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The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. Still, the optimal use and the value of pharmacological personalization of the taxanes is still controversial. We give an overview on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamic relations and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most effective and safe regimen, the recommended initial dose, and pharmacological dosing individualization. The taxanes are among the most widely used anticancer drugs in patients with solid malignancies. Despite their longtime use in clinical routine, the optimal dosing strategy (weekly versus 3-weekly) or optimal average dose (cabazitaxel, nab-paclitaxel) has not been fully resolved, as it may differ according to tumour entity and line of treatment. The value of pharmacological individualization of the taxanes (TDM, TCI) has been partly explored for 3-weekly paclitaxel and docetaxel, but remains mostly unexplored for cabazitaxel and nab-paclitaxel at present., (© 2020 British Pharmacological Society.)

Background: Infliximab therapy during pregnancy in inflammatory bowel disease is challenged by a dilemma between maintaining adequate maternal disease control while minimizing fetal infliximab exposure. We investigated the effects of pregnancy on infliximab pharmacokinetics., Methods: The study population comprised 23 retrospectively identified pregnancies. Patients with inflammatory bowel disease were generally in clinical remission at pregnancy conception (74%) and received steady infliximab maintenance therapy (5 mg/kg q8w n = 17; q6w n = 4; q10w n = 1; 10 mg/kg q8w n = 1). Trough blood samples had been obtained in the same patients prior to pregnancy (n = 119), the first trimester (n = 16), second trimester (n = 18), third trimester (n = 7), and postpregnancy (n = 12). Data were analyzed using nonlinear mixed-effects population pharmacokinetic modeling., Results: Dose-normalized infliximab concentrations were significantly higher during the second trimester (median 15 mg/ml/kg, interquartile range 10-21) compared to prepregnancy (7, 2-12; p = 0.003), the first trimester (9, 1-12; p = 0.04), or postpregnancy (6, interquartile range 3-11; p > 0.05) in patients with inflammatory bowel disease. Similar trends were observed in the third trimester (13, 7-36; p > 0.05). A one-compartment model with linear elimination described the pharmacokinetics of infliximab (volume of distribution n = 18.2 L; clearance 0.61 L/day). Maternal infliximab exposure was influenced by the second and third trimester of pregnancy and anti-infliximab antibodies, and not by pregnancy-imposed physiological changes in, for example, body weight or albumin. Infliximab clearance decreased significantly during the second and third trimesters by up to 15% as compared to pre- and postpregnancy and the first trimester. The increased maternal infliximab exposure was weakly associated with lowered clinical disease activity. Pharmacokinetic model simulations of virtual patients indicated the increased maternal infliximab trough concentrations imposed by pregnancy will not completely counteract the decrease in infliximab concentration if therapy is paused in the third trimester., Conclusion: Infliximab clearance decreases significantly in the second and third trimesters, leading to increasing maternal infliximab concentrations in any given regimen. Maternal infliximab levels may thus be maintained as constant in a de-intensified regimen by therapeutic drug monitoring guidance in inflammatory bowel disease., (© 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Objective: Target-site concentrations obtained via the catheter-based minimally invasive microdialysis technique often exhibit high variability. Catheter calibration is commonly performed via retrodialysis, in which a transformation factor, termed relative recovery (RR), is determined. Leveraging RR values from a rich data set of a very large clinical microdialysis study, promised to contribute critical insight into the origin of the reportedly high target-site variability. The present work aimed (i) to quantify and explain variability in RR associated with the patient (including non-obese vs. obese) and the catheter, and (ii) to derive recommendations on the design of future clinical microdialysis studies., Methods: A prospective, age- and sex-matched parallel group, single-centre trial in non-obese and obese patients (BMI=18.7-86.9 kg/m 2 ) was performed. 1-3 RR values were obtained in the interstitial fluid of the subcutaneous fat tissue in one catheter per upper arm of 120 patients via the retrodialysis method (n RR =1008) for a panel of drugs (linezolid, meropenem, tigecycline, cefazolin, fosfomycin, piperacillin and acetaminophen). A linear mixed-effects model was developed to quantify the different types of variability in RR and to explore the association between RR and patient body size descriptors., Results: Estimated RR was highest for acetaminophen (69.7%, 95%CI=65.0% to 74.3%) and lowest for piperacillin (40.4%, 95%CI=34.6% to 46.0%). The linear mixed-effects modelling analysis showed that variability associated with the patient (σ=15.9%) was the largest contributor (46.7%) to overall variability, whereas the contribution of variability linked to the catheter (σ=5.55%) was ~1/6 (16.8%). The relative contribution of residual unexplained variability (σ=12.0%, including intracatheter variability) was ~1/3 (36.4%). The limits of agreement of repeated RR determinations in a single catheter ranged from 0.694-1.64-fold (linezolid) to 0.510-3.02-fold (cefazolin). Calculated fat mass affected RR, explaining the observed lower RR in obese (ΔRR mean = -29.7% relative reduction) versus non-obese patients (p<0.001); yet only 15.8% of interindividual variability was explained by this effect. No difference in RR was found between catheters implanted into the left or right arm (p=0.732)., Conclusions: Three recommendations for clinical microdialysis trial design were derived: 1) High interindividual variability underscored the necessity of measuring individual RR per patient. 2) The low relative contribution of intercatheter variability to overall variability indicated that measuring RR with a single catheter per patient is sufficient for reliable catheter calibration. 3) The wide limits of agreement from multiple RR in the same catheter implied an uncertainty of a factor of two in target-site drug concentration estimation necessitating to perform catheter calibration (retrodialysis sampling) multiple times per patient. To allow routine clinical use of microdialysis, research efforts should aim at further understanding and minimising the method-related variability. Optimised study designs in clinical trials will ultimately yield more informative microdialysis data and increase our understanding of this valuable sampling technique to derive target-site drug exposure., (Copyright © 2020. Published by Elsevier B.V.)

Advanced lung cell culture models provide physiologically-relevant and complex data for mathematical models to exploit host-pathogen responses during anti-infective drug testing., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: This controlled clinical study aimed to investigate the impact of obesity on plasma and tissue pharmacokinetics of meropenem., Methods: Obese (body mass index (BMI) ≥ 35 kg/m 2 ) and age-/sex-matched nonobese (18.5 kg/m 2 ≥ BMI ≤ 30 kg/m 2 ) surgical patients received a short-term infusion of 1000-mg meropenem. Concentrations were determined via high performance liquid chromatography-ultraviolet (HPLC-UV) in the plasma and microdialysate from the interstitial fluid (ISF) of subcutaneous tissue up to eight h after dosing. An analysis was performed in the plasma and ISF by noncompartmental methods., Results: The maximum plasma concentrations in 15 obese (BMI 49 ± 11 kg/m 2 ) and 15 nonobese (BMI 24 ± 2 kg/m 2 ) patients were 54.0 vs. 63.9 mg/L (95% CI for difference: -18.3 to -3.5). The volume of distribution was 22.4 vs. 17.6 L, (2.6-9.1), but the clearance was comparable (12.5 vs. 11.1 L/h, -1.4 to 3.1), leading to a longer half-life (1.52 vs. 1.31 h, 0.05-0.37) and fairly similar area under the curve (AUC) 8h (78.7 vs. 89.2 mg*h/L, -21.4 to 8.6). In the ISF, the maximum concentrations differed significantly (12.6 vs. 18.6 L, -16.8 to -0.8) but not the AUC 8h (28.5 vs. 42.0 mg*h/L, -33.9 to 5.4). Time above the MIC (T > MIC) in the plasma and ISF did not differ significantly for MICs of 0.25-8 mg/L., Conclusions: In morbidly obese patients, meropenem has lower maximum concentrations and higher volumes of distribution. However, due to the slightly longer half-life, obesity has no influence on the T > MIC, so dose adjustments for obesity seem unnecessary.

