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Neurologic complications are common in patients with sickle cell anemia (SCA), but conventional tools such as MRI and transcranial Doppler ultrasonography (TCD) do not fully assess cerebrovascular pathology. Cerebral tissue oximetry measures mixed oxygen saturation in the frontal lobes (SCT O2 ) and provides early prognostic information about tissue at risk of ischemic injury. Untreated patients with SCA have significantly lower SCT O2 than healthy controls that declines with age. Hydroxyurea is effective in preventing many SCA-related complications, but the degree to which it preserves normal neurophysiology is unclear. We analyzed participants enrolled in the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154), which enrolled participants initiating hydroxyurea using individualized dosing (New Cohort) and those previously taking hydroxyurea (Old Cohort) and was designed to monitor the long-term benefits of hydroxyurea. Cerebral oximetry was performed at baseline and annually. For the New Cohort (median starting age = 12 months, n = 55), mean baseline SCT O2 was normal before starting hydroxyurea (mean 65%, 95% CI 58-72%) and significantly increased after two years (mean 72%, 95% CI 65-79%, p = 0.00001). The SCT O2 for patients receiving long-term hydroxyurea (median age = 9.6 years) was normal at study entry (mean 66%, 95% CI 58-74%) and remained stable across two years. Both cohorts had significantly higher SCT O2 than published data from predominantly untreated SCA patients. Cerebral oximetry is a non-invasive method to assess cerebrovascular pathology that complements conventional imaging. Our results indicate that hydroxyurea suggests protection against neurophysiologic changes seen in untreated SCA. This article is protected by copyright. All rights reserved.

Background/Objective We report the first analysis of an extended half‐life recombinant factor IX, nonacog beta pegol (N9‐GP), in previously untreated patients (PUPs) and minimally treated patients with hemophilia B. Methods Paradigm 6 (Safety and Efficacy of Nonacog Beta Pegol [N9‐GP] in Previously Untreated Patients With Haemophilia B) is a multicenter, open‐label, single‐arm, phase 3 trial. Main inclusion criteria were males aged

Considerable inter- and intra-patient variability exist in serum activity levels of PEGasparaginase, essential for pediatric acute lymphoblastic leukemia (ALL) treatment. A population pharmacokinetic (popPK) model was developed, identifying patient characteristics that explain these variabilities. Patients (n=92) were treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol, using therapeutic drug monitoring to individualize PEGasparaginase doses. Non-linear mixed effects modeling (NONMEM) was used to analyze popPK evaluating several covariates. The final model was validated using an independent database (n=28). Guidelines for starting doses and dose adjustments were developed. A one-compartment model with time-dependent clearance was adequately described in popPK. Normalization of clearance and volume of distribution by body surface area reduced inter-individual variability. Clearance was 0.084 L/day/m2 for 12.7 days, increasing by 0.082 L/day/m2/day thereafter. Clearance was 38% higher during an infection, and 11-19% higher during induction treatment than during intensification and maintenance (P2 (induction) and 600 IU/m2 (intensification) is advised. In conclusion, variability of PEGasparaginase activity levels can be explained by body surface area, the treatment phase and the occurrence of an infection. With this popPK model, PEGasparaginase treatment can be individualized further, taking into account the covariates and the dosing guidelines provided. (clinicaltrials gov. Identifier [CCMO register]: NL50250.078.14).

Precise prescription of medication dosing is crucial to patients, especially among Intensive Care Unit (ICU) patients. However, improper administration of some sensitive therapeutic medications (e.g., heparin) might place patients at unneeded risk, even life-threatening. Numerous factors such as a patient's clinical phenotype, genotype, and environmental factors will affect the heparin dose response. As a result, it is challenging to prescribe the optimal initial dose of heparin. In this paper, an individualized dosing policy is proposed to determine the optimal initial dose and minimize the risk of mis-dosing, as well as preventing the patients from late complications associated with medications dosing. A latent batch-constrained deep reinforcement learning (RL) algorithm is proposed to guarantee the safety of the medication recommendation system. The agent can observe a latent representation of patents and generate medication dosing solutions in successive and limited action spaces. The individualized dosing policy aims to reduce the extrapolation errors in the off-policy algorithms, by evaluating over-dosing and under-dosing of heparin in patients. Our results evaluated on Medical Information Mart for Intensive Care III (MIMIC-III) database demonstrate that the latent batch-constrained RL algorithm can work effectively from the retrospective data, showing promise to be used in future medication dosing policies.(C)& nbsp;2021 Elsevier B.V. All rights reserved.

Fixed dosing of oral targeted therapies is inadequate in the era of precision medicine. Personalized dosing, based on pharmacokinetic (PK) exposure, known as therapeutic drug monitoring (TDM), is rational and supported by increasing evidence. The purpose of this perspective is to discuss whether randomized studies are needed to confirm the clinical value of precision dosing in oncology. PK-based dose adjustments are routinely made for many drugs and are recommended by health authorities, for example, for patients with renal impairment or for drug–drug interaction management strategies. Personalized dosing simply extrapolates this paradigm from selected patient populations to each individual patient with suboptimal exposure, irrespective of the underlying cause. If it has been demonstrated that exposure is related to a relevant clinical outcome, such as efficacy or toxicity, and that exposure can be optimized by PK-guided dosing, it could be logically assumed that PK-guided dosing would result in better treatment outcomes without the need for randomized confirmatory trials. We propose a path forward to demonstrate the clinical relevance of individualized dosing of molecularly-targeted anticancer drugs.

