Physiologically Based Pharmacokinetic Modeling of Doxepin Related to CYP2D6 Genetic Polymorphism for Personalized Pharmacotherapy

석주희 성균관대학교 일반대학원 2026 국내박사

Doxepin, a tricyclic antidepressant, is used for the treatment of major depression, anxiety disorders, and insomnia. Doxepin undergoes extensive hepatic metabolism involving multiple CYP enzymes; clinical evidence suggests that CYP2D6 has a greater impact on overall doxepin clearance, whereas CYP2C19 mainly contributes to the formation of N-desmethyldoxepin. Because CYP2D6 is highly polymorphic, genetic variability and co-administration with enzyme inhibiting drugs can markedly influence the pharmacokinetics of doxepin and its active metabolite. This study aimed to develop physiologically based pharmacokinetic (PBPK) models of doxepin and N-desmethyldoxepin to characterize CYP2D6 genotype–dependent PK variability and to predict drug-drug interactions (DDIs) with cimetidine, a nonspecific inhibitor of CYP1A2, CYP2C19, CYP2D6, and CYP3A4. Clinical PK and pharmacogenomic data were used for model development. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) parameters were obtained from literature, predicted by PK-Sim®, or optimized to reflect observed plasma concentration–time profiles. Model performance was assessed by comparing predicted PK parameters and profiles with clinical data. The final models adequately captured plasma profiles of both compounds, and most predicted AUC and Cmax values fell within the twofold error range across non-genotyped populations and CYP2D6 genotypes. The model also reliably reproduced the observed DDI when doxepin was co-administered with cimetidine. Simulations demonstrated genotype-dependent differences in systemic exposure, influencing predicted DDI magnitude and suggesting the potential need for dose adjustments in individuals with reduced CYP2D6 activity. In conclusion, the PBPK models successfully described PK alterations arising from CYP2D6 polymorphism and DDIs with cimetidine and can serve as a useful tool to predict doxepin PK across various demographic and clinical conditions, supporting individualized pharmacotherapy. 본 연구에서는 삼환계 항우울약인 doxepin과 이로부터 생성되는 활성 대사체인 N-desmethyldoxepin의 약물동태를 예측하기 위하여, CYP2D6 유전다형성과 약물상호작용을 통합적으로 반영한 생리기반약물동태 (PBPK) 모델을 개발하고 평가하였다. doxepin은 CYP2D6와 CYP2C19에 의해 대사되며, 특히 CYP2D6 유전형에 따라 약물 노출의 개인간 변이가 크게 나타나는 약물이다. 또한 cimetidine과 같은 CYP 억제제와 병용할 경우, 약물 노출이 증가하여 용량 조절이나 이상반응 관리가 요구될 수 있다. 본 연구는 이러한 유전적 요인과 약리학적 상호작용을 정량적으로 반영한 예측 모델을 구축함으로써 개인맞춤 약물요법의 근거를 마련하는 것을 목적으로 하였다. 임상 자료를 기반으로 구축한 PBPK 모델의 예측 성능을 평가한 결과, doxepin과 N-desmethyldoxepin의 관찰된 농도–시간 곡선 및 AUC 및 Cmax를 대부분 2배수 기준(twofold criterion) 이내에서 적절히 재현하였고, CYP2D6 유전형에 따른 약물 노출 차이도 적절히 재현하였다. Cimetidine 병용 시, doxepin의 노출은 뚜렷하게 증가한 반면, N-desmethyldoxepin의 변화는 상대적으로 제한적이었다. 이는 CYP2C19 억제로 인한 대사체 생성 감소와 CYP2D6 억제로 인한 대사체 제거 지연 효과가 상쇄되었기 때문으로 해석된다. 특히 CYP2D6 기능이 낮은 IM 및 PM에서 cimetidine 병용 효과가 더 크게 나타나, 유전형이 약물상호작용의 크기를 결정하는 중요한 요인임을 확인하였다. 본 연구는 doxepin에 대해 CYP2D6 유전다형성과 CYP 억제제에 의한 DDI를 동시에 고려한 최초의 PBPK 모델을 제시한다는 점에서 의의가 있다. 본 모델은 유전형과 병용 약물 정보를 통합하여 doxepin의 개인맞춤 약물요법을 지원할 수 있는 기초 자료를 제공하며, 향후 임상적 용량 조절 및 안전성 평가에 활용될 수 있다.

Are There Sex-Specific Differences in Obesity Treatment Outcomes in the Pediatric Population?

