Quality of FDM 3D Printed Medicines for Pediatrics: Considerations for Formulation Development, Filament Extrusion, Printing Process and Printer Design

Abstract3d printing is capable of providing dose individualization for pediatric medicines and translating the precision medicine approach into practical application. In pediatrics, dose individualization and preparation of small dosage forms is a requirement for successful therapy, which is frequently not possible due to the lack of suitable dosage forms. For precision medicine, individual characteristics of patients are considered for the selection of the best possible API in the most suitable dose with the most effective release profile to improve therapeutic outcome. 3d printing is inherently suitable for manufacturing of individualized medicines with varying dosages, sizes, release profiles and drug combinations in small batch sizes, which cannot be manufactured with traditional technologies. However, understanding of critical quality attributes and process parameters still needs to be significantly improved for this new technology. To ensure health and safety of patients, cleaning and process validation needs to be established. Additionally, adequate analytical methods for the in-process control of intermediates, regarding their printability as well as control of the final 3d printed tablets considering any risk of this new technology will be required. The PolyPrint consortium is actively working on developing novel polymers for fused deposition modeling (FDM) 3d printing, filament formulation and manufacturing development as well as optimization of the printing process, and the design of a GMP-capable FDM 3d printer. In this manuscript, the consortium shares its views on quality aspects and measures for 3d printing from drug-loaded filaments, including formulation development, the printing process, and the printed dosage forms. Additionally, engineering approaches for quality assurance during the printing process and for the final dosage form will be presented together with considerations for a GMP-capable printer design.

1101. Implementing a Beta-Lactam Therapeutic Drug Monitoring Program: Experience from a Large Academic Medical Center

Background Beta-lactams (BL) are the cornerstone of antimicrobial treatment for infections. Beta-lactam therapeutic drug monitoring (BL-TDM) optimizes drug concentrations to ensure maximal efficacy and minimal toxicity. The goals of this study were to describe the implementation process of a BL-TDM program and to further describe our experience using BL-TDM in clinical practice. Methods This was a retrospective review of adult patients with available BL-TDM between January 2016 and November 2019 at the University of Florida (UF) Health Shands Hospital. Total serum concentrations of BL were measured in the Infectious Diseases Pharmacokinetics Lab (IDPL) at UF, using a validated ultrahigh pressure liquid chromatography assay with triple quadrupole mass spectroscopy (LC-MS-MS). At our institution, TDM is available for 11 BLs and in-house assays are performed from Mon-Fri for most BLs. Results A total of 3,030 BL concentrations were obtained. An analysis was performed on the first BL-TDM encounter in 1,438 patients. The median age was 57 years (IQR, 41-69) and the median BMI was 27.5 kg/m2 (IQR, 22.5-34.5). On the day of BL-TDM, the median serum creatinine was 0.83 (IQR, 0.59-1.30). Fifty-one percent of patients (n=735) were in an ICU at the time of BL-TDM with a median SOFA score of 6 (IQR, 3-9). BL-TDM was most frequently performed on cefepime (61%, n=882), piperacillin (15%, n=218), and meropenem (11%, n=151). The BL was administered as a continuous infusion in 211 (15%) patients. An interim analysis of 548 patients showed that BL-TDM was performed a median of 2 days (IQR, 1-4) from the start of BL therapy and resulted in a dosage adjustment in 26% (n=145). Conclusion BL-TDM was performed in older, non-obese patients with normal renal function. Over half of the evaluated patients were in an ICU at the time of TDM. This finding emphasizes the value of BL-TDM in the ICU setting because altered pharmacokinetics during critical illness has been linked to enhanced BL clearance. Interestingly, BL-TDM resulted in dosage adjustment in 1 in 4 patients who were receiving licensed BL dosing regimens, thus highlighting the role of TDM in dose individualization. BL-TDM was performed most commonly within the 72-hours of therapy initiation. Early BL-TDM has been shown to improve patient outcomes and should be promoted. Disclosures Venugopalan Veena, PharmD, Melinta (Other Financial or Material Support, Received a stipend for participation in a drug registry)Merck (Other Financial or Material Support, Received a stipend for participation in a drug registry) Charles A. Peloquin, Pharm.D., Nothing to disclose

Dosage individualization proposed for anti-gout medications among the patients with gout