Fixed dose regimen is currently the standard administration method for TKI. However, this case report indicated that TDM may by a useful approach to individualized dosing of TKI for the treatment of CML when initiating dialysis.

Background 3D-printing, compared to conventional medicine manufacturing technologies, is a versatile and highly modifiable technique that has the flexibility to produce medicine that meet patients' specific requirements such as individualized dosing, but also to customize the appearance of the dosage form, e.g., shape and colour. Objective To explore polypharmacy patients' perceptions and preferences regarding 3D-printed medicine, including their acceptability of patient-designed medicine. Setting The study was conducted in Zealand, Denmark. Method Polypharmacy patients were recruited using convenience sampling (mostly on Facebook) and interviewed twice using semi-structured interviews. Interviews were analysed thematically into five predetermined themes (shapes, colours, embossing designs, polypills, and patient-designed dosage forms). At the first interview patients were asked about their perceptions and preferences towards 3D-printed solid dosage forms, and were presented to different shapes, colours, embossing designs and examples of polypills. They were also invited to design their own medicine from the ones presented. Their self-designed medicines were presented at the second interview, where acceptability of both their self-designed medicine and the concept of designing one's own medicine, was investigated. Main outcome measure Patients' perceptions, preferences towards and acceptability of 3D-printed medicines. Results Eight patients were included. They tended to prefer shapes similar to conventional medicine. Different colours were preferred by different people. The presented embossing designs seemed to be irrelevant. Polypills were generally believed to be a good idea due to the reduction of number of medicines. Acceptability of patient-designed medicine was mainly determined by whether patients thought 3Dprinting technology was reliable or not. Conclusions The patients had various perceptions and preferences of 3D-printed medicine. Factors affecting the patient views were aesthetic (appealing), physiological (swallowing), practical (handling), pedagogical (understanding) and psychological (relate to). Trust in the technology seemed to be important for acceptability.

Introduction The optimal treatment modality for haemophilia A is lifelong prophylaxis which is expensive and may not be implementable everywhere where factor VIII (FVIII) availability is limited. A less costly alternative to prophylaxis is low-dose prophylaxis (LDP) which was compared to conventional prophylaxis in this model-based simulation study. Aim To explore whether LDP is motivated where standard prophylaxis is not implementable, including evaluating LDP efficacy compared to high-dose prophylaxis and investigating the potential economic benefit of individualized dosing. Methods For a virtual adult haemophilia A population, FVIII activity levels were simulated following alternative treatment regimens, based on a published population PK model. The regimens included very LDP, LDP and conventional prophylaxis twice and thrice weekly. The annual probability of bleeding was predicted based on the weekly time spent below 1 IU/dL, using a previously published relationship. Additionally, PK-based dose individualization was evaluated to determine FVIII savings using Bayesian forecasting. Results A treatment regimen of 10 IU/kg administered thrice weekly cost 75% less than a standard high-dose regimen and was predicted to have a 5% higher median probability of annual bleeds. PK-based dose individualization may result in further cost-savings, but implementation needs benefit versus feasibility consideration. Conclusion Based on simulations, a promising LDP regimen was identified that decreased treatment costs compared with standard high-dose prophylaxis at a small increase in bleeding risk. The results indicate that LDP is advocated where the standard-of-care is on-demand treatment; however, the results should be considered in the context of any limitations of the applied models.

Background: Biologics for moderate-to-severe psoriasis are expensive and treatment substitutions may vastly increase cost. Moreover, administration regimens in routine practice may differ from recommended guidelines. Objectives: To evaluate long-term effectiveness, regimen, drug-survival, and efficiency of self-administered biologics in clinical practice. Methods: We performed a 5-year retrospective study in 72 patients (44 ± 14 years old) with moderate-to-severe psoriasis at the University Hospital La Plana (Vila-real, Spain), treated with subcutaneous biologics. We determined the effectiveness (PASI 75 or PASI < 5), and drug-survival using Kaplan-Meier estimates, and analyzed reasons for treatment interruption, drug substitution patterns, and costs. Results: Etanercept was less effective (45%) than ustekinumab (85%) and adalimumab (71%). In 15% of patients, optimal responses were maintained despite dose intervals lengthening. Drug-survival was significantly lower for etanercept than for the other biologics (p