Jang, Su Bin University of Minnesota ProQuest Dissertations & T 2025 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

The rising prevalence of childhood obesity is a significant public health problem due to the increased risk of developing various comorbid conditions. Children with obesity are likely to still live with obesity in adulthood, which further increases the risk of comorbid conditions. There are several options for obesity interventions, including lifestyle modification, pharmacotherapy, and metabolic and bariatric surgery, with some interventions being very effective. With sex differences in physiological characteristics between males and females, it is possible that they respond differently to obesity interventions; however, the literature on this topic is limited. This dissertation examined sex differences in weight loss responses to lifestyle modification intervention, pharmacotherapy, and metabolic/bariatric surgery among the children and adolescent population. The following manuscripts are secondary data analyses.Manuscript 1 evaluated sex differences in response to lifestyle modification interventions. Two harmonized datasets (family-based intervention and nutrition-focused intervention) were used for the analyses. We found modest sex differences in the family-based intervention, and males lost more weight compared with females in the nutrition-focused intervention.Manuscript 2 assessed sex differences in response to obesity pharmacotherapy. Two high-quality randomized controlled trials (phentermine/topiramate and metformin) were utilized for the analyses. We found modest sex differences in response to either phentermine/topiramate or metformin. We further explored whether the pubertal stage modified the sex differences in response to each pharmacotherapy and observed that it modified the association in the metformin study.Manuscript 3 analyzed sex differences in response to metabolic and bariatric surgery. Four high-quality studies were harmonized into a single dataset. We found that males experienced greater weight loss compared to females.In summary, we found notable sex differences occur in some obesity interventions, but not in others. Understanding whether these sex differences are clinically meaningful in response to various obesity intervention types may guide obesity precision medicine.

(The) reporting quality of randomised controlled trials related to COVID-19 treatment

정연주 중앙대학교 대학원 2022 국내박사