Paclitaxel-associated peripheral neuropathy (PN), a major dose-limiting toxicity, significantly impacts patients' quality of life/treatment outcome. Evaluation of risk factors often ignores time of PN onset, precluding the impact of time-dependent factors, e.g., drug exposure, needed to comprehensively characterize PN. We employed parametric time-to-event (TTE) analysis to describe the time course of risk of first occurrence of clinically relevant PN grades ≥2 (PN2+, n = 105, common terminology criteria v4.0) and associated patient/treatment characteristics, leveraging data from 365 patients (1454 cycles) receiving paclitaxel every 3 weeks (plus carboplatin AUC = 6 or cisplatin 80 mg/m 2 ) for ≤6 cycles. Paclitaxel was intravenously administered (3 hours) as standard 200-mg/m 2 doses ( n = 182) or as pharmacokinetic-guided dosing ( n = 183). A cycle-varying hazard TTE model linking surge in hazard of PN2+ to paclitaxel administration [PN2+ proportions (i.e., cases per 1000 patients), 1 st day, cycle 1: 4.87 of 1000; cycle 6: 7.36 of 1000] and linear decline across cycle (last day, cycle 1: 1.64 of 1000; cycle 6: 2.48 of 1000) adequately characterized the time-varying hazard of PN2+. From joint covariate evaluation, PN2+ proportions (1 st day, cycle 1) increased by 1.00 per 1000 with 5-μmol·h/l higher paclitaxel exposure per cycle (AUC between the start and end of a cycle, most relevant covariate), 0.429 per 1000 with 5-year higher age, 1.31 per 1000 (smokers vs. nonsmokers), and decreased by 0.670 per 1000 (females vs. males). Compared to 200 mg/m 2 dosing every 3 weeks, model-predicted cumulative risk of PN2+ was significantly higher (42%) with 80 mg/m 2 weekly dosing but reduced by 11% with 175 mg/m 2 dosing every 3 weeks. The established TTE modeling framework enables quantification and comparison of patient's cumulative risks of PN2+ for different clinically relevant paclitaxel dosing schedules, sparing patients PN2+ to improve paclitaxel therapy. SIGNIFICANCE STATEMENT: Characterization of risk factors of paclitaxel-associated peripheral neuropathy (PN) typically involves time-independent comparison of PN odds in patient subpopulations, concealing the impact of time-dependent factors, e.g., changing paclitaxel exposure, required to comprehensively characterize PN. We developed a parametric time-to-event model describing the time course in risk of clinically relevant paclitaxel-associated PN, identifying the highest risk in older male smokers with higher paclitaxel area under the plasma concentration-time curve between the start and end of a cycle. The developed framework enabled quantification of patient's risk of PN for clinically relevant paclitaxel dosing schedules, facilitating future dosing decisions., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

This study aimed to explore the currently competing and new semimechanistic clearance models for monoclonal antibodies and the impact of clearance model misspecification on exposure metrics under different study designs exemplified for cetuximab. Six clearance models were investigated under four different study designs (sampling density and single/multiple-dose levels) using a rich data set from two cetuximab clinical trials (226 patients with metastatic colorectal cancer) and using the nonlinear mixed-effects modeling approach. A two-compartment model with parallel Michaelis-Menten and time-decreasing linear clearance adequately described the data, the latter being related to post-treatment response. With respect to bias in exposure metrics, the simplified time-varying linear clearance (CL) model was the best alternative. Time-variance of the linear CL component should be considered for biotherapeutics if response impacts pharmacokinetics. Rich sampling at steady-state was crucial for unbiased estimation of Michaelis-Menten elimination in case of the reference (parallel Michaelis-Menten and time-varying linear CL) model., (© 2020 Merck Healthcare KGaA. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Context: Accurate hydrocortisone dosing in children with adrenal insufficiency is important to avoid the risks of over and under treatment including iatrogenic Cushing's syndrome and adrenal crisis., Objective: To establish a population pharmacokinetic model of hydrocortisone in children and use this to refine hydrocortisone replacement regimens., Design and Methods: Pharmacokinetic study of hydrocortisone granules, available in 0.5, 1, 2 and 5 mg dose strengths, in 24 children with adrenal insufficiency aged 2 weeks to 6 years. Cortisol concentrations quantified by LC-MS/MS were used to refine an adult pharmacokinetic model to a paediatric population model which was then used to simulate seven different hydrocortisone treatment regimens., Results: Pre-dose cortisol levels were undetectable in 54% of the 24 children. The developed pharmacokinetic model had good predictive performance. Simulations for the seven treatment regimens using either three- or four-times daily dosing showed treatment regimens delivered an AUC0-24h within the 90% reference range for healthy children except in neonates where two regimens had an AUC below the 5th percentile. Cortisol concentrations at individual time points in the 24 h were outside the 90% reference range for healthy individuals in 50%, 55-65% and 70-75% for children, infants and neonates, respectively, with low cortisol levels being most prevalent., Conclusions: Current paediatric hydrocortisone treatment regimens based on either three- or four-times daily administration replicate cortisol exposure based on AUC0-24h, but the majority of cortisol levels are above or below physiological cortisol levels with low levels very common before the next dose.

Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (C SS,min ENDX ) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on C SS,min ENDX using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact C SS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget C SS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget C SS,min ENDX compared with elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing., (© 2020 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Infection and sepsis are a main cause of acute-on-chronic liver failure (ACLF). Adequate dosing of antimicrobial therapy is of central importance to improve outcome. Liver failure may alter antibiotic drug concentrations via changes of drug distribution and elimination. We studied the pharmacokinetics of meropenem in critically ill patients with ACLF during continuous veno-venous hemodialysis (CVVHD) and compared it to critically ill patients without concomitant liver failure (NLF)., Methods: In this prospective cohort study, patients received meropenem 1 g tid short-term infusion (SI). Meropenem serum samples were analyzed by high-performance liquid chromatography. A population pharmacokinetic analysis was performed followed by Monte Carlo simulations of (A) meropenem 1 g tid SI, (B) 2 g loading plus 1 g prolonged infusion tid (C) 2 g tid SI, and (D) 2 g loading and continuous infusion of 3 g/day on days 1 and 7. Probability of target attainment (PTA) was assessed for 4× the epidemiological cut-off values for Enterobacterales (4 × 0.25 mg/L) and Pseudomonas spp. (4 × 2 mg/L)., Results: Nineteen patients were included in this study. Of these, 8 patients suffered from ACLF. A two-compartment model with linear clearance from the central compartment described meropenem pharmacokinetics. The peripheral volume of distribution (V 2 ) was significantly higher in ACLF compared to NLF (38.6L versus 19.7L, p = .05). PTA for Enterobacterales was achieved in 100% for all dosing regimens. PTA for Pseudomonas spp. in ACLF on day 1/7 was: A: 18%/80%, B: 94%/88%, C: 85%/98% D: 100%/100% and NLF: A: 48%/65%, B: 91%/83%, C: 91%/93%, D: 100%/100%., Conclusion: ALCF patients receiving CVVHD had a higher V 2 and may require a higher loading dose of meropenem. For Pseudomonas, high doses or continuous infusion are required to reach PTA in ACLF patients.

Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. Methods: As a controlled clinical model, critically ill obese and non-obese patients undergoing intra-abdominal surgery received 600 mg linezolid as a single infusion. Concentrations in the plasma and microdialysate from the ISF of subcutaneous tissue were determined up to 8 h after dosing. Pharmacokinetic analysis was performed by non-compartmental methods. As a therapeutic target, we used f AUC/MIC > 80. Results: Fifteen obese (BMI: 48.7 ± 11.2 kg/m 2 ) and 15 non-obese (23.9 ± 2.1 kg/m 2 ) patients were analyzed. AUC 0-8 in ISF decreased by -1.69 mg*h/L (95% CI: -2.59 to -0.79, p < 0.001) for every 10 kg increase in weight. PK in obese patients were characterized by lower maximal plasma concentrations (median 3.8 vs. 8.3 mg/L, p < 0.001) and a higher volume of distribution (41.0 vs. 30.8 L, p < 0.001), and the therapeutic target was not reached for MIC ≥ 1 mg/L in ISF and ≥ 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC ≥ 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients.