Whilst the monitoring of drug therapies based on the determination of drug concentrations in biological materials is certainly an important instrument for individualized dosing and dose adjustment with a broad variety of pharmaceuticals, its role is limited by the fact that it does not reflect pharmacodynamic and toxicodynamic interactions such as those caused by individual and environment-related factors. However, these interactions are important for both the efficacy and the safety of the drug therapy. Therefore, during recent years there is an increased interest in personalized drug therapy as reflected by the development and clinical implementation of molecular “biomarkers” that are direct or surrogate markers of pharmacological effects (pharmacodynamic therapeutic drug monitoring, PD TDM). Moreover, this process is driven by new developments in instrumentation, such as mass spectrometry and array technologies, and in computational biology/pharmacology, data bases and bioinformatics. This Focus Issue of the journal focuses on current achievements in and status of PD TDM with different classes of drugs. The contributions to the present issue of Therapeutic Drug Monitoring provide a critical analysis of current practices of TDM with their limitations, introduce newer promising biomarkers in the field of PD TDM, discuss the challenges faced to date in translating preclinical tools into clinical settings and point out recent advances in the establishment of modeling approaches that apply to pharmacokinetics/pharmacodynamics (PK/PD) as well as pharmacogenetic information.

Background: 3D printing technology is a new chapter in pharmaceutical manufacturing and has gained vast interest in the recent past as it offers significant advantages over traditional pharmaceutical processes. Advances in technologies can lead to the design of suitable 3D printing device capable of producing formulations with intended drug release. Methods: This review summarizes the applications of 3D printing technology in various drug delivery systems. The applications are well arranged in different sections like uses in personalized drug dosing, complex drugrelease profiles, personalized topical treatment devices, novel dosage forms and drug delivery devices and 3D printed polypills. Results: This niche technology seems to be a transformative tool with more flexibility in pharmaceutical manufacturing. Typically, 3D printing is a layer-by-layer process having the ability to fabricate 3D formulations by depositing the product components by digital control. This additive manufacturing process can provide tailored and individualized dosing for treatment of patients different backgrounds with varied customs and metabolism pattern. In addition, this printing technology has the capacity for dispensing low volumes with accuracy along with accurate spatial control for customized drug delivery. After the FDA approval of first 3D printed tablet Spritam, the 3D printing technology is extensively explored in the arena of drug delivery. Conclusion: There is enormous scope for this promising technology in designing various delivery systems and provides customized patient-compatible formulations with polypills. The future of this technology will rely on its prospective to provide 3D printing systems capable of manufacturing personalized doses. In nutshell, the 3D approach is likely to revolutionize drug delivery systems to a new level, though need time to evolve.

Continuously manufactured orodispersible films (ODFs) offer a promising approach for individualized therapy with an easy to administer solid dosage form. The aim of this study was to develop a long ODF containing warfarin sodium to enable safe and more flexible dosing. Formulation development was conducted systematically for the continuous film coating process. A continuously working pilot-scale coating bench was used for film manufacturing and the viscosities of the polymer solutions were investigated to obtain processible formulations. The investigation of the mechanical properties of the long film was an integral part of the study, because the handling of the long film during flexible dosing differs distinctly from the handling of a single dosed ODF. The secant modulus and the yield stress were evaluated as parameters with high information value about the deformation behavior of the ODF. A long warfarin ODF was successfully produced using the pilot-scale coating bench equipped with an optical probe for in-line film thickness measurement. It was feasible to use the principle of a tape dispenser for flexible and, therefore, individualized dosing as proof of concept. Combining the long ODF with a dosing device allows individualized therapy with warfarin for all age groups manageable by the patient himself.

INTRODUCTION: : Emerging studies suggest that antibiotic pharmacokinetics (PK) are difficult to predict in critically ill patients. The high intra- and inter-patient PK variability makes it challenging to accurately predict the appropriate dosage required for a given patient. Identifying patients at risk could help clinicians to consider more individualized dosing regimens and perform therapeutic drug monitoring. We provide an overview of relevant predictors associated with target (non-)attainment of β-lactam antibiotics in critically ill patients. AREAS COVERED: : This narrative review summarizes patient and clinical characteristics that can help to predict the attainment of target serum concentrations and to provide guidance on antimicrobial dose optimization. Literature was searched using Embase and Medline database, focusing on β-lactam antibiotics in critically ill patients. EXPERT OPINION: : Adequate concentration attainment can be anticipated in critically ill patients prior to initiating empiric β-lactam antibiotic therapy based on readily available demographic and clinical factors. Male gender, younger age, and augmented renal clearance were the most significant predictors for target non-attainment and should be considered in further investigations to develop dosing algorithms for optimal β-lactam therapy.

Tamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (CSS,min ENDX) &gt, 5.97 ng/mL have been associated with favorable outcome. Endoxifen formation is mediated by the enzyme CYP2D6, and impaired CYP2D6 function has been associated with lower CSS,min&nbsp, ENDX. In the Women’s Healthy Eating and Living (WHEL) study proposing the target concentration, 20% of patients showed subtarget CSS,min ENDX at tamoxifen standard dosing. CYP2D6 allele frequencies vary largely between populations, and as 87% of the patients in the WHEL study were White, little is known about the risk for subtarget CSS,min ENDX in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget CSS,min ENDX at tamoxifen standard dosing and the need for dose individualization in nine different biogeographical groups with distinct CYP2D6 allele frequencies. The high variability in CYP2D6 allele frequencies amongst the biogeographical groups resulted in an up to three-fold difference in the percentages of patients with subtarget CSS,min ENDX. Based on their CYP2D6 allele frequencies, East Asian breast cancer patients were identified as the population for which personalized, model-informed precision dosing would be most beneficial (28% of patients with subtarget CSS,min ENDX).