Objective. This study aimed to assess the reporting quality of randomised controlled trials (RCT) full-text reports related to Coronavirus disease 2019 (COVID-19) pharmacotherapy. Methods. PubMed, National Institutes of Health, EMBASE, Cochrane, and Web of Science were searched for RCTs published from inception to 31 December 2020. RCTs on pharmacotherapy of COVID-19 were selected and included for reporting quality analysis according to the Consolidated Standards for Reporting of Trials (CONSORT) 2010. Relevant reporting quality factors were analysed by linear regression analysis. Results. Of the 10,704 studies identified, 87 RCTs were included. The average adherence rate for CONSORT 2010 was 77.4% (95% confidence interval (CI): 69.4%–85.4%). Although most checklist items were addressed adequately, five items in the Methods and Results domains had adherence rates of <30%. Journal impact factors between 10 and 50 (β = 1.6, 95% CI: 0.05%–3.2%), abstract word counts (β = 0.01, 95% CI: 0–0.02), and sample size> 100 (β = 2.1, 95% CI: 0.6–3.7) were associated with better reporting quality, whereas first author of Africa regions (β = −5.9, 95% CI: −9.3 to −2.5) and ≥2 primary outcomes (β = −1.32, 95% CI: −2.5 to −0.2) were associated with poor quality. Conclusions. The reporting quality of RCTs related to COVID-19 treatment was found to be adequate, but some items considered to be optional were inadequate. These findings may provide a standard for selection of COVID-19 RCTs to guide clinical practice and public policies. 배경 코로나바이러스감염증-19(COVID-19)로 인한 전세계 위기를 극복하기 위한 노력 중 보건의료계는 기존의 관련 근거의 부재를 해결하고 근거에 기반한 치료를 위해 세계 각지에서 급박히 연구가 진행되고 발표되고 있다. 유래없이 단기간의 연구 출판물의 결과는 전세계의 환자에게 빠르고 직접적으로 영향을 미칠 수 있으므로 연구 설계 및 연구결과가 명확히 보고되고 정확히 전달되는 것은 매우 중요하다. 목적 COVID-19와 관련한 약물학적 치료연구 중 근거 수준이 가장 높은 무작위대조군연구 출판물의 보고의 질을 Consolidated Standards for Reporting of Trials (CONSORT) 2010에 의거하여 평가하고자 하였다. 방법 COVID-19가 발생한 이후로부터 2020년 12월 31일까지 발표된, PubMed, National Institutes of Health, EMBASE, Cochrane, Web of Science에서 추출한 COVID-19 약물치료요법에 관한 출판물 10,704편 중, 기준에 부합한 무작위대조군연구 87편을 선정하여 CONSORT 2010 평가도구에 의거하여 보고의 질을 평가하였고 질 평가 점수에 대한 영향 인자를 회귀분석하였다. 결과 및 토론 COVID-19 약물치료와 관련한 87편의 무작위대조군연구 출판물의 보고의 질은 순응률이 77.4%(95% 신뢰구간: 69.4 ~ 85.4%)로 적절한 것으로 평가되었다. 다만, 방법 및 결과 중 다섯 항목의 순응률이 30% 미만으로 낮은 것으로 평가되었다. 보고의 질에 관한 영향 인자 분석 결과, impact factor가 10 ~ 50점인 저널 군(β= 1.6, 95% CI: 0.05%–3.2%), 초록 단어수가 많은 군(β = 0.01, 95% CI: 0–0.02), 연구 대상자수가 100보다 큰 군(β = 2.1, 95% CI: 0.6–3.7)에서 보고의 질이 높고, 제1저자가 아프리카인 군(β = −5.9, 95% CI: −9.3 to −2.5), 일차결과지표가 두 가지 이상인 군(β = −1.32, 95% CI: −2.5 to −0.2)에서 보고의 질이 낮다는 것을 확인하였다. 결론 COVID-19 약물치료와 관련한 무작위대조군연구는 판데믹 상황에서 단기간에 출판되었음에도 불구하고 연구 보고의 질은 일부 항목을 제외하고 적절한 수준이었다. 향후 본 연구 결과에서 확인된 보고 수준이 낮은 항목들에 대한 개선이 이루어져 독자들에게 좀더 정확한 정보가 전달되고 임상지침에 적절히 활용될 수 있는 무작위대조군연구가 출판되기를 기대한다.

