin /D was higher and EVR dose tended to be lower on PCZ-tab than on PCZ-susp. CONCLUSION The greater PCZ exposure achieved during PCZ-tab treatment increased drug-drug interactions with TAC and EVR, resulting in greater exposure, potentially exposing patients to higher risks of adverse effects.

Background Vancomycin is the standard therapy for methicillin-resistant Staphylococcus aureus (MRSA) infection; however, nephrotoxicity happened with a high incidence of 15%~40%. Weighting the risk before receiving vancomycin treatment facilitates timely prevention of nephrotoxicity, but no standardized strategy exists for this purpose. Methods A retrospective cohort study was performed. A total of 524 hospitalized patients treated with vancomycin were included in this study. They were divided into derivation cohort (n=341) and externally validation cohort (n=183) according to their admission time. Using univariate and multivariable logistic regression, we identified potential predictors of vancomycin-associated acute kidney injury (AKI) and developed a risk score by plotting nomogram. The predictive performance of this novel risk score was assessed and validated by discrimination and calibration. Besides, the risk score was also compared with existing prediction models according to integrated discrimination index (IDI) and net reclassification index (NRI). Results The incidence of AKI was 16.1% (55/341) in the derivation cohort and 16.4% (30/183) in the validation cohort. Three factors (vancomycin serum trough concentration, piperacillin/tazobactam and furosemide) were determined as predictors for vancomycin-associated AKI. The established three-item risk score showed a comparable discrimination in both derivation cohort (AUC=0.793, 95% CI: 0.732-0.855) and validation cohort (AUC=0.788, 95% CI: 0.698-0.877). The risk score also demonstrated a good calibration in the derivation cohort (χ2=6.079, P=0.638>0.05) and validation cohort (χ2=5.665, P=0.686>0.05). Compared with prediction by Cmin alone, this risk score significantly improved reclassification accuracy (IDI=0.050, 95% CI: 0.024-0.076, P