Background: The MeroRisk-calculator, an easy-to-use tool to determine the risk of meropenem target non-attainment after standard dosing (1000 mg, q8h), uses a patient’s creatinine clearance and the minimum inhibitory concentration (MIC) of the pathogen. In clinical practice, however, the MIC is rarely available. The objectives were to evaluate the MeroRisk-calculator and to extend risk assessment by including general pathogen sensitivity data. Methods: Using a clinical routine dataset (155 patients, 891 samples), a direct data-based evaluation was not feasible. Thus, in step 1, the performance of a pharmacokinetic model was determined for predicting the measured concentrations. In step 2, the PK model was used for a model-based evaluation of the MeroRisk-calculator: risk of target non-attainment was calculated using the PK model and agreement with the MeroRisk-calculator was determined by a visual and statistical (Lin’s concordance correlation coefficient (CCC)) analysis for MIC values 0.125–16 mg/L. The MeroRisk-calculator was extended to include risk assessment based on EUCAST-MIC distributions and cumulative-fraction-of-response analysis. Results: Step 1 showed a negligible bias of the PK model to underpredict concentrations (−0.84 mg/L). Step 2 revealed a high level of agreement between risk of target non-attainment predictions for creatinine clearances &gt, 50 mL/min (CCC = 0.990), but considerable deviations for patients &lt, 50 mL/min. For 27% of EUCAST-listed pathogens the median cumulative-fraction-of-response for the observed patients receiving standard dosing was &lt, 90%. Conclusions: The MeroRisk-calculator was successfully evaluated: For patients with maintained renal function it allows a reliable and user-friendly risk assessment. The integration of pathogen-based risk assessment substantially increases the applicability of the tool.

Model-informed precision dosing (MIPD) has become synonymous with modern approaches for individualizing drug therapy, in which the characteristics of each patient are considered as opposed to applying a one-size-fits-all alternative. This review provides a brief account of the current knowledge, practices, and opinions on MIPD while defining an achievable vision for MIPD in clinical care based on available evidence. We begin with a historical perspective on variability in dose requirements and then discuss technical aspects of MIPD, including the need for clinical decision support tools, practical validation, and implementation of MIPD in health care. We also discuss novel ways to characterize patient variability beyond the common perceptions of genetic control. Finally, we address current debates on MIPD from the perspectives of the new drug development, health-care economics, and drug regulations. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 7, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

A key goal in drug development is optimized dosing for patients. Interactions between drug developers and regulatory scientists throughout development are important for the optimization of dosing and serve as a forum to discuss approaches for optimal dosing such as precision or individualized dosing. To date, there has not been a systematic assessment of the advice provided by the US Food and Drug Administration (FDA) to drug developers from an individualized dosing perspective. Here, we reviewed FDA recommendations on dose selection for efficacy trials at End-of-Phase (EOP) meetings between the FDA and drug developers for 76 New Molecular Entities (NMEs) approved between 2013–2017 that are considered amenable for an individualized dosing method, response-guided titration (RGT). Forty FDA dosing recommendations were identified as specific to dose selection and design of the respective efficacy trials and subsequently: 1) characterized based on if they were supportive of individualized dosing and 2) compared with dosing regimens used in efficacy trials and labeling at approval to evaluate if FDA recommendations were implemented. Of these 40 recommendations for efficacy trials, 35 (88%) were considered supportive of individualized dosing. Eighteen of these 40 recommendations (45%) were incorporated into efficacy trials and 11 (28%) were incorporated into labeling. This research suggests that early FDA-sponsor interactions can support the study of doses in efficacy trials that may lead to individualized dosing strategies in labeling.

Fluoropyrimidines are widely used in the treatment of several types of solid tumors. Although most often well tolerated, severe toxicity is encountered in similar to 20-30% of the patients. Individualized dosing for these patients can reduce the incidence of severe fluoropyrimidine-related toxicity. However, no consensus has been achieved on which dosing strategy is preferred. The most established strategy for individualized dosing of fluoropyrimidines is upfront genotyping of the DPYD gene. Prospective research has shown that DPYD-guided dose-individualization significantly reduces the incidence of severe toxicity and can be easily applied in routine daily practice. Furthermore, the measurement of the dihydropyrimidine dehydrogenase (DPD) enzyme activity has shown to accurately detect patients with a DPD deficiency. Yet, because this assay is time-consuming and expensive, it is not widely implemented in routine clinical care. Other methods include the measurement of pretreatment endogenous serum uracil concentrations, the uracil/dihydrouracil-ratio, and the 5-fluorouracil (5-FU) degradation rate. These methods have shown mixed results. Next to these methods to detect DPD deficiency, pharmacokinetically guided follow-up of 5-FU could potentially be used as an addition to dosing strategies to further improve the safety of fluoropyrimidines. Furthermore, baseline characteristics, such as sex, age, body composition, and renal function have shown to have a relationship with the development of severe toxicity. Therefore, these baseline characteristics should be considered as a dose-individualization strategy. We present an overview of the current dose-individualization strategies and provide perspectives for a future multiparametric approach.