Prediction of gastric pH-mediated drug exposure changes using physiologically based pharmacokinetic modeling: A case study of itraconazole

양은솔 서울대학교 대학원 2022 국내박사

서론: 위 pH 변화는 특히 pH 의존적 용해도를 가진 약물 흡수의 주요 변동성 원인 인자이며, 이는 의도치 않은 치료 반응의 변화를 초래할 수 있다. 본 연구에서는 이트라코나졸을 사례 약물로 선정하여서 생리학 기반 약물동태 모델링을 통해 위 pH 매개 약물 노출 변화를 정량적으로 예측할 수 있다는 개념 증명을 확립하고자 하였다. 방법: 위 pH 또는 음식물이 이트라코나졸 약동학에 미치는 영향을 평가하고자, 12명의 건강한 한국인 성인 남성을 대상으로 공개, 단일 순서군 교차 시험을 수행하였다. 각 치료기에는 이트라코나졸 200 mg (스포라녹스캡슐)을 단독으로 공복 또는 식후 상태(정상 위산도 조건)에 단회 경구 투여하거나, esomeprazole 전처리 후 공복 상태(유도된 무산증 조건)에 단회 경구 투여하였다. 또한, in vitro 데이터 모델링을 포함한 단계적 in vitro-in vivo extrapolation 접근법을 통해 이트라코나졸의 기전적 생리학 기반 약물동태 모델을 구축하였고, 본 임상시험 결과를 이용하여 정상 위산도 및 유도된 무산증 조건에서 구축된 생리학 기반 약물동태 모델의 예측 성능을 평가하였다. 최종적으로 생리학 기반 약물동태 모델을 이용하여 가상의 무산증 집단에서의 위 pH에 의한 노출 변화를 정량적으로 예측하고 기전적으로 해석하였다. 결과: 이트라코나졸 흡수는 정상 위산도 대비 유도된 무산증 조건에서 다소 감소하였고(~13%), 음식 섭취 후 지연되고 증가하였다(~14%). 구축된 이트라코나졸 생리학 기반 약물동태 모델은 본 임상시험에서 관찰된 음식 및 위 pH 매개 약동학 변이를 적절히 예측하였다. 모델 기반 시뮬레이션 결과, 정상 위산도 집단 대비 무산증 집단에서 이트라코나졸의 예측 흡수 분율이 공복 상태에서 42%, 식후 상태에서 31% 감소하였고, 이로 인해 예측 체내 노출이 공복 상태에서 59%, 식후 상태에서 31% 감소하였다. 민감도 분석을 포함한 모델 기반 시뮬레이션을 통해, 이트라코나졸의 위 pH 매개 노출 변화를 용해도, 용출 및 흡수 관점에서 기전적으로 해석할 수 있었다. 결론: 본 개념 증명 연구를 통해 위 pH 매개 약물 노출 변화를 정량적으로 예측할 수 있다는 생리학 기반 약물동태 모델링의 유용성을 확인하였다. 해당 연구 결과는 추후 다른 약물의 위 pH 매개 노출 변화 평가에 근간으로 작용할 것이며, 이는 궁극적으로 맞춤약물요법에 기여할 수 있다. Introduction: Gastric pH variation is a significant source of variability in the absorption of drugs with especially pH-dependent solubility profiles, potentially resulting in an undesirable therapeutic response. The aim of this study was to establish a proof-of-concept that the physiologically based pharmacokinetic (PBPK) modeling framework can quantitatively predict gastric pH-mediated drug exposure changes by using itraconazole as a case drug through a robust approach from clinical investigation to PBPK modeling. Methods: An open-label, fixed-sequence crossover study was conducted in healthy 12 Korean male subjects to evaluate the effect of gastric pH or food on the pharmacokinetics (PK) of itraconazole. In each treatment period, a single oral dose of itraconazole 200 mg (Sporanox® Capsule) was administered alone in fasted or fed condition (i.e., normal gastric acidity), or with esomeprazole in fasted condition (i.e., induced achlorhydria). Furthermore, a mechanistic PBPK model for itraconazole was developed using a stepwise in vitro-in vivo extrapolation approach, including in vitro data modeling, and its predictive performance was validated using the current clinical study results under normal gastric acidity and induced achlorhydria. The final PBPK model was applied to virtual achlorhydric populations to quantitatively predict and mechanistically interpret gastric pH-mediated exposure changes. Results: Itraconazole absorption was slightly reduced (~13%) under induced achlorhydria than under normal gastric acidity, and was delayed and increased (~14%) after food intake. The developed PBPK model for itraconazole exerted reasonable predictive performance for food and gastric pH-mediated PK variability observed in the current clinical investigation. In achlorhydric populations, the predicted fraction absorbed of itraconazole was reduced by 42% at fasted state and 31% at fed state, thereby decreasing the predicted AUCinf of itraconazole up to 59% at fasted state and 31% at fed state, than in populations with normal gastric acidity. Gastric pH-mediated exposure changes of itraconazole could be mechanistically interpreted according to sequential variations in solubility, dissolution, and absorption based on model-based simulations, including sensitivity analyses. Conclusion: This study provided a proof-of-concept for the utility of PBPK modeling in quantitative prediction of gastric pH-mediated exposure changes, especially for drugs sensitive to gastric pH alteration. Our findings will serve as a foundation for further mechanistic assessment of exposure changes in terms of gastric pH for other drugs, ultimately contributing to personalized pharmacotherapy.

