Paediatric clinical study of 3D printed personalised medicines for rare metabolic disorders.

Rare diseases are infrequent, but together they affect up to 6-10 % of the world's population, mainly children. Patients require precise doses and strict adherence to avoid metabolic or cardiac failure in some cases, which cannot be addressed in a reliable way using pharmaceutical compounding. 3D printing (3DP) is a disruptive technology that allows the real-time personalization of the dose and the modulation of the dosage form to adapt the medicine to the therapeutic needs of each patient. 3D printed chewable medicines containing amino acids (citrulline, isoleucine, valine, and isoleucine and valine combinations) were prepared in a hospital setting, and the efficacy and acceptability were evaluated in comparison to conventional compounded medicines in six children. The inclusion of new flavours (lemon, vanilla and peach) to obtain more information on patient preferences and the implementation of a mobile app to obtain patient feedback in real-time was also used. The 3D printed medicines controlled amino acid levels within target levels as well as the conventional medicines. The deviation of citrulline levels was narrower and closer within the target concentration with the chewable formulations. According to participants' responses, the chewable formulations were well accepted and can improve adherence and quality of life. For the first time, 3DP enabled two actives to be combined in the same formulation, reducing the number of administrations. This study demonstrated the benefits of preparing 3D printed personalized treatments for children diagnosed with rare metabolic disorders using a novel technology in real clinical practice.

Medication adherence to obeticholic acid: a real-world experience using medication event monitoring systems.

OBJECTIVE: We designed a clinical study to analyze patterns of adherence to  obeticholic acid, factors influencing the adherence and potential correlation with  treatment efficacy by using MEMS® cap in practice daily. Method: A multicenter prospective observational study of patients with primary  biliary cholangitis. Adherence will be measured by MEMS® cap, pill count, and  patient-reported outcomes during 3 months. The quality of life will be self- reported using the Chronic Liver Disease Questionnaire test, European Quality of  Life 5-Dimension Questionnaire test and Itch Severity Scale. CONCLUSIONS: We expect to clarify if there is correlation between adherence with  treatment efficacy and to identify causes for poor compliance and introduce  measures to reduce its prevalence.

OBJETIVO: Diseñamos un estudio clínico para analizar los patrones de adherencia al ácido obeticólico, los factores que influyen en la adherencia y  la posible correlación con la eficacia del tratamiento mediante el uso de  MEMS® cap en la práctica clínica diaria.Método: Estudio observacional prospectivo multicéntrico de pacientes con  colangitis biliar primaria. La adherencia se medirá mediante MEMS® cap, el  recuento de comprimidos y se registrarán los resultados comunicados por el  paciente durante 3 meses. La calidad de vida será autoinformada utilizando el  Cuestionario de Enfermedad Hepática Crónica, el Cuestionario Europeo de  Calidad de Vida en cinco dimensiones y la Escala de Intensidad del Picor. CONCLUSIONES: Esperamos identificar si existe una relación entre la adherencia  con la efectividad del tratamiento e identificar las causas de la  falta de adherencia para poder introducir medidas para reducir su prevalencia.

Adherencia terapéutica de ácido obeticólico: experiencia real utilizando sistemas demonitorización de medicación electrónicos / Medication adherence to obeticholic acid: a real-world experience using medication event monitoring systems

Objetivo: Diseñamos un estudio clínico para analizar los patrones deadherencia al ácido obeticólico, los factores que influyen en la adherencia y la posible correlación con la eficacia del tratamiento mediante eluso de MEMS® cap en la práctica clínica diaria.Método: Estudio observacional prospectivo multicéntrico de pacientescon colangitis biliar primaria. La adherencia se medirá mediante MEMS®cap, el recuento de comprimidos y se registrarán los resultados comunicados por el paciente durante 3 meses. La calidad de vida será autoinformada utilizando el Cuestionario de Enfermedad Hepática Crónica,el Cuestionario Europeo de Calidad de Vida en cinco dimensiones y laEscala de Intensidad del Picor.Conclusiones: Esperamos identificar si existe una relación entre laadherencia con la efectividad del tratamiento e identificar las causasde la falta de adherencia para poder introducir medidas para reducir suprevalencia. (AU)