WHAT IS KNOWN AND OBJECTIVE Population pharmacokinetic (PopPK) models of valproic acid (VPA) have been developed to aid individualized drug dosing, but most of these have been based on the treatment of epileptic patients and recent evidence shows that VPA clearance (CLVPA ) in manic patients differs from that in epileptic patients. In the light of this, the predictive ability of selected VPA PopPK models based on epileptic patients was assessed to determine whether they could be used with patients with mania. METHODS VPA PopPK models that were based on the treatment of epileptic patients and developed using a non-linear mixed-effect approach with a one-compartment structure were selected and used to predict the VPA concentrations of a validation data set. The mean absolute prediction error (MAPE) and root mean square error (RMSE) were used to assess the accuracy and precision of the model. RESULTS The validation data set consisted of 235 Thai manic patients with a mean age of 39.6 years and a mean weight of 62.8 kg. Five models were selected to predict VPA concentrations in patients suffering from mania, and these were labelled A, C, E, F and G. The results showed that all models sufficiently predicted VPA concentrations in patients with mania, and of the models studied, G provided the most accurate and precise predictions, with MAPE and RMSE of 23% and 29.75, respectively. WHAT IS NEW AND CONCLUSION VPA PopPK models developed using patients with epilepsy can also be used for individualized dosing of patients with mania, but before implementation, the accuracy of these models' predictions should be assessed in the target population.

Linda Tahaineh,1 Sahar M Edaily,1 Shadi F Gharaibeh2 1Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology (JUST), Irbid, Jordan; 2Department of Pharmaceutical Sciences, Faculty of Pharmacy, Jerash University, Jerash, Jordan Objectives: To evaluate the degree of anticoagulation achieved with different enoxaparin dosing regimens used in obese and morbidly obese patients in a hospital setting in Jordan.Methods: All obese adult patients who were prescribed enoxaparin for various indications were invited to participate in the study. The anti-factor Xa (anti-Xa) level was checked once after 4–6 hours of the third or fourth dose of enoxaparin (at steady state). Patients were followed daily to evaluate drug efficacy and safety through their hospital course.Results: Enoxaparin daily dose used for prophylaxis indications ranged from 0.3 to 0.85 mg/kg and from 0.31 to 2.25 mg/kg in case of certain treatment indications. Most participants who received enoxaparin for treatment indications (76.9%) were on capping dosing regimens, which was 0.05). No bleeding events or thrombocytopenia were noticed, and there was one case of recurrent thrombosis.Conclusion: Enoxaparin dosing regimens that were used for obese patients varied based on prescribing physicians. Regardless of the regimen used, the majority of participants had nontherapeutic anti-Xa. Individualized dosing regimens based on anti-Xa levels are warranted for obese patients on enoxaparin. Keywords: anti-factor Xa, anticoagulation, enoxaparin, obesity

Fixed dosage regimen is currently the standard therapy with tyrosine kinase inhibitors (TKI). This case report demonstrates successful determination of nilotinib dosage by therapeutic drug monitoring (TDM) in a patient with chronic myeloid leukemia (CML). TDM may provide useful marker for individualized dosing of TKI for the treatment of CML.

This paper addresses dose finding in clinical trials where individuals exhibit biologic characteristics that alter the toxicity risks of the individuals. In these situations, instead of determining a dose that works for every patient, the trial aims to identify a dosing algorithm that prescribes dose according to the patient's biomarker or pharmacokinetic expression. Specifically, we aim to dose patients around a pre-specified level of area under the curve of irinotecan concentration using the patients' baseline phenotypes that predict drug clearance. We propose least squares recursion procedures to estimate the dosing algorithm sequentially with an aim to treat patients in the trial around the true unknown dosing algorithm, and introduce a novel application of an eigenvalue theory that guarantees convergence to the true dosing algorithms. Our simulation study demonstrates that using an eigenvalue constraint improves the efficiency of the recursion by as large as 40%, while concentrating in-trial patient allocation around the true dosing algorithm. We also provide practical guidance on design calibration, and design future irinotecan studies based on data from our first trial.

The prospect of precision dosing in oncology is attractive for several reasons. Many anticancer drugs display narrow therapeutic indices, where suboptimal therapy may lead to severe patient outcomes. Clinical study participant recruitment is seldom extended beyond the intended patient population, leading to difficulties in patient recruitment in dedicated clinical trials. The high rate of non-responders and high cost of cancer therapy warrant novel solutions to increase clinical effectiveness and cost-benefit, pharmacokinetic (PK) modeling and model-informed precision dosing (MIPD) can help to maximize these. PK modeling provides a quantitative framework to account for inter-individual variability in drug exposure, the influence of covariates and extrapolation to special populations or drug-drug interactions, using physiologically-based PK (PBPK) modeling. Here we present the current state of PK modeling in precision dosing of anticancer drugs and illustrate its utility, based on an extensive literature review and numerous case examples from both pharmaceutical industry and healthcare focused research. While some great progress has been made in implementing model-informed dosage guidance in the drug label and much research has been carried out to address clinically relevant dosing questions, the uptake of MIPD has been modest in healthcare. The success of PK modeling in industry has been made possible through collaborative efforts between regulators, industry and academia. Collaboration between academia, healthcare and industry, and financial support for research into patient benefit, cost-benefit and clinical effectiveness of these approaches is imperative for wider adaption of PK modeling in precision dosing of anticancer drugs