Prediction of vutiglabridin exposure in gastric bypass surgery patients and pediatrics using physiologically based pharmacokinetic modeling

나주영 서울대학교 대학원 2023 국내박사

Introduction: Vutiglabridin is an anti-obesity agent which is currently under development. Its efficacy has been demonstrated in preclinical studies, and its safety, pharmacokinetic, and pharmacodynamic properties have been evaluated through several clinical studies. This study aimed to establish a physiologically based pharmacokinetic (PBPK) model for vutiglabridin to predict pharmacokinetic (PK) profiles in gastric bypass surgery patients and pediatric patients and to comprehend absorption process mechanistically. Methods: For PBPK model building, both the bottom-up approach using in vitro data and top-down approach using clinical data were utilized. The advanced dissolution, absorption, and metabolism (ADAM) model was utilized for mechanistic absorption modeling. The predictive performance of the model was verified using results from previous clinical studies. The final PBPK model was applied to virtual sensitive population (gastric bypass surgery patients and pediatrics) for PK prediction and to mechanistically interpret the vutiglabridin absorption process. Results: The final PBPK model adequately predicted vutiglabridin PK profiles in healthy and obese subjects. The ratios of predicted-to-observed values of PK parameters were between 0.5 to 2.0-fold range, indicating the model had good predictive performance. The simulation result demonstrated that the systemic vutiglabridin exposure after multiple administrations of 720 mg in gastric bypass surgery patient population was reduced by 16.8% compared to obese population. The recommended pediatric doses according to PBPK model were similar to doses computed using simple scaling (Young’s rule). The vutiglabridin systemic exposure changes after food intake could be mechanistically interpreted by the final model. Conclusion: This study established a PBPK model that adequately predicted vutiglabridin pharmacokinetic profiles in healthy and obese subjects. Using this model, vutiglabridin pharmacokinetic profiles in virtual sensitive population was predicted, and mechanistical interpretation for absorption process in diverse conditions was available. Considering that vutiglabridin is currently under development, by refining this model with additional data, it can be applied as evidence-based dosing strategies, ultimately contributing to personalized pharmacotherapy. 서론: 부티글라브리딘은 잠재적인 비만 치료제로서 현재 개발 중에 있는 약물이다. 전임상실험에서 부티글라브리딘의 유효성이 확인되었으며, 여러 임상시험에서는 안전성과 약동학 및 약력학적 특성을 확인하였다. 본 연구의 목적은 부티글라브리딘의 생리학 기반 약물동태 모델을 개발하여 가상의 위장절제술 환자군과 소아에서의 부티글라브리딘의 약동학적 특성을 예측하고 흡수 과정을 기계론적으로 이해하는 것이다. 방법: 생리학 기반 약물동태 모델 구축을 위해 생체외 데이터를 기반으로한 하향식 접근법과 임상 데이터를 기반으로한 상향식 접근법을 사용하였다. 흡수 과정을 기계론적으로 모델링하기 위해 아담(ADAM) 모델을 사용하였고, 모델의 예측력은 임상시험을 통해 얻어진 관찰값과의 비교를 통해 검증되었다. 최종 생리학 기반 약물동태 모델은 가상의 민감집단(위장절제술 환자군과 소아집단)에서의 부티글라브리딘의 약동학적 특성을 예측하기 위해 사용되었고, 추가적으로 부티글라브리딘의 흡수 과정을 기계론적으로 해석하기 위해 사용되었다. 결과: 최종 생리학 기반 약물동태 모델은 건강인과 비만군에서 부티글라브리딘의 약동학적 특성을 적절하게 예측하였다. 약동학 파라미터의 예측값 대비 관측값의 모든 비는 0.5와 2.0 사이였으며, 이를 통해 모델이 좋은 예측력을 가짐을 확인하였다. 시뮬레이션 결과, 위장절제술을 받은 환자군은 부티글라브리딘 720 mg을 다회투여 하였을 때 비만군보다 약 16.8% 감소된 전신 노출도를 보였으며, 최종 모델에서 권고한 소아에서의 부티글라브리딘의 용량은 단순 상대 성장 축적 계산을 통해 얻은 용량과 유사하였다. 또한, 최종 모델은 식이 영향으로 생긴 부티글라브리딘의 전신 노출의 변화를 기전적으로 해석할 수 있었다. 결론: 최종 생리학 기반 약물동태 모델은 부티글라브리딘의 약동학적 양상을 건강인과 비만군에서 적절히 예측하였다. 모델을 사용하여 위장절제술 환자군과 소아에서의 약동학적 특성이 예측되었고 다양한 조건에서의 흡수 과정이 기전적으로 해석되었다. 부티글라브리딘이 현재 개발 중에 있으므로 추후 생성되는 추가 데이터 확보를 통해 모델을 개선하여 증거 중심의 약물 요법에 적용할 수 있겠으며, 이는 궁극적으로 맞춤약물요법에 기여할 수 있다.

Evaluation and prediction of drug transporter-mediated drug-drug interactions of methotrexate using physiologically based pharmacokinetic modeling