Objective: We designed a clinical study to analyze patterns of adherence to obeticholic acid, factors influencing the adherence and potentialcorrelation with treatment efficacy by using MEMS® cap in practice daily.Method: A multicenter prospective observational study of patients withprimary biliary cholangitis. Adherence will be measured by MEMS® cap,pill count, and patient-reported outcomes during 3 months. The qualityof life will be self-reported using the Chronic Liver Disease Questionnairetest, European Quality of Life 5-Dimension Questionnaire test and ItchSeverity Scale.Conclusions: We expect to clarify if there is correlation between adherence with treatment efficacy and to identify causes for poor complianceand introduce measures to reduce its prevalence. (AU)

Impact of CYP2C19 Genotype and Drug Interactions on Voriconazole Plasma Concentrations: A Spain Pharmacogenetic-Pharmacokinetic Prospective Multicenter Study.

BACKGROUND: Voriconazole, a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by cytochrome P450 (CYP) 2C19. A significant portion of patients fail to achieve therapeutic voriconazole trough concentrations, with a consequently increased risk of therapeutic failure. OBJECTIVE: To show the association between subtherapeutic voriconazole concentrations and factors affecting voriconazole pharmacokinetics: CYP2C19 genotype and drug-drug interactions. METHODS: Adults receiving voriconazole for antifungal treatment or prophylaxis were included in a multicenter prospective study conducted in Spain. The prevalence of subtherapeutic voriconazole troughs was analyzed in the rapid metabolizer and ultra-rapid metabolizer patients (RMs and UMs, respectively), and compared with the rest of the patients. The relationship between voriconazole concentration, CYP2C19 phenotype, adverse events (AEs), and drug-drug interactions was also assessed. RESULTS: In this study 78 patients were included with a wide variability in voriconazole plasma levels with only 44.8% of patients attaining trough concentrations within the therapeutic range of 1 and 5.5 µg/ml. The allele frequency of *17 variant was found to be 29.5%. Compared with patients with other phenotypes, RMs and UMs had a lower voriconazole plasma concentration (RM/UM: 1.85 ± 0.24 µg/ml vs other phenotypes: 2.36 ± 0.26 µg/ml). Adverse events were more common in patients with higher voriconazole concentrations (p<0.05). No association between voriconazole trough concentration and other factors (age, weight, route of administration, and concomitant administration of enzyme inducer, enzyme inhibitor, glucocorticoids, or proton pump inhibitors) was found. CONCLUSION: These results suggest the potential clinical utility of using CYP2C19 genotype-guided voriconazole dosing to achieve concentrations in the therapeutic range in the early course of therapy. Larger studies are needed to confirm the impact of pharmacogenetics on voriconazole pharmacokinetics.

Automated therapy preparation of isoleucine formulations using 3D printing for the treatment of MSUD: First single-centre, prospective, crossover study in patients.

Maple syrup urine disease (MSUD) is a rare metabolic disorder with a worldwide prevalence of 1 in every 185,000 live births. However, certain populations display a significant overexpression of the disorder where incidence is reported to be 1 in every 52,541 new-borns. The first-line therapy for MSUD involves a strict dietary leucine restriction and oral supplementation of isoleucine and valine. The dose administered to patients requires strict tailoring according to age, weight and blood levels. In current clinical practice, however, practitioners still have to prepare extemporaneous formulations due to the lack of suitable oral treatments for MSUD. Herein, we evaluate the first time use of 3D printing in a hospital setting for the preparation of personalised therapies with the aim of improving safety and acceptability to isoleucine supplementation in paediatric patients suffering from MSUD. This investigation was a single-centre, prospective crossover experimental study. Four paediatric patients with MSUD (aged 3-16 years) were treated at the Clinic University Hospital in Santiago de Compostela, Spain which is a MSUD reference hospital in Europe. The primary objective was to evaluate isoleucine blood levels after six months of treatment with two types of formulations; conventional capsules prepared by manual compounding and personalised chewable formulations prepared by automated 3D printing. A secondary investigation was to evaluate patient acceptability of 3D printed formulations prepared with different flavours and colours. Isoleucine blood levels in patients were well controlled using both types of formulations, however, the 3D printed therapy showed mean levels closer to the target value and with less variability (200-400 µM). The 3D printed formulations were well accepted by patients regarding flavour and colour. The study demonstrates for the first time that 3D printing offers a feasible, rapid and automated approach to prepare oral tailored-dose therapies in a hospital setting. 3D printing has shown to be an effective manufacturing technology in producing chewable isoleucine printlets as a treatment of MSUD with good acceptability.