The number of publications applying nonlinear mixed-effect (NLME) modeling has increased yearly since its first appearance in 1979. Here, we evaluated articles that have used NLME modeling, were published in journals that attract a broader audience, and we discussed the standard of presentation of these to stimulate target audience-specific improvements for increased impact in the future., (© 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Introduction: At tamoxifen standard dosing, ∼20% of breast cancer patients do not reach proposed target endoxifen concentrations >5.97 ng/mL. Thus, better understanding the large interindividual variability in tamoxifen pharmacokinetics (PK) is crucial. By applying non-linear mixed-effects (NLME) modeling to a pooled 'real-world' clinical PK database, we aimed to (i) dissect several levels of variability and identify factors predictive for endoxifen exposure and (ii) assess different tamoxifen dosing strategies for their potential to increase the number of patients reaching target endoxifen concentrations., Methods: Tamoxifen and endoxifen concentrations with genetic and demographic data of 468 breast cancer patients from six reported studies were used to develop a NLME parent-metabolite PK model. Different levels of variability on model parameters or measurements were investigated and the impact of covariates thereupon explored. The model was subsequently applied in a simulation-based comparison of three dosing strategies with increasing degree of dose individualization for a large virtual breast cancer population. Interindividual variability of endoxifen concentrations and the fraction of patients at risk for not reaching target concentrations were assessed for each dosing strategy., Results and Conclusions: The integrated NLME model enabled to differentiate and quantify four levels of variability (interstudy, interindividual, interoccasion, and intraindividual). Strong influential factors, i.e., CYP2D6 activity score, drug-drug interactions with CYP3A and CYP2D6 inducers/inhibitors and age, were reliably identified, reducing interoccasion variability to <20% CV. Yet, unexplained interindividual variability in endoxifen formation remained large (47.2% CV). Hence, therapeutic drug monitoring seems promising for achieving endoxifen target concentrations. Three tamoxifen dosing strategies [standard dosing (20 mg QD), CYP2D6-guided dosing (20, 40, and 60 mg QD) and individual model-informed precision dosing (MIPD)] using three therapeutic drug monitoring samples (5-120 mg QD) were compared, leveraging the model. The proportion of patients at risk for not reaching target concentrations was 22.2% in standard dosing, 16.0% in CYP2D6-guided dosing and 7.19% in MIPD. While in CYP2D6-guided- and standard dosing interindividual variability in endoxifen concentrations was high (64.0% CV and 68.1% CV, respectively), it was considerably reduced in MIPD (24.0% CV). Hence, MIPD demonstrated to be the most promising strategy for achieving target endoxifen concentrations., (Copyright © 2020 Klopp-Schulze, Mueller-Schoell, Neven, Koolen, Mathijssen, Joerger and Kloft.)

An essential component of therapeutic drug/biomarker monitoring (TDM) is to combine patient data with prior knowledge for model-based predictions of therapy outcomes. Current Bayesian forecasting tools typically rely only on the most probable model parameters (maximum a posteriori (MAP) estimate). This MAP-based approach, however, does neither necessarily predict the most probable outcome nor does it quantify the risks of treatment inefficacy or toxicity. Bayesian data assimilation (DA) methods overcome these limitations by providing a comprehensive uncertainty quantification. We compare DA methods with MAP-based approaches and show how probabilistic statements about key markers related to chemotherapy-induced neutropenia can be leveraged for more informative decision support in individualized chemotherapy. Sequential Bayesian DA proved to be most computationally efficient for handling interoccasion variability and integrating TDM data. For new digital monitoring devices enabling more frequent data collection, these features will be of critical importance to improve patient care decisions in various therapeutic areas., (© 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Objectives: Patients with congenital adrenal hyperplasia (CAH) require lifelong replacement therapy with glucocorticoids. Optimizing hydrocortisone therapy is challenging, since there are no established cortisol concentration targets other than the cortisol circadian rhythm profile. 17-hydroxyprogesterone (17-OHP) concentrations are elevated in these patients and commonly used to monitor therapy. This study aimed to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of cortisol using 17-OHP as a biomarker in pediatric patients with CAH and to assess different hydrocortisone dosing regimens., Methods: Cortisol and 17-OHP concentrations from 30 CAH patients (7-17 years of age) receiving standard hydrocortisone replacement therapy (5-20 mg) twice (n = 17) or 3 times (n = 13) daily were used to develop a PK/PD model. Sequentially, simulated cortisol concentrations for clinically relevant 3- and 4-times daily dosing regimens were compared with cortisol and 17-OHP target ranges and to concentrations in healthy children., Results: Cortisol concentration-time profiles were accurately described by a 2-compartment model with first-order absorption and expected high bioavailability (82.6%). A time-delayed model with cortisol-mediated inhibition of 17-OHP synthesis accurately described 17-OHP concentrations. The cortisol concentration inhibiting 50% of 17-OHP synthesis was 48.6 nmol/L. A 4-times-daily dosing better attained the target ranges and mimicked the cortisol concentrations throughout the 24-hour period than 3-times-daily., Conclusions: A PK/PD model following hydrocortisone administration has been established. An improved dosing regimen of 38% at 06:00, 22% at 12:00, 17% at 18:00, and 22% at 24:00 of the daily hydrocortisone dose was suggested. The 4-times-daily dosing regimen was superior, avoiding subtherapeutic cortisol concentrations and better resembling the circadian rhythm of cortisol., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Postoperative local infection is a major complication after pancreatic surgery. The aim of this prospective clinical trial was to assess the potential of moxifloxacin (MXF) to treat pancreatic infections from a pharmacokinetic (PK)/pharmacodynamic (PD) perspective. The PK of MXF in serum and pancreatic juice, via an inserted tube in the pancreatic duct, was determined in 19 patients up to day 7 after pancreatoduodenectomy. PK data in both specimens was analyzed with NONMEM 7.3. Intraoperative swipes were performed for microbiological examination. PK/PD target attainment was assessed in both matrices using unbound area under the plasma concentration-time curve/minimum inhibitory concentration (MIC) targets of ≥30 and ≥100, for gram-positive and gram-negative pathogens, respectively. A 2-compartment population PK model in which the measurements in pancreatic juice were assigned to a scaled peripheral compartment best described the PK in both specimens simultaneously. Median (10th-90th percentile) area under the plasma concentration-time curve values after the third dose were 28.9 mg · h/L (18.6-42.0) in serum and 55.8 mg · h/L (23.7-81.4) in pancreatic juice. Target attainment rate for the intraoperatively isolated bacterial strains was ≥0.88 after the third MXF dose. For gram-negatives, high probability of target attainment ≥0.84 was observed in serum for MIC ≤ 0.125 mg/L and in pancreatic juice for MIC ≤ 0.25 mg/L. For gram-positives, the probability of target attainment was 0.84-1 in serum for MIC ≤ 0.5 mg/L and in pancreatic juice for MIC ≤ 1 mg/L. In conclusion, penetration of MXF into pancreatic juice was substantial. The PK/PD analysis indicated that treatment of pancreatic infections by isolates with MIC ≤ 0.25 mg/L (gram-negative) and ≤1 mg/L (gram-positive) should be evaluated in further studies., (© 2019, The American College of Clinical Pharmacology.)