황세정 서울대학교 대학원 2023 국내박사

Introduction: Methotrexate is an antifolate agent widely used in the treatment of various diseases, such as rheumatoid arthritis and cancer. As a substrate of various transporters, methotrexate should be monitored carefully when coadministered with other drugs. This study aimed to quantitatively interpret drug-drug interactions (DDIs) of methotrexate mediated by drug transporters using physiologically based pharmacokinetic (PBPK) modeling. According to this study, a mechanistic evaluation and prediction system about drug transporter- mediated DDIs of methotrexate was developed and applied for personalized pharmacotherapy of methotrexate. Methods: A randomized, open-label, 4-treatment, 6-sequence, 4-period crossover study (NCT05575297) was conducted to evaluate the effect of rifampicin and febuxostat on methotrexate pharmacokinetics (PK) in healthy volunteers. Subjects received each treatment according to the assigned sequence, and 4-treatments included the administration of a single dose of methotrexate 2.5 mg alone, coadministration of methotrexate with a single dose of rifampicin 600 mg, with febuxostat 80 mg, or both. Blood samples for PK analysis were collected up to 24 hours post-dose. The PBPK model of methotrexate, rifampicin and febuxostat was developed based on the in vitro and in vivo data, and the performance of the final PBPK model was validated using the clinical study. The final PBPK model was used to quantitatively interpret the methotrexate DDIs and simulated the high-dose methotrexate with administered with febuxostat in cancer patients. Results: In the clinical study, when methotrexate was coadministered with rifampicin or febuxostat, the systemic exposure of methotrexate increased by 33% and 17%, respectively, compared to those administered alone. When methotrexate was coadministered with both rifampicin and febuxostat, the systemic exposure increased by 52% compared to those administered alone. The final PBPK model showed a good prediction performance of the observed clinical data. The impact of drug transporter about DDIs on the methotrexate PK was quantitively evaluated based on the sensitivity analysis and simulation using the PBPK model. The PBPK model showed that the presence of febuxostat resulted in increase of AUC0-24h by 30% in virtual cancer patients. Conclusion: This study investigated the clinical potential activity of febuxostat with rifampicin for the breast cancer resistance protein (BCRP) inhibition. Furthermore, the PBPK model of methotrexate was well developed in this study and can be used as the mechanistic model to predict and evaluate the drug- transporter mediated DDIs of methotrexate with other drugs and contributed to personalized pharmacotherapy. 서론: 메토트렉세이트는 류마티스 관절염 및 암과 같은 다양한 질병의 치료에 널리 사용되는 항엽산제이다. 다양한 수송체의 기질로 알려진 메토트렉세이트는 다른 약물과 병용 투여 시 주의 깊게 모니터링해야 한다. 본 연구는 생리학적 기반 약동학(PBPK) 모델링을 사용하여 약물 수송체에 의해 매개되는 메토트렉세이트 약물-약물 상호작용을 정량적으로 해석하고자 하였다. 또한 본 연구를 통해 메토트렉세이트의 약물수송체 매개 약물-약물 상호작용에 대한 기전 평가 및 예측 시스템을 개발하여 메토트렉세이트의 개인 맞춤형 약물 요법에 적용하고자 하였다. 방법: 건강한 지원자에서 메토트렉세이트 약동학에 대한 리팜피신 및 페북소스타트의 영향를 평가하기 위해 무작위배정, 공개, 4-치료군, 6-순서군, 4-기간 교차 시험을 수행하였다. 대상자들은 할당된 순서에 따라 각 치료를 받았고, 4-치료군은 메토트렉세이트 2.5mg 단독 투여, 메토트렉세이트와 리팜피신 600mg 병용투여, 메토트렉세이트와 페북소스타트 80mg 병용투여 또는 3제 병용투여로 구성되었다. 약동학 분석을 위한 혈액 샘플을 임상시험용의약품 투여 후 24시간까지 수집하였다. 메토트렉세이트, 리팜피신 및 페북소스타트의 PBPK 모델은 생체 외(in vitro) 및 생체 내(in vivo) 연구를 기반으로 개발하였으며, 최종 PBPK 모델의 예측 성능은 임상 연구를 통해 검증하였다. 최종 PBPK 모델은 메토트렉세이트의 약물수송체 매개 약물-약물 상호작용을 정량적으로 해석하고 암 환자에서 페북소스타트와 고용량 메토트렉세이트를 병용투여 시 약물-약물상호작용을 시뮬레이션 하였다. 결과: 본 연구에서 수행한 임상시험에서 메토트렉세이트와 리팜피신 또는 페북소스타트와 병용 투여했을 때 메토트렉세이트의 전신 노출은 단독 투여에 비해 각각 33% 및 17% 증가하였다. 메토트렉세이트를 리팜피신, 페북소스타트와 병용 투여했을 때 전신 노출은 단독 투여에 비해 52% 증가하였다. 최종 PBPK 모델은 관찰된 임상 데이터를 잘 예측하는 것을 확인하였다. 최종 PBPK 모델에서 민감도 분석을 이용하여 메토트렉세이트 약물-약물 상호작용에서 메토트렉세이트 약동학에 대한 약물수송체의 기여를 정량적으로 해석할 수 있었다. 또한 최종 PBPK 모델을 이용하여 가상 암 환자에서 메토트렉세이트 고용량과 페북소스타트를 병용투여 시 약동학을 시뮬레이션 하였을 때 메토트렉세이트 전신 노출이 약 30% 증가하였다. 결론: 본 연구는 페북소스타트의 유방암내성단백질(BCRP) 억제제로서의 잠재적인 활성을 평가하였다. 또한, 본 연구에서 메토트렉세이트의 PBPK 모델이 적절하게 개발되었고 다른 약물과 메토트렉세이트의 약물수송체 매개 약물-약물 상호작용을 예측 및 평가하는 모델으로서 맞춤약물요법에 활용할 수 있을 것으로 예상한다.