Background The conventional one-size-fits-all approach has been criticized for almost all drugs used especially for chronic diseases, including gout. The present study was aimed to explore the need of individualization and optimization of the dose of anti-gout medications among gout patients. Methods Cross-sectional study was carried out among 384 randomly selected new gout patients visiting two gout treatment centers at Lalitpur Metropolitan City, Nepal and who were taking antigout medications. Patients not taking anti-gout medications and not showing willingness to participate were excluded. The eGFR was calculated with the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation (2009). Doses to be individualized were decided based on the Renal Drug Handbook and verified with the BNF 80. Data were analyzed via R 4.0.3 by applying the multinomial logistic regression to analyze statistical significance of risk with various predictors, and considering a p-value <0.05 statistically significant. Comorbidities were coded as per the ICD-11 coding and medicines were coded according to the WHO Guidelines for ATC classification and DDD assignment 2020. Results The high risk of progression to CKD increased in the age range 54–63 and ≥84 years by 17.77 and 43.02 times, respectively. Also, high risk increased by 29.83 and 20.2 times for the overweight and the obese respectively. Aceclofenac 100mg was prescribed for maximum patients (30.5%). Need of dose individualization was realized in 30 patients, with maximum (7) in case of etoricoxib 90mg. Various glucocorticoids were prescribed for 36.9% patients, out of whom 3.8%required dose individualization and 15.9% patients with xanthine oxidase inhibitors, out of whom 1.3% required dose individualization. Conclusion Thirty cases required dose individualization, which was although minimal but could have meaningful impact on the clinical success of the individual patient. Based on the recommendation on dose individualization, those patients could be optimized on their therapy on future follow ups.

Advances in Therapeutic Drug Monitoring in Biologic Therapies for Pediatric Inflammatory Bowel Disease

In the current era of treat-to-target strategies, therapeutic drug monitoring (TDM) has emerged as a potential tool in optimizing the efficacy of biologics for children diagnosed with inflammatory bowel disease (IBD). The incorporation of TDM into treatment algorithms, however, has proven to be complex. “Proactive” TDM is emerging as a therapeutic strategy due to a recently published pediatric RCT showing a clear benefit of “proactive” TDM in anti-TNF therapy. However, target therapeutic values for different biologics for different disease states [ulcerative colitis (UC) vs. Crohn's disease (CD)] and different periods of disease activity (induction vs. remission) require further definition. This is especially true in pediatrics where the therapeutic armamentarium is limited, and fixed weight-based dosing may predispose to increased clearance leading to decreased drug exposure and subsequent loss of response (pharmacokinetic and/or immunogenic). Model-based dosing for biologics offers an exciting insight into dose individualization thereby minimizing the chances of losing response. Similarly, point-of-care testing promises real-time assessment of drug levels and individualized decision-making. In the current clinical realm, TDM is being used to prolong drug durability and efficacy and prevent loss of response. Ongoing innovations may transform it into a personalized tool to achieve optimal therapeutic endpoints.

Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups

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) >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 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).

CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry

Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05–0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6.

Model-Optimized Fluconazole Dose Selection for Critically Ill Patients Improves Early Pharmacodynamic Target Attainment without the Need for Therapeutic Drug Monitoring

ABSTRACT Fluconazole has been associated with higher mortality compared with the echinocandins in patients treated for invasive candida infections. Underexposure from current fluconazole dosing regimens may contribute to these worse outcomes, so alternative dosing strategies require study. The objective of this study was to evaluate fluconazole drug exposure in critically ill patients comparing a novel model-optimized dose selection method with established approaches over a standard 14-day (336-h) treatment course. Target attainment was evaluated in a representative population of 1,000 critically ill adult patients for (i) guideline dosing (800-mg loading and 400-mg maintenance dosing adjusted to renal function), (ii) guideline dosing followed by therapeutic drug monitoring (TDM)-guided dose adjustment, and (iii) model-optimized dose selection based on patient factors (without TDM). Assuming a MIC of 2 mg/liter, free fluconazole 24-h area under the curve (fAUC24) targets of ≥200 mg · h/liter and <800 mg · h/liter were used for assessment of target attainment. Guideline dosing resulted in underexposure in 21% of patients at 48 h and in 23% of patients at 336 h. The TDM-guided strategy did not influence 0- to 48-h target attainment due to inherent procedural delays but resulted in 37% of patients being underexposed at 336 h. Model-optimized dosing resulted in ≥98% of patients meeting efficacy targets throughout the treatment course, while resulting in less overexposure compared with guideline dosing (7% versus 14%) at 336 h. Model-optimized dose selection enables fluconazole dose individualization in critical illness from the outset of therapy and should enable reevaluation of the comparative effectiveness of this drug in patients with severe fungal infections.