Effective antibiotic dosing is vital for therapeutic success in critically ill patients. This work aimed to develop an algorithm to identify appropriate meropenem dosing in critically ill patients. Population pharmacokinetic (PK) modelling was performed in NONMEM®7.3 based on densely sampled meropenem serum samples (n patients  = 48; n samples  = 1376) and included a systematic analysis of 27 pre-selected covariates to identify factors influencing meropenem exposure. Using Monte Carlo simulations newly considering the uncertainty of PK parameter estimates, standard meropenem dosing was evaluated with respect to attainment of the pharmacokinetic/pharmacodynamic (PK/PD) target and was compared with alternative infusion regimens (short-term, prolonged, continuous; daily dose, 2000-6000 mg). Subsequently, a dosing algorithm was developed to identify appropriate dosing regimens. The two-compartment population PK model included three factors influencing meropenem pharmacokinetics: the Cockcroft-Gault creatinine clearance (CLCR CG ) on meropenem clearance; and body weight and albumin on the central and peripheral volume of distribution, respectively; of these, only CLCR CG was identified as a vital influencing factor on PK/PD target attainment. A three-level dosing algorithm was developed (considering PK parameter uncertainty), suggesting dosing regimens depending on renal function and the level (L) of knowledge about the infecting pathogen (L1, pathogen unknown; L2, pathogen known; L3 (-MIC) , pathogen and susceptibility known; L3 (+MIC) , MIC known). Whereas patients with higher CLCR CG and lower pathogen susceptibility required mainly intensified dosing regimens, lower than standard doses appeared sufficient for highly susceptible pathogens. In conclusion, a versatile meropenem dosing algorithm for critically ill patients is proposed, indicating appropriate dosing regimens based on patient- and pathogen-specific information., (Copyright © 2019. Published by Elsevier B.V.)

To assess pharmacokinetics of amoxicillin (AMX) in mice, limitations such as a small sampling volume and low drug concentrations have to be addressed. Similar challenges are faced in a clinical framework, e.g. for therapeutic drug monitoring in neonates or small-scale in vitro investigations. An assay enabling quantification of small sample volumes but still at very low concentrations covering a broad concentration range is thus needed. A simple, rapid and highly sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and successfully validated for quantification of AMX in mouse serum according to European Medicines Agency guidelines. Sample preparation enabled the use of only 10 μL of serum, which is 5-fold less than comparable assays and allows to reduce the number of mice used in pharmacokinetic studies. After protein precipitation with 40 μL chilled methanol and dilution of the supernatant with water, the sample was injected into the LC system on a Poroshell 120 Phenyl Hexyl column (2.1 × 100 mm, 2.7 μm). Chromatographic separation was achieved using a gradient method consisting of acetonitrile and ultra-pure water, both with 0.1% (V/V) formic acid. Positive electrospray ionisation in multiple reaction monitoring mode was used for detection and quantification of AMX. Application to murine study samples demonstrated the reliability of the developed method being accurate and precise with a quantification range from 0.01 to 10 μg/mL. The assay is easily transferable due to a simple sample preparation and confirmed stability of AMX under various applied conditions., (Copyright © 2019. Published by Elsevier B.V.)

Voriconazole, a second-generation triazole frequently used for the prophylaxis and treatment of invasive fungal infections, undergoes complex metabolism mainly involving various (polymorphic) cytochrome P450 enzymes in humans. Although high inter- and intraindividual variability in voriconazole pharmacokinetics have been observed and the therapeutic range for this compound is relatively narrow, the metabolism of voriconazole has not been fully elucidated yet. The available literature data investigating the multiple different pathways and metabolites are extremely unbalanced and thus the absolute or relative contribution of the different pathways and enzymes involved in the metabolism of voriconazole remains uncertain. Furthermore, other factors such as nonlinear pharmacokinetics caused by auto-inhibition or -induction and polymorphisms of the metabolizing enzymes hinder safe and effective voriconazole dosing in clinical practice and have not yet been studied sufficiently. This review aimed at amalgamating the available literature on the pharmacokinetics of voriconazole in vitro and in vivo , with a special focus on metabolism in adults and children, in order to congregate an overall landscape of the current body of knowledge and identify knowledge gaps, opening the way towards further research in order to foster the understanding, towards better therapeutic dosing decisions.

Context: Optimization of hydrocortisone replacement therapy is important to prevent under- and over dosing. Hydrocortisone pharmacokinetics is complex as circulating cortisol is protein bound mainly to corticosteroid-binding globulin (CBG) that has a circadian rhythm., Objective: A detailed analysis of the CBG circadian rhythm and its impact on cortisol exposure after hydrocortisone administration., Design and Methods: CBG was measured over 24 hours in 14 healthy individuals and, employing a modelling and simulation approach using a semi-mechanistic hydrocortisone pharmacokinetic model, we evaluated the impact on cortisol exposure (area under concentration-time curve and maximum concentration of total cortisol) of hydrocortisone administration at different clock times and of the changing CBG concentrations., Results: The circadian rhythm of CBG was well described with two cosine terms added to the baseline of CBG: baseline CBG was 21.8 µg/mL and interindividual variability 11.9%; the amplitude for the 24 and 12 hours cosine functions were relatively small (24 hours: 5.53%, 12 hours: 2.87%) and highest and lowest CBG were measured at 18:00 and 02:00, respectively. In simulations, the lowest cortisol exposure was observed after administration of hydrocortisone at 23:00-02:00, whereas the highest was observed at 15:00-18:00. The differences between the highest and lowest exposure were minor (≤12.2%), also regarding the free cortisol concentration and free fraction (≤11.7%)., Conclusions: Corticosteroid-binding globulin has a circadian rhythm but the difference in cortisol exposure is ≤12.2% between times of highest and lowest CBG concentrations; therefore, hydrocortisone dose adjustment based on time of dosing to adjust for the CBG concentrations is unlikely to be of clinical benefit., (© 2019 John Wiley & Sons Ltd.)

Voriconazole, a broad-spectrum antifungal drug used to prevent and treat invasive fungal infections, shows complex pharmacokinetics and is primarily metabolised by various CYP enzymes. An adequate unbound antibiotic concentration-time profile at the target-site of an infection is crucial for effective prophylaxis or therapy success. Therefore, the aim was to evaluate the pharmacokinetics of voriconazole after the approved sequence dosing in healthy volunteers in interstitial space fluid, assessed by microdialysis, and in plasma. Moreover, potential pharmacogenetic influences of CYP2C19 polymorphisms on pharmacokinetics were investigated. The prospective, open-labelled, uncontrolled long-term microdialysis study included 9 healthy male individuals receiving the approved sequence dosing regimen for voriconazole. Unbound voriconazole concentrations were sampled over 84 h in interstitial space fluid of subcutaneous adipose tissue and in plasma and subsequently quantified via high-performance liquid chromatography. For pharmacokinetic data analysis, non-compartmental analysis was used. High interindividual variability in voriconazole concentration-time profiles was detected although dosing was adapted to body weight for the first intravenous administrations. Due to nonlinear pharmacokinetics, target-site exposure of voriconazole in healthy volunteers was found to be highly comparable to plasma exposure, particularly after multiple dosing. Regarding the CYP2C19 genotype-predicted phenotype, the individuals revealed a broad spectrum, ranging from poor to rapid metaboliser status. A strong relation between CYP2C19 genotype-predicted phenotype and voriconazole clearance was identified., (Copyright © 2019. Published by Elsevier B.V.)