Improving Access to Alcohol Use Disorder Pharmacotherapy in Hepatology: A Quality Improvement Initiative

Collier, Summer Brianne University of California, Los Angeles ProQuest Dis 2025 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Background: Alcohol-associated liver disease (ALD) is the leading cause of liver-related morbidity and mortality in North America. Despite strong evidence supporting pharmacologic treatment for alcohol use disorder (AUD), pharmacotherapy remains significantly underutilized in hepatology settings. Identified barriers include provider unfamiliarity, safety concerns in cirrhosis, and system-level workflow limitations. Aim: To increase prescription rates of AUD pharmacotherapy in a high-volume hepatology clinic through targeted, scalable quality improvement interventions integrated into existing workflows. Methods: This single-center, quasi-experimental quality improvement study compared two cohorts of adults with ALD and active alcohol use seen in a hepatology clinic: pre-intervention (January-March 2023; n=143) and post-intervention (January-March 2025; n=175). Interventions included provider education, standardized alcohol screening, integration of decision-support tools (including a prescribing algorithm and documentation templates), and improved access to long-acting injectable medication. Outcomes were assessed via retrospective chart review. Multivariable logistic regression using backward stepwise elimination was performed to identify predictors of alcohol use disorder pharmacotherapy initiation. Results: AUD pharmacotherapy prescribing increased significantly from 10% pre-intervention to 43% post-intervention (p<0.00001). Documented discussions of pharmacotherapy rose from 33% to 80% (p<0.00001), while deferral to psychiatry or primary care decreased from 7% to 1% (p=0.006), indicating enhanced provider engagement and prescribing autonomy. Among those prescribed treatment, use of first-line agents such as oral naltrexone and acamprosate increased, and long-acting medication (Vivitrol) was newly adopted. Regression analysis (AUC=0.77) identified three independent predictors of pharmacotherapy initiation: post-intervention year (OR=6.03, 95% CI [3.20-11.34], p<0.001), recent positive phosphatidylethanol (PEth) test (OR=2.44 vs. no PEth, 95% CI [1.28-4.64], p=0.007), and a trend toward lower Child-Turcotte Pugh (CTP) scores (OR=0.87, 95% CI [0.75-1.00], p=0.057). Model deviance R² was 16.2%, reflecting moderate fit likely influenced by unmeasured variables such as patient readiness for behavioral change. Conclusion: Embedded, interdisciplinary quality improvement interventions can substantially increase alcohol use disorder pharmacotherapy rates in hepatology without requiring structural clinic overhauls. This approach enhanced provider autonomy, reduced unnecessary deferrals, and optimized the use of clinical tools such as PEth testing. Findings support broader implementation of pragmatic, evidence-based strategies to improve alcohol use disorder care for patients with alcohol-associated liver disease in specialty settings.

Frequency of Pharmacotherapy and Psychosocial Therapy Among Anxiety, Opioid Use, and Co-Occurring Disorders in an Outpatient Behavioral Health Program

Mccullough, Jessica Nicole Case Western Reserve University ProQuest Dissertat 2025 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Background: A growing body of literature supports the increasing prevalence of co-occurring anxiety and opioid use disorders. Diagnosing an anxiety disorder alongside an opioid use disorder is complex. Evidence indicates that individuals with co-occurring disorders receive fragmented or isolated care and face higher morbidity and mortality rates than those with a single condition. Treatment recommendations for these disorders follow different trajectories, often being multifaceted and conflicting. Psychosocial and pharmacotherapies play significant roles in treatment modalities; however, current empirical evidence lacks recommendations for integrating methods to manage co-occurring disorders.Problem: Research on pharmacotherapy and psychosocial therapies for individuals with co-occurring anxiety and opioid use disorders is limited. Although treatment modalities for each disorder individually are well established in the literature, those with both conditions face poorer treatment outcomes, higher relapse rates, and increased morbidity and mortality.Purpose: The purpose of this exploratory study was to examine the frequency of pharmacotherapy and psychosocial therapy among individuals diagnosed with anxiety disorders, opioid use disorders, and co-occurring disorders within an outpatient mental health and substance use treatment program.Method: This retrospective, descriptive, comparative, cross-sectional chart review analyzed data from a community outpatient mental health and substance use treatment center. The study examined differences in pharmacotherapy and psychosocial therapy among 250 patients diagnosed with anxiety disorders, opioid use disorders, and co-occurring disorders. The frequency of each disorder was assessed across groups. Data analysis included descriptive statistics (frequencies and percentages) and a chi-square test of independence with cross-tabulations to compare pharmacotherapy and psychosocial therapy use across diagnostic groups.Results: This study confirms that generalized anxiety disorder is the most common among those with opioid use disorder. Access to pharmacotherapy was consistent across groups. It suggests a link between psychosocial therapy and opioid use with co-occurring disorders (p<.001). Results showed varying outcomes for combined treatments. The implications involve integrating mental health and substance use treatment. Additionally, variations in anxiety disorder subtypes among opioid users suggest a need for further investigation into how specific opioids affect anxiety symptoms and treatment outcomes.