Background Clinicians alter dosing for desoxycorticosterone pivalate (DOCP) to mitigate costs, but this practice has not been critically evaluated in a prospective clinical trial. Hypothesis/Objectives The duration of action of DOCP is longer than 30 days in dogs with primary hypoadrenocorticism (PH). Animals A total of 53 client-owned dogs with PH. Twenty-four dogs with newly diagnosed PH (Group 1) and 29 dogs with treated PH (Group 2). Methods Prospective, multicenter, clinical trial. For phase I, DOCP was administered and plasma sodium and potassium concentrations were measured until the dog developed hyponatremia or hyperkalemia at a planned evaluation, or displayed clinical signs with plasma electrolyte concentrations outside of the reference interval independent of a planned evaluation, thus defining DOCP duration of action. Plasma electrolyte concentrations then were assessed at the end of the individualized dosing interval (IDI; i.e., DOCP duration of action minus 7 days, phase II and at least 3 months after concluding phase II, phase III). Results The duration of action of DOCP in dogs in phase I with naive PH (n = 24) ranged from 32 to 94 days (median, 62 days; 95% confidence interval [CI], 57, 65) and previously treated PH (n = 29) from 41 to 124 days (median, 67 days; CI, 56, 72). Overall, the final DOCP dosing interval for all dogs that completed phase II (n = 36) ranged from 38 days to 90 days (median, 58 days; CI, 53, 61). No dog that completed phase III (n = 15) required reduction in the IDI. The DOCP duration of action, independent of group, was not significantly associated with several baseline variables. The median drug cost reduction using IDI was approximately 57.5% per year. Conclusion and Clinical Importance The duration of action of DOCP in dogs with PH is >30 days, and plasma sodium and potassium concentrations can be maintained with an IDI >30 days long term.

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. However, relapse disease and graft-versus-host disease (GVHD) remain to be the main obstacle for a successful HCT. Thus, adequate immune suppression to minimize the risk of high-grade GVHD while not over suppression of donor immunity to allow graft versus tumor effect is crucial. Matched unrelated donor transplant has a higher rate of GVHD as compared to matched sibling donor transplant due to minor histocompatibility mismatch. Rabbit antithymocyte globulin (ATG), a polyclonal antibody produced by immunizing rabbits with human thymocytes, has been utilized as prophylaxis against GVHD. ATG dosing by weight has been the standard. Recent pharmacokinetic (PK) studies revealed that ATG levels and clearance vary significantly among patients receiving weight-based dosing of ATG. Recipient lymphocyte count before receiving ATG has been described as a modulator of both ATG PK and clinical outcomes after ATG-conditioned HCT. The Parachute-Study utilizing an individualized ATG dosing approach has shown more rapid immune reconstitution without affecting the incidence of acute GVHD and graft failure. In this study, we are comparing the outcomes of individualized dosing of ATG versus weight-based dosing. Method: This is a single institutional study carried out at the Bone Marrow Transplant Program at the University of Oklahoma Health Science Center. It was started as a case-control cohort study in July 2018 when individualized dosing of ATG was initiated, and continues as a historically controlled non-randomized prospective clinical study investigating individualized versus weight-based dosing of ATG. Subjects over 18 years of age who are undergoing matched unrelated donor (MUD) stem cell transplant, with myeloablative or reduced-intensity conditioning, peripheral blood or bone marrow stem cell source, for myeloid or lymphoid malignancies were included in the study. We excluded subjects with HLA mismatch or sibling donors. Individualized dosing was based on the previously validated PK model with cumulative doses varying between 2 to 10 mg/kg, based on weight, recipient lymphocyte counts before the first dose of ATG, and stem cell source, starting day -9; while the standard weight-based dosing of ATG is 4 mg/kg divided into 3 days pre-transplant. The study endpoints are to evaluate the difference between treatment groups on (1) GVHD and its severity; (2) relapse-free survival (RFS) and (3) overall survival (OS). Univariate logistic regression analysis was used to evaluate the probabilities of GVHD in both treatment arms. Multivariable analysis was done to adjust for all covariates between study arms using adjusted logistic. OS and RFS were computed using the Kaplan-Meier curves. Results: The study included 38 subjects undergoing MUD HCT for myeloid or lymphoid malignancies. Subjects included are in 2 cohorts, 19 subjects in the intervention arm using individualized targeted ATG (tATG group), and 19 subjects in the matched control arm using weight-based dosing ATG (ATG group). In a univariate unadjusted logistic regression analysis, the risk of developing GVHD is numerically higher in the ATG group than in the tATG group (OR=1.339, p=0.70). However, the proportion of acute GVHD is significantly higher in the tATG group than the ATG group (73.68% vs 31.58%, p=0.022). Also, the proportion of higher grade acute GVHD is significantly higher in the tATG group than the ATG group (31.58% vs 0%, p=0.020). RFS is longer in the tATG group than the ATG group, tending statistical significance (p=0.063). However, there is no difference in OS between study arms (p=0.645). [Figures 1 and 2] In a multivariable-adjusted logistic regression, adjusting for age at HCT, diagnosis, disease status at HCT, prior lines of therapy, and stem cell source, no confounder was found to be significantly associated with GVHD. Conclusion: Individualized targeted dosing of ATG (tATG), based on weight, recipient lymphocyte counts and stem cell source, increases the risk of acute GVHD when compared to standard fixed-dosing method, however, it improves RFS, implying possibly better immune reconstitution providing improved graft versus leukemia effect. Disclosures No relevant conflicts of interest to declare.