Background: Circulating infliximab (IFX) concentrations correlate with clinical outcomes, forming the basis of the IFX concentration monitoring in patients with Crohn's disease. This study aims to investigate and refine the exposure-response relationship by linking the disease activity markers "Crohn's disease activity index" (CDAI) and C-reactive protein (CRP) to IFX exposure. In addition, we aim to explore the correlations between different disease markers and exposure metrics., Methods: Data from 47 Crohn's disease patients of a randomized controlled trial were analyzed post hoc. All patients had secondary treatment failure at inclusion and had received intensified IFX of 5 mg/kg every 4 weeks for up to 20 weeks. Graphical analyses were performed to explore exposure-response relationships. Metrics of exposure included area under the concentration-time curve (AUC) and trough concentrations (Cmin). Disease activity was measured by CDAI and CRP values, their change from baseline/last visit, and response/remission outcomes at week 12., Results: Although trends toward lower Cmin and lower AUC in nonresponders were observed, neither CDAI nor CRP showed consistent trends of lower disease activity with higher IFX exposure across the 30 evaluated relationships. As can be expected, Cmin and AUC were strongly correlated with each other. Contrarily, the disease activity markers were only weakly correlated with each other., Conclusions: No significant relationship between disease activity, as evaluated by CDAI or CRP, and IFX exposure was identified. AUC did not add benefit compared with Cmin. These findings support the continued use of Cmin and call for stringent objective disease activity (bio-)markers (eg, endoscopy) to form the basis of personalized IFX therapy for Crohn's disease patients with IFX treatment failure.

The need for pharmacokinetic knowledge about antibiotics directly at the site of infection, typically the interstitial space fluid (ISF) of tissues, is gaining acceptance for effective and safe treatment. One option to acquire such data is the microdialysis technique employing a catheter with a semipermeable membrane inserted directly in the ISF. A prerequisite is catheter calibration, e.g. via retrodialysis, yielding a conversion factor from measured to true ISF concentrations, termed relative recovery. This value can be influenced by various factors. The present investigation assessed the impact of three of them on relative recovery using seven drugs: (I) drug combinations/order, (II) air in the microdialysis system, (III) flow rate changes inherent when using common in vivo microdialysis pumps. All experiments were performed in a standardised in vitro microdialysis system. (I) Relative recovery of single antibiotics (linezolid, meropenem, cefazolin, metronidazole, tigecycline) was determined in microdialysis and retrodialysis settings and compared with values using either antibiotic or antibiotic+analgesic (acetaminophen and metamizole) combinations or single drugs with reversed microdialysis order. For assessing these factors for lower relative recovery values (as in in vivo), these were mimicked by increasing the flow rate for linezolid. (II) For the impact of air, linezolid relative recovery of freshly carbonated solutions was compared to degassed ones in microdialysis and retrodialysis settings. For each condition in (I) and (II), summary statistics of relative recovery were calculated and for the impact of the factors a linear mixed-effect model developed. (III) From samples taken during an automatic flush sequence (15 μL/min) of an in vivo pump and afterwards switching to the flow rate of 1 and 2 μL/min for 120 min, the time necessary for relative recovery to reach equilibrium was determined. (I) High relative recovery values (flow rate 2 μL/min: ≥84%; flow rate 5 μL/min: ≥65%) were observed for all investigated single drugs. Intra- and intercatheter variability ranged from 0.3%-11% and 3%-25%, respectively. Based on these values and on the statistical model, the impact of drug combination versus single drug as well as of reversed order was small with changes in relative recovery of smaller equal 9%. (II) Compared to degassed solutions, relative recovery in carbonated solutions was 23% and 19% lower (relative reduction) in the microdialysis and retrodialysis setting, respectively, with increased intercatheter variability (up to 37%). (III) As expected, relative recovery increased after the flush sequence and was constant 10-15 min after the switch to the typical 1 and 2 μL/min flow rate. Given the intercatheter variability, combinations and the order of drugs showed minor but clinically negligible impact on relative recovery. In contrast, air in the microdialysis catheter/system caused falsely low and inconsistent relative recovery values and must be avoided when performing a trial. Also changes in flow rate at the end of pump flush sequence impacted relative recovery. Hence, a sufficient equilibration time of 10-15 min prior to sampling should be implemented in sampling protocols. In vitro microdialysis presents a highly valuable complementary platform to clinical microdialysis studies impacting the design, sampling schedule and data analysis of such trials to gain knowledge of target-site pharmacokinetics for contributing to better informed decisions in the individual patient/special populations in future., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Competing Interests: Conflict of interest:CK declares receiving research grants from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grünenthal GmbH, F. Hoffmann-La Roche Ltd, Merck KGaA and SANOFI) as well as research grants from the Innovative Medicines Initiative–Joint Undertaking (DDMoRe) and Diurnal Ltd. The other authors have no interests to declare.

The inhalation route is frequently used to administer drugs for the management of respiratory diseases such as asthma or chronic obstructive pulmonary disease. Compared with other routes of administration, inhalation offers a number of advantages in the treatment of these diseases. For example, via inhalation, a drug is directly delivered to the target organ, conferring high pulmonary drug concentrations and low systemic drug concentrations. Therefore, drug inhalation is typically associated with high pulmonary efficacy and minimal systemic side effects. The lung, as a target, represents an organ with a complex structure and multiple pulmonary-specific pharmacokinetic processes, including (1) drug particle/droplet deposition; (2) pulmonary drug dissolution; (3) mucociliary and macrophage clearance; (4) absorption to lung tissue; (5) pulmonary tissue retention and tissue metabolism; and (6) absorptive drug clearance to the systemic perfusion. In this review, we describe these pharmacokinetic processes and explain how they may be influenced by drug-, formulation- and device-, and patient-related factors. Furthermore, we highlight the complex interplay between these processes and describe, using the examples of inhaled albuterol, fluticasone propionate, budesonide, and olodaterol, how various sequential or parallel pulmonary processes should be considered in order to comprehend the pulmonary fate of inhaled drugs.

Background: Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients., Objectives: To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function., Methods: A population pharmacokinetic model was developed in NONMEM® 7.3 based on steady-state meropenem concentrations (CSS) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRCG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90% of the patients. Probability of target attainment was determined for efficacy (CSS ≥8 mg/L) and potentially increased likelihood of adverse drug reactions (CSS >32 mg/L)., Results: In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P0.05 - P0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/3940 mg were required to reach a target CSS = 8 mg/L in 90% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions (<0.5%) was associated with these doses., Conclusions: A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population.

Cytokines and chemokines play important roles in cell signalling, and microdialysis is a promising tool for monitoring these inflammation markers ex vivo. Therefore, the collecting of these mediators at the highest concentrations possible is crucial. Depending on the size of the mediator of interest, the collection of these high molecular mass molecules has thus far been difficult due to their low recovery, even when using high cut-off (100 kDa) microdialysis membranes. This study aimed to optimize the recovery of various cytokines and chemokines by validating the use of different perfusates in cutaneous microdialysis, and comparing intravenous (i.v.) colloids, crystalloids, and a lipid emulsion formulations that are approved for i.v., Methods: In vitro and in vivo recovery experiments using six recombinant cytokines varying in molecular size (interleukin-2 (15 kDa), interleukin-6 (20.5 kDa), interleukin-8 (8 kDa), interleukin-12p70 (70 kDa), TNF-&alpha; (17.5 kDa), and vascular endothelial growth factor (VEGF) (38 kDa)) were performed in the presence of different perfusates for i.v., Applications: Ringer&rsquo;s lactate, dextran 60 kDa, hydroxyethyl starch 70 kDa, and hydroxyethyl starch 200 kDa solutions as well as a lipid emulsion formulation. Recovery was determined through (i) microdialysis of cytokines and chemokines in Ringer&rsquo;s lactate solution or human serum in vitro, and (ii) retrodialysis of excised porcine and human skin cadavers in vitro and porcine skin in vivo. Furthermore, we used skin trauma (catheter insertion) and Ultraviolet B irradiation of 3 &times; 3 cm² skin areas to sample cytokines and chemokines in vivo and compared the amounts that were obtained using crystalloid and colloid perfusates. All the cytokines and chemokines within the dialysates were quantified through a flow cytometry-based bead array assay., Results: Overall, recovery was strongly increased by the colloids, particularly hydroxyethyl starch 70 kDa, in vitro, ex vivo, and in vivo. When compared with the recovery achieved using Ringer&rsquo;s lactate, this increase was most effective for proteins ranging from 8 to 20.5 kDa. Hydroxyethyl starch 70 kDa significantly increased the recovery of interleukin (IL)-8 in human serum in vitro when compared with Ringer&rsquo;s lactate. More cytokines and chemokines were recovered using colloids compared with crystalloids. However, the increase in recovery values was lower for IL-12p70 and VEGF., Conclusions: Regarding the dialysate volumes and final dialysate concentrations, colloid perfusates are overall superior to crystalloid perfusates, such as Ringer&rsquo;s lactate, when sampling cytokines and chemokines, resulting in higher recoveries. However, the sampling of high-molecular-mass cytokines during microdialysis remains challenging, and experimental in vitro data are not completely comparable with data obtained ex vivo or in vivo.