Applications and challenges in therapeutic drug monitoring of cancer treatment: A review

Most anticancer agents show wide variability in pharmacokinetics (PK) and have a narrow therapeutic index which makes fixed dosing suboptimal. To achieve the best therapeutic outcomes with these agents, many studies have postulated using PK or therapeutic drug monitoring (TDM)-guided dosing. However, multiple factors contribute to the variability in PKs making the application of TDM in practice challenging. Also, despite the known association with clinical outcomes, standard guidelines on PK-guided dosing are lacking for most agents. Understanding the factors that contribute to PK variability and their impact is essential for dose individualization. The purpose of this review is to discuss the factors that contribute to the PK variability of anticancer agents and the challenges faced in practice when individualizing doses for certain widely used agents. Searching the literature has identified several gaps and efforts are needed to ensure better targeting of cancer therapeutics.

Dosage individualization proposed for anti-gout medications among the patients with gout: a bicentric study in Nepal

BackgroundThe conventional one-size-fits-all approach has been criticized for almost all drugs used especially for chronic diseases, including gout. The present study was aimed to individualize and optimize the dose of anti-gout medications among gout patients.Methods and findingsBicentric cross-sectional study was carried out among 384 randomly selected new gout patients visiting two gout treatment centers at Lalitpur Metropolitan City, Nepal and taking antigout medications. Patients not taking anti-gout medications and not showing unwillingness to participate were excluded. The eGFR was calculated with the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation (2009). Doses to be individualized were decided based on the Renal Drug Handbook and BNF 80. Data were analyzed via R 4.0.3. Multinomial logistic regression analysis was performed to analyze statistical significance of risk with various predictors, considering a p-value <0.05 statistically significant. Comorbidities were coded as per the ICD-11 coding and ATC classification of medicines as per the WHO Guidelines for ATC classification and DDD assignment 2020. High risk of progression to CKD increased in the age range 54-63 and ≥84 years by 17.77 and 43.02 times, respectively. High risk of gout increased by 29.83 and 20.2 times for overweight and obese patients respectively. Aceclofenac 100 mg was prescribed for maximum patients (117, 30.5%). Need of dose individualization was realized altogether in case of 30 patients (8%), with maximum (7, 1.8%) in case of etoricoxib 90 mg (i.e., avoid if possible). There were 260 (67.7%) cases without associated comorbidities, followed by 37 (9.6%) patients with hyperthyroidism. Various glucocorticoids were prescribed for 141 (36.9%) patients, out of whom 14 (3.8%) required dose individualization. Altogether 61 (15.9%) patients were prescribed with xanthine oxidase inhibitors, out of whom 5 (1.3%) required dose individualization.ConclusionsThirty (8%) cases required dose individualization, which was although minimal but could have meaningful impact on clinical success of individual patient. Based on the recommendation on dose individualization, those patients could be optimized on their therapy on future follow ups. Also, future randomized controlled trials may be based on these to derive a more conclusive evidence base for gout management.Author summaryWhy was this study done?Dosage individualization helps optimize drug selection and dosing based on pathogenesis, mechanism of action of drugs, and their dose exposure-response relationships.Very limited researches have been undertaken in Nepal to individualize medications for chronic medication users including gout patients. The present study was probably the first of its kind in Nepal aiming to individualize the dose of anti-gout medications among gout patients.What did the researchers do and find?Bicentric cross-sectional study was carried out among 384 new gout patients visiting two gout treatment centers in Nepal and taking antigout medications.Doses to be individualized were decided based on standard references of the Renal Drug Handbook and the British National Formulary 80. Dose to be individualized was later discussed with the prescribing physicians.Need of dose individualization was realized altogether in case of 30 patients (8%), with maximum (7, 1.8%) in case of etoricoxib 90 mg (i.e., avoid if possible).What do these findings mean?The present simple effort of individualization of antigout medications might help the physicians optimize the therapeutic success for the patients, once they implement it and patients adhere to it.Since the study was limited to only two gout and rheumatic diseases treatment centers, it might not represent the whole gout patients in the nation but it might provide the evidence base for future large controlled clinical trials.