Background Ustekinumab (UST) is a human monoclonal antibody used to treat moderate-to-severe Crohn disease by blocking the interleukin-12/23 pathway. Although an optimized therapeutic concentration of UST is associated with clinical response and improved prognosis, the availability of clinical laboratory methods for UST monitoring is limited. Furthermore, the commercially available methods are immunoassays that are prone to interference of antidrug antibodies. This study aimed to develop a liquid chromatography-tandem mass spectrometry method for quantification of UST in human serum specimens. Methods A tryptic peptide that is specific to the heavy chain variable region of UST was selected. Quantification of UST was performed by selective reaction monitoring on a quadrupole TQ-XS with an internal standard. After digestion with trypsin, peptides were separated by reverse-phase C18 liquid chromatography; peptides were detected by MS/MS, and analyte to internal standard peak area ratios were used for the quantification. Finally, serum samples from patients treated with UST were collected at trough levels (n = 66). Results The assay showed a broad dynamic range with linearity between 0.4 and 20 mg/L (R = 0.995). The lower limit of quantification was found to be 0.4 mg/L. The reproducibility was tested with 3 different UST concentrations (2, 8, and 16 mg/L). The coefficients of intra-assay and interassay variations were 2.2%-4.0% and 2.7%-5.3%, respectively. UST serum concentrations of 2-16 mg/L were stable for up to 14 days when specimens were left at room temperature (20°C). Conclusions The newly developed LC/MS-based method was shown to be feasible for UST quantification. This analytical approach may lead to individualized dosing and improved patient care.

Diabetic macular edema (DME) is the most common cause of vision loss among patients with diabetes mellitus (DM), rendering it an important growing challenge in ophthalmology. In the past decades, the management strategies for DME had a few paradigm shifts, and the advent of an expanding number of anti-vascular endothelial growth factor (VEGF) agents also calls for an in-depth examination of the currently available evidence. This article was composed with the intention to provide recommendations for practicing clinicians to improve the management and, through it the outcomes of DME. Drawing from current guideline recommendations, clinical trial findings and local clinical experiences, these consensus recommendations for the management of DME were formed by an expert panel through iterations of discussion and voting. First, the treatment goal of DME is to achieve best visual outcome with edema improvement while minimizing treatment burden. Second, anti-VEGF therapy should be considered as the first-line treatment for patients with center-involving DME causing vision loss. Baseline visual acuity (VA) and central subfield thickness (CST) should be taken into consideration when choosing anti-VEGF agents. Third, early intensive anti-VEGF therapy (at least 3 monthly doses) is important for better patients’ VA and anatomical improvement. In non-responders who have already been treated with 3-5 injections of anti-VEGF agents, it is reasonable to switch to other modalities, such as steroids. Finally, for the follow-up phase, fixed or individualized dosing should be considered based on VA and OCT.

International audience; Objective To compare response to rituximab (RTX) between adult patients positive for myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) antibodies. Methods We prospectively studied adult patients with MOG or AQP4 antibodies who received RTX under an individualized dosing schedule adapted to the biological effect of RTX monitored by memory B-cell measurement. Memory B cells were counted monthly and when relapse occurred. The biological effect of RTX was considered significant with