Background and Objective: Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort ® oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency., Methods: Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort ® or 20 mg of Infacort ® /hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model., Results: Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline cort ,15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing <20 kg., Conclusions: Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing <20 kg. EudraCT number: 2013-000260-28, 2013-000259-42.

A growing understanding of complex processes in biology has led to large-scale mechanistic models of pharmacologically relevant processes. These models are increasingly used to study the response of the system to a given input or stimulus, e.g., after drug administration. Understanding the input-response relationship, however, is often a challenging task due to the complexity of the interactions between its constituents as well as the size of the models. An approach that quantifies the importance of the different constituents for a given input-output relationship and allows to reduce the dynamics to its essential features is therefore highly desirable. In this article, we present a novel state- and time-dependent quantity called the input-response index that quantifies the importance of state variables for a given input-response relationship at a particular time. It is based on the concept of time-bounded controllability and observability, and defined with respect to a reference dynamics. In application to the brown snake venom-fibrinogen (Fg) network, the input-response indices give insight into the coordinated action of specific coagulation factors and about those factors that contribute only little to the response. We demonstrate how the indices can be used to reduce large-scale models in a two-step procedure: (i) elimination of states whose dynamics have only minor impact on the input-response relationship, and (ii) proper lumping of the remaining (lower order) model. In application to the brown snake venom-fibrinogen network, this resulted in a reduction from 62 to 8 state variables in the first step, and a further reduction to 5 state variables in the second step. We further illustrate that the sequence, in which a recursive algorithm eliminates and/or lumps state variables, has an impact on the final reduced model. The input-response indices are particularly suited to determine an informed sequence, since they are based on the dynamics of the original system. In summary, the novel measure of importance provides a powerful tool for analysing the complex dynamics of large-scale systems and a means for very efficient model order reduction of nonlinear systems.

Background and Objectives: A better understanding of the highly variable pharmacokinetics (PK) of tamoxifen and its active metabolite endoxifen in breast cancer patients is crucial to support individualised treatment. This study used a modelling and simulation approach to quantitatively assess the influence of cytochrome P450 (CYP) 2D6 activity and other relevant factors on tamoxifen and endoxifen PK to identify subgroups at risk for subtherapeutic endoxifen concentrations., Methods: Simulations were performed using two previously published PK models jointly describing tamoxifen and endoxifen with CYP2D6 and CYP3A4/5 enzyme activities implemented as covariates. Steady-state predictions were compared between models and with the literature values. Factors potentially causing between-model discrepancies were explored. A previously published threshold (6 ng/mL) was used to identify patients with subtherapeutic endoxifen concentrations and to perform a dose adaptation study., Results: Steady-state predictions of tamoxifen and endoxifen were considerably different between the models. The factors, differences in sampling time, adherence and bioavailability, were not able to fully capture between-model variability. Endoxifen steady-state fluctuations within a dosing interval were minimal (<6%). Poor (97%) and intermediate (54%) CYP2D6 metabolisers failed to achieve therapeutic endoxifen concentrations, suggesting adapted doses of tamoxifen 80 and 40 mg, respectively, achieving therapeutic endoxifen concentrations in 89.7% of patients (standard dosing 45.2%). However, interindividual variability remained., Conclusions: To achieve therapeutic endoxifen concentrations early in treatment, it is advisable to initiate treatment by CYP2D6 genotype/phenotype-guided dosing, followed by therapeutic drug monitoring at steady-state. We strongly advocate to adequately measure, report and prospectively investigate influential factors (i.e. adherence, bioavailability, time to PK steady-state) in clinical trials.

To determine and address medication non-adherence is important and may improve patient outcomes. Our aim was to perform a systematic review on the operationalization of adherence measures in patients with heart failure using claims data. We searched the MEDLINE, EMBASE, and Cochrane databases. A quality check of the full-text articles was performed using the Quality in Prognosis Studies tool. We included 28 studies. Eleven studies used the medication possession ratio, 15 the proportion of days covered, and six studies used own methods to calculate medication adherence. Almost all studies used an observation period of 1 year. Twenty-one studies considered angiotensin converting enzyme inhibitors or angiotensin receptor antagonists, 17 beta-blockers, 11 diuretics, eight mineralocorticoid receptor antagonists, six digitalis-glycosides, and six statins. Eight studies looked at single substance classes; 18 studies analyzed more than one drug class. Different assumptions for the dosage were used. In seven studies, switching within therapeutic classes was allowed. Three studies allowed stockpiling, nine studies censored hospital stays, and four studies censored death. Seventeen studies dichotomized the results, applying the cutoff ≥ 0.8 to define a patient as adherent. Eight studies analyzed adherence as a continuous value. The reporting quality of the methodology applied varied widely between studies. A gold standard is currently not available for the quantification of medication adherence in patients with chronic heart failure via claims data. To assess the methodology, the following parameters should be described: method of measurements, observation period, substances, dosing, switches, stockpiling, truncations, statistical analysis, and cutoff for adherence.

Purpose: In 2014, FDA released a warning for prescription of doripenem for ventilator-associated bacterial pneumonia due to unsatisfactory clinical cure rates. The present study explores if the observed lack of efficacy might be explained by insufficient target site pharmacokinetics in intensive care patients after two different infusion schemes., Methods: Plasma and bronchoalveolar lavage sampling was performed in 16 intubated patients with pneumonia receiving doripenem either as 1-h or as 4-h infusion. Doripenem concentrations were measured at steady state in plasma over 8 h, bronchoalvoelar lavage was performed in each patient once either after 0 h, 2 h, 4 h or 6 h., Results: In plasma, mean values of C max , T max and AUC 0-8 were 16.87 mg/L, 0.69 h and 52.98 mg/L × h after 1 h of infusion, and 12.94 mg/L, 3.21 h and 70.64 mg/L × h after 4 h of infusion, respectively. While the later t max in plasma was with delay mirrored in the lung, for ELF, much lower concentrations were observed (C max , T max and AUC 0-8 after 1-h infusion of 4.6 mg/L, 2 h and 15.3 mg/L × h and after 4-h infusion 6.9 mg/L, 4 h and 14.8 mg/L × h)., Conclusion: The difference in plasma pharmacokinetics after 1-h and 4-h infusion reflects in the concentration versus time profile in the lung, but concentration at the target site was not only considerably lower but also subject to high inter-individual variability. We hypothesise that insufficient concentrations at the target site might have contributed to the previously described lack of clinical efficacy and confirmed the demand for assessment of target site pharmacokinetics in larger patient collectives.

Background: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application., Methods: A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCR CG ). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100%T >MIC , 50%T >4×MIC ) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCR CG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment., Results: Large inter- and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100%T >MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50%T >4×MIC . A hyperbolic relationship between CLCR CG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C 8h ) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment)., Conclusions: The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy- and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed., Trial Registration: Clinicaltrials.gov, NCT01793012 . Registered on 24 January 2013.

Erlotinib is metabolized by cytochrome p450 (CYP) 3A and CYP1A. This study assessed CYP3A4 (midazolam) and CYP1A2 (caffeine) phenotyping in plasma and dried blood spots (DBS) for predicting the pharmacokinetics and toxicity of erlotinib in 36 patients with advanced NSCLC. On day 1, erlotinib 150 mg OD was initiated, and the two oral probe drugs midazolam (2 mg) and caffeine (100 mg) were added on day 1. Plasma and DBS were collected for erlotinib, OSI-420 and probe drugs for up to 6 hr on day 1 and 2-weekly up to week 10. Probe drugs, erlotinib and OSI-420 were analysed using LC-MS-MS, and PK data were processed using population modelling. A high correlation was found between plasma and DBS concentrations for erlotinib (R 2  = 0.960, p < 0.0001), OSI-420 (R 2  = 0.971, p < 0.0001), midazolam (R 2  = 0.995, p < 0.0001) and caffeine (R 2  = 0.968, p < 0.0001). Apparent oral caffeine clearance was significantly correlated with erlotinib clearance (R 2  = 0.33, p = 0.048), while midazolam clearance was not (R 2  = -0.09, p = 0.596). Erlotinib clearance was lower in patients experiencing grade 2 or 3 rash as compared to patients experiencing grade 0 or 1 rash (3.15 versus 3.93 L/hr, p = 0.086 for Student's t-test). The results suggest that probe drug phenotyping is unlikely to substitute therapeutic drug monitoring of erlotinib in patients with advanced NSCLC, but erlotinib PK sampling from DBS may replace more invasive venous sampling and facilitate TDM in patients with cancer., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objectives: Due to the lack of paediatric-licensed formulations, children are often treated with individualized pharmacy-compounded adult medication. An international web-based survey about the types of medication in children with adrenal insufficiency (AI) revealed that the majority of paediatric physicians are using pharmacy-compounded medication to treat children with AI. Observations of loss of therapy control in children with congenital adrenal hyperplasia with compounded hydrocortisone capsules and regained control after prescribing a new hydrocortisone batch led to this 'real world' evaluation of pharmacy-compounded paediatric hydrocortisone capsules., Methods: Capsule samples were collected randomly from volunteering parents of treated children suffering from congenital adrenal hyperplasia from all over Germany. Analysis of net mass and hydrocortisone content by high-performance liquid chromatography with ultraviolet (HPLC-UV) detection method was performed based on the European Pharmacopeia., Results: In a total of 61 batches that were sent, 5 batches could not be analysed because of missing dose information, insufficient number of capsules or were not possible to be evaluated. Fifty-six batches containing 1125 capsules were evaluated. 21.4% of the batches revealed insufficiency in uniformity of net mass or drug content and additional 3.6% failed because they did not contain the labelled drug., Conclusions: Compounded medication is a possible cause of variation of steroid doses in children with adrenal insufficiency or congenital adrenal hyperplasia, putting these vulnerable patients at risk of poor disease control and adrenal crisis. These data may apply to other individualized compounded oral medication as well, emphasizing the need for development of licensed paediatric formulations approved by regulatory authorities., (© 2017 European Society of Endocrinology.)

Immunodeficient mice are crucial models to evaluate the efficacy of monoclonal antibodies (mAbs). When studying mAb pharmacokinetics (PK), protection from elimination by binding to the neonatal Fc receptor (FcRn) is known to be a major process influencing the unspecific clearance of endogenous and therapeutic IgG. The concentration of endogenous IgG in immunodeficient mice, however is reduced, and this effect on the FcRn protection mechanism and subsequently on unspecific mAb clearance is unknown, yet of great importance for the interpretation of mAb PK data. We used a PBPK modelling approach to elucidate the influence of altered endogenous IgG concentrations on unspecific mAb clearance. To this end, we used PK data in immunodeficient mice, i.e. nude and severe combined immunodeficiency mice. To avoid impact of target-mediated clearance processes, we focussed on mAbs without affinity to a target antigen in these mice. In addition, intravenous immunoglobulin (IVIG) data of immunocompetent mice was used to study the impact of increased total IgG concentrations on unspecific therapeutic antibody clearance. The unspecific clearance is linear, whenever therapeutic IgG concentrations, i.e. mAb and IVIG concentrations are lower than FcRn; it can be non-linear if therapeutic IgG concentrations are larger than FcRn and endogenous IgG concentrations (e.g., under IVIG therapy). Unspecific mAb clearance of immunodeficient mice is effectively linear (under mAb doses as typically used in human). Studying the impact of reduced endogenous IgG concentrations on unspecific mAb clearance is of great relevance for the extrapolation to clinical species, e.g., when predicting mAb PK in immunosuppressed cancer patients.

Paclitaxel is a commonly used cytotoxic anticancer drug with potentially life-threatening toxicity at therapeutic doses and high interindividual pharmacokinetic variability. Thus, drug and effect monitoring is indicated to control dose-limiting neutropenia. Joerger et al. (2016) developed a dose individualization algorithm based on a pharmacokinetic (PK)/pharmacodynamic (PD) model describing paclitaxel and neutrophil concentrations. Furthermore, the algorithm was prospectively compared in a clinical trial against standard dosing (Central European Society for Anticancer Drug Research Study of Paclitaxel Therapeutic Drug Monitoring; 365 patients, 720 cycles) but did not substantially improve neutropenia. This might be caused by misspecifications in the PK/PD model underlying the algorithm, especially without consideration of the observed cumulative pattern of neutropenia or the platinum-based combination therapy, both impacting neutropenia. This work aimed to externally evaluate the original PK/PD model for potential misspecifications and to refine the PK/PD model while considering the cumulative neutropenia pattern and the combination therapy. An underprediction was observed for the PK (658 samples), the PK parameters, and these parameters were re-estimated using the original estimates as prior information. Neutrophil concentrations (3274 samples) were overpredicted by the PK/PD model, especially for later treatment cycles when the cumulative pattern aggravated neutropenia. Three different modeling approaches (two from the literature and one newly developed) were investigated. The newly developed model, which implemented the bone marrow hypothesis semiphysiologically, was superior. This model further included an additive effect for toxicity of carboplatin combination therapy. Overall, a physiologically plausible PK/PD model was developed that can be used for dose adaptation simulations and prospective studies to further improve paclitaxel/carboplatin combination therapy., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Objectives: We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients., Methods: Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid. All data were analysed simultaneously by a population approach also considering methodological aspects of microdialysis. The impact of covariates on the attainment of the pharmacokinetic/pharmacodynamic targets, AUC/MIC = 100 (area under the concentration-time curve/minimum inhibitory concentration) and fT >MIC  = 99 % (time that unbound concentrations exceed the MIC), was assessed by deterministic and Monte Carlo simulations., Results: A two-compartment pharmacokinetic model with nonlinear elimination and tissue distribution factors accounting for differences between plasma and ISF concentrations adequately predicted all measurements. Clearance (CL) was highest in septic patients (11.2 L/h vs. CL Healthy /CL Cystic fibrosis /CL Diabetic  = 7.67/6.87/6.35 L/h). Penetration into subcutaneous adipose ISF was lowest in diabetic patients (-34.9 % compared with healthy volunteers). Creatinine clearance and total body weight further impacted linezolid exposure. To achieve timely efficacious therapy, front-loaded dosing and continuous infusion seemed beneficial in septic patients., Conclusions: Our analysis suggests that after standard linezolid doses, particularly patients with sepsis and conserved renal function are at risk of not attaining pharmacokinetic/pharmacodynamic targets and would benefit from initial dose intensification.