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

Background Unique amongst brain stimulation tools, transcranial direct current stimulation (tDCS) currently lacks an easy or widely implemented method for individualizing dosage. Objective We developed a method of reverse-calculating electric-field (E-field) models based on Magnetic Resonance Imaging (MRI) scans that can estimate individualized tDCS dose. We also evaluated an MRI-free method of individualizing tDCS dose by measuring transcranial magnetic stimulation (TMS) motor threshold (MT) and single pulse, suprathreshold transcranial electrical stimulation (TES) MT and regressing it against E-field modeling. Key assumptions of reverse-calculation E-field modeling, including the size of region of interest (ROI) analysis and the linearity of multiple E-field models were also tested. Methods In 29 healthy adults, we acquired TMS MT, TES MT, and anatomical T1-weighted MPRAGE MRI scans with a fiducial marking the motor hotspot. We then computed a “reverse-calculated tDCS dose” of tDCS applied at the scalp needed to cause a 1.00 V/m E-field at the cortex. Finally, we examined whether the predicted E-field values correlated with each participant’s measured TMS MT or TES MT. Results We were able to determine a reverse-calculated tDCS dose for each participant using a 5 × 5 x 5 voxel grid region of interest (ROI) approach (average = 6.03 mA, SD = 1.44 mA, range = 3.75–9.74 mA). The Transcranial Electrical Stimulation MT, but not the Transcranial Magnetic Stimulation MT, significantly correlated with the ROI-based reverse-calculated tDCS dose determined by E-field modeling (R2 = 0.45, p Conclusions Reverse-calculation E-field modeling, alone or regressed against TES MT, shows promise as a method to individualize tDCS dose. The large range of the reverse-calculated tDCS doses between subjects underscores the likely need to individualize tDCS dose. Future research should further examine the use of TES MT to individually dose tDCS as an MRI-free method of dosing tDCS.

Item does not contain fulltext BACKGROUND: Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to efficacy and toxicity. Despite this knowledge, these drugs are still administered in a one-size-fits-all approach. Consequently, individual patients have a high probability to be either underdosed, which can lead to decreased antitumor efficacy, or overdosed, which could potentially result in increased toxicity. Therapeutic drug monitoring (TDM), personalized dosing based on measured drug levels, could be used to circumvent underdosing and overdosing and thereby optimize treatment outcomes. METHODS: In this prospective clinical study (www.trialregister.nl; NL6695), the feasibility, tolerability, and efficacy of TDM of oral anticancer drugs will be evaluated. In total, at least 600 patients will be included for (at least) 23 different compounds. Patients starting regular treatment with one of these compounds at the approved standard dose can be included. PK sampling will be performed at 4, 8, and 12 weeks after the start of treatment and every 12 weeks thereafter. Drug concentrations will be measured, and trough concentrations (Cmin) will be calculated. In cases where Cmin falls below the predefined target and acceptable toxicity, a PK-guided intervention will be recommended. This could include emphasizing compliance, adapting concomitant medication (due to drug-drug interactions), instructing to take the drug concomitant with food, splitting intake moments, or recommending a dose increase. DISCUSSION: Despite a strong rationale for the use of TDM for oral anticancer drugs, this is currently not yet widely adopted in routine patient care. This prospective study will be a valuable contribution to demonstrate the additional value of dose optimization on treatment outcome for these drugs.

Depth of anesthesia (DoA) monitors are widely used during general anesthesia to guide individualized dosing of hypnotics. Other than age and specific drugs, there are few reports on which comorbidities may influence the brain and the resultant electroencephalogram (EEG) of patients undergoing general anesthesia. We present a case of a patient undergoing 3 cardiac operations within 7 months with severe illness and comorbidity, leading to pronounced physical frailty and significant changes of frontal alpha power in the EEG and increased sensitivity to volatile anesthetics. These findings may have important clinical implications and should trigger further investigations on this topic.

OBJECTIVE: The stability of anti-Müllerian hormone (AMH) across and between menstrual cycles has been the subject of debate. The objective of this analysis was to study the inter- and intracycle variability in repeated measurements and assess the impact on an individualized gonadotropin dosing algorithm and predicted oocyte yield. DESIGN: Retrospective analysis of repeat AMH measures from a randomized controlled trial. PATIENTS: A total of 1326 women aged 18-40 years. MEASUREMENTS: Serum AMH levels at screening and at cycle day 2-3 in up to three ovarian stimulation cycles. AMH variability and its impact on gonadotropin dose and the predicted number of oocytes. RESULTS: Repeat serum AMH measurements were strongly correlated within individual women (correlation coefficient 0.92). AMH exhibited limited within-subject variation (coefficient of variation 23%), a small time-related decline (mean 6% decrease/y), but no systematic variation across the menstrual cycle. Irrespective of whether the AMH screening value or the AMH at the initiation of ovarian stimulation was used, for women with an AMH level

1. Several tacrolimus population pharmacokinetic (PPK) models in hematopoietic stem cell transplantation (HSCT) patients have been set up to recommend an optimal dosage schedule. However, the PPK model of Chinese pediatric HSCT patients has not been reported. The study is to investigate whether published PPK models of HSCT patients can be used to simulate Chinese pediatric HSCT patients and establish the tacrolimus PPK model of Chinese pediatric HSCT patients.2. Published PPK models were collected from the literature and assessed using Chinese pediatric HSCT patients via the individual prediction error method. The establishment of tacrolimus PPK model in Chinese pediatric HSCT patients was characterized with nonlinear mixed-effects modeling (NONMEM).3. Three published HSCT PPK models were identified, two of which could be applied to our external dataset. However, these models were dissatisfactory in terms of individual prediction error and, hence, inadequate for extrapolation. Finally, a new tacrolimus PPK model in Chinese pediatric HSCT patients was established. Based on the simulation results of our model, new initial dosage suggestions were recommended. In conclusion, the tacrolimus PPK model in Chinese pediatric HSCT patients was presented and the model could be used to predict individualized dosing regimens in children with HSCT.