AZD5423 is a non-steroidal glucocorticoid receptor modulator, with low aqueous solubility, developed for treatment of asthma and COPD. In this work, we aim to evaluate and compare the absorption pharmacokinetics (PK) of AZD5423 after inhalation via four devices, (Spira®, I-neb®, Turbuhaler® and a new dry powder inhaler (new DPI)) with two formulations using differently sized primary particles, and to compare the pulmonary bioavailability with the predicted lung deposited dose. Plasma concentration-time data after intravenous, oral and inhaled administration via four devices were available from two clinical studies in healthy and asthmatic subjects. A population PK modelling approach was taken to sequentially incorporate each route of administration, assuming parallel absorption compartments for inhaled AZD5423. A non-compartmental analysis for derivation of PK parameters was performed for comparison. Pulmonary bioavailability varied between devices, with the lowest estimates for I-neb (27%) and Turbuhaler (30%) and the highest for the new DPI (46%) and Spira (35-49%). The pulmonary bioavailability was substantially lower than the predicted lung deposited dose (range 59-90%). Lung absorption was separated into a faster and a slower process in the model. The half-life of the faster absorption appeared formulation-dependent, while the slower absorption (half-life of 0.59-0.78 h) appeared independent of formulation. The large difference in the estimated pulmonary bioavailability and the predicted lung deposited dose for AZD5423 implies an impact of mucociliary clearance. The lung absorption half-life indicates that AZD5423 is retained in the lung for a relatively short time.

Antibodies (Abs) against infliximab (IFX) increase IFX clearance and can result in treatment failure and acute hypersensitivity reactions. However, interpretation of their clinical value is complicated by individual differences in Ab responses and methods used for quantification. The increase in IFX clearance imposed by anti-IFX Abs has generally been evaluated using a binary classification, i.e., positive or negative. This analysis aimed to investigate if anti-IFX Ab concentrations provide a more adequate prediction of alterations in clearance. Data originated from a clinical trial on Crohn's disease patients with IFX treatment failure. The trial was not originally designed for pharmacokinetic analysis. Therefore, published pharmacokinetic models were utilized as priors to enable covariate investigation. The impact of anti-IFX Abs on clearance was assessed using different mathematical relationships and exploiting information from two different quantification assays, measuring semi-quantitative "total" or "unbound neutralizing" concentrations of anti-IFX Ab, respectively. Inclusion of anti-IFX Ab status/concentration improved the model's performance for all investigated relationships. The anti-IFX Ab concentrations were superior to the binary classifications, indicating that the magnitude of increase in IFX clearance imposed by anti-IFX Abs closely relates to their concentration. Furthermore, total anti-IFX Ab concentrations appeared superior to the unbound neutralizing fraction in identifying high clearance individuals. Simulations showed that even at low concentrations, anti-IFX Abs lead to sub-therapeutic IFX concentrations, supporting a need of treatment interventions in all anti-IFX Ab positive patients. The developed model can serve as a basis for further investigations to refine treatment recommendations for patients with anti-IFX Abs.

Drug treatment of epidermal growth factor receptor (EGFR) positive non-small cell lung cancer has improved substantially by targeting activating mutations within the receptor tyrosine kinase domain. However, the development of drug resistance still limits this approach. As root causes, large heterogeneity between tumour entities but also within tumour cells have been suggested. Therefore, approaches to identify these multitude and complex mechanisms are urgently required. Affinity purification coupled with high resolution mass spectrometry was applied to isolate and characterise the EGFR interactome from HCC4006 non-small cell lung cancer cells and their variant HCC4006 r ERLO 0.5 adapted to grow in the presence of therapeutically relevant concentrations of erlotinib. Bioinformatics analyses were carried out to identify proteins and their related molecular functions that interact differentially with EGFR in the untreated state or when incubated with erlotinib prior to EGFR activation. Across all experimental conditions 375 proteins were detected to participate in the EGFR interactome, 90% of which constituted a complex protein interaction network that was bioinformatically reconstructed from literature data. Treatment of HCC4006 r ERLO 0.5 cells carrying a resistance phenotype to erlotinib was associated with an increase of protein levels of members of the clathrin-associated adaptor protein family AP2 (AP2A1, AP2A2, AP2B1), structural proteins of cytoskeleton rearrangement as well as signalling molecules such as Shc. Validation experiments confirmed activation of the Ras-Raf-Mek-Erk (MAPK)-pathway, of which Shc is an initiating adaptor molecule, in HCC4006 r ERLO 0.5 cells. Taken together, differential proteins in the EGFR interactome of HCC4006 r ERLO 0.5 cells were identified that could be related to multiple resistance mechanisms including alterations in growth factor receptor expression, cellular remodelling processes suggesting epithelial-to-mesenchymal transition as well as alterations in downstream signalling. Knowledge of these mechanisms is a pivotal step to build an integrative model of drug resistance in a systems pharmacology manner and to be able to investigate the interplay of these mechanisms and ultimately recommend combinatorial treatment strategies to overcome drug resistance., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: A standardized medication plan for patients has been developed and recently enacted into German law depicting all medicines taken. It can only increase medication safety if patients use and understand it. We evaluated patients' comprehensibility of the medication plan and analyzed potential variables influencing patients' understanding., Methods: The medication plan template v2.0 was first tested in N = 40 patients, and the "Evaluation Tool to test the handling of the Medication Plan" (ET-MP) was developed, rating patients' understanding from 0 to 100 %. The cut-off, distinguishing if patients understand the medication plan, was set at 90 %. The ET-MP was then applied to an amended medication plan questioning N = 40 general internal medicine (GIM) and N = 50 patients with chronic heart failure (CHF)., Results: The mean (± standard deviation (SD)) age of the study cohort was 69 ± 13 years, 47 % female. Patients took 8 ± 3 drugs chronically. The CHF patients had a lower level of education compared to the GIM group (p = 0.004). The overall ET-MP score was 82 ± 21 % (GIM 86 ± 19 %, CHF 78 ± 23 %; p = 0.16). Forty-three percent achieved a score >90 %. A moderate correlation was found between the ET-MP score and the level of education (r = 0.45) and age (r = -0.46), respectively (both p < 0.001). Cognitively impaired CHF patients (p = 0.03) and patients with advanced CHF (p = 0.006) achieved a lower ET-MP score. In the CHF cohort, signs of depression or a lower level of self-care behaviour were not associated with a lower ET-MP score., Conclusion: The ET-MP is suitable to explore patients' understanding of a medication plan. Less than 50 % of the patients reached a score above 90 %. Higher age and lower level of education but not the diagnosis of CHF seem to correlate with impaired understanding of the standardized medication plan. In addition to a medication plan, a significant number of patients are in need of further and continuous care to improve medication safety.

Aims: Olodaterol is an orally inhaled β2 -agonist for treatment of chronic obstructive pulmonary disease (COPD). The aims of this population pharmacokinetic (PK) analysis were: (1) to investigate systemic PK and thereby make inferences about pulmonary PK in asthmatic patients, COPD patients and healthy volunteers, and (2) to assess whether differences in pulmonary efficacy might be expected based on pulmonary PK characteristics., Methods: Plasma and urine data after olodaterol inhalation were available from six clinical trials comprising 710 patients and healthy volunteers (single and multiple dosing). To investigate the relevance of covariates, full fixed-effect modelling was applied based on a previously developed healthy volunteer systemic disposition model., Results: A pulmonary model with three parallel absorption processes best described PK after inhalation in patients. The pulmonary bioavailable fraction (PBIO) was 48.7% (46.1-51.3%, 95% confidence interval) in asthma, and 53.6% (51.1-56.2%) in COPD. In asthma 87.2% (85.4-88.8%) of PBIO was slowly absorbed with an absorption half-life of 18.5 h (16.3-21.4 h), whereas in COPD 80.1% (78.0-82.2%) was absorbed with a half-life of 37.8 h (31.1-47.8 h). In healthy volunteers absorption was faster, with a half-life of 18.5 h (16.3-21.4 h) of the slowest absorbed process, which characterized 74.6% (69.1-80.2%) of PBIO., Conclusions: The modelling approach successfully described data after olodaterol inhalation in patients and healthy volunteers. Slow pulmonary absorption was demonstrated both in asthma and COPD. Absorption characteristics after olodaterol inhalation indicated even more beneficial lung targeting in patients compared to healthy volunteers., (© 2016 The British Pharmacological Society.)