Predicting Response for Pharmacotherapy Using Neuroanatomical Single-Subject Pattern Recognition in Obsessive-Compulsive Disorder

윤제연 서울대학교 대학원 2016 국내박사

Background: Primary pharmacotherapy regimen for obsessive-compulsive disorder (OCD) named Serotonin reuptake inhibitors (SRIs) does not attain sufficient symptom improvement in 40-60% of OCD. We aimed to decode the differential profile of OCD-related brain pathology per subject in the context of cortical surface area (CSA) or thickness (CT)-based individualized structural covariance (ISC) and to demonstrate the potential of which as a biomarker of treatment response to SRI-based pharmacotherapy in OCD using the support vector machine (SVM). Methods: T1-weighted magnetic resonance imaging was obtained at 3T from 56 unmedicated OCD subjects and 75 healthy controls (HCs) at baseline. After 4 months of SRI-based pharmacotherapy, the OCD subjects were classified as responders (OCD-R, N=25; ≥35% improvement) or nonresponders (OCD-NR, N=31; <35% improvement) according to the percentage change in the Yale-Brown Obsessive Compulsive Scale total score. Cortical ISCs sustaining between-group difference (p < .001) for every run of leave-one-out group-comparison were packaged as feature set for group classification using the SVM. Results: An optimal feature set of the top 12 ISCs including a CT-ISC between the dorsolateral prefrontal cortex versus precuneus, a CSA-ISC between the anterior insula versus intraparietal sulcus, as well as perisylvian area-related ISCs predicted the initial prognosis of OCD as OCD-R or OCD-NR with an accuracy of 89.0% (sensitivity 88.4%, specificity 90.1%). Extended sets of ISCs distinguished the OCD subjects from the HCs with 90.7-95.6% accuracy (sensitivity 90.8-96.2%, specificity 91.1-95.0%). Conclusion: We showed the potential of cortical morphology-based ISCs, which reflect dysfunctional cortical maturation process, as a possible biomarker that predicts the clinical treatment response to SRI-based pharmacotherapy in OCD.

EFFICACY OF ADDING CLINICAL ART THERAPY TO PHARMACOTHERAPY IN THE TREATMENT OF MAJOR DEPRESSIVE DISORDER IN ADULT

최한 차의과학대학교 대학원 2015 국내박사

The aim of this study is to evaluate the clinical effectiveness of combined therapy, art therapy and pharmacotherapy has advantage over pharmacotherapy alone for adult with major depressive disorder. 6 weeks structured individual clinical art therapy program was performed then depression, anxiety, interpersonal relationship and self-esteem were measured. Combined therapy group as delivered in this study did improved depressive and anxiety symptoms. As for the satisfaction level of treatment, combined therapy had higher satisfaction level than pharmacotherapy alone. Given the probable outcomes of the results, clinical efficacy seems more favourable to combined therapy. It was an opportunity for an art therapy to build a strong case for effective intervention for MDD. 본 연구는 HDRS 8점 이상으로 임상적으로 우울 상태에 있는 만 18세 이상 65세 이하의 성인 주요우울장애 환자들로서 연구 개시 전 항우울제 약물치료가 시행되고 있는 대상자들에게 임상미술치료와 약물치료의 결합치료 효과를 알아보았다. 6주 동안 주 1회로 우울감을 감소시키는데 효과가 있다고 보고된 구조화된 임상미술치료 프로그램을 실시하여 치료 전․후 대인관계, 우울, 불안, 자아존중감 그리고 대인관계의 변화를 알아보았다. 연구 결과, 임상미술치료를 추가하기 전과 후에서 본 연구의 일차 유효성 변인인 HDRS는 집단 별로 유의한 수준으로 감소하였고, 집단 간에 차이가 유의하였다. 또한, 이와 함께 이차 유효성 변인인 불안은 유의한 수준으로 호전되었다. 추가적으로 환자의 주관적 관점에서 결합치료와 약물치료 중 어느 치료의 만족도가 높았는지 살펴본 결과 결합치료 집단은 실시하지 않은 단독적인 약물치료 집단 보다 치료만족도가 높았다. 결합치료 집단은 각각의 측정구간에서 치료만족도도 증가할수록 우울감이 감소하는 흐름을 보였다. 결론적으로 본 연구를 통해 약물치료와 결합된 임상미술치료는 우울증상을 유의한 수준으로 감소시키는 것으로 나타나, 심리치료와 약물치료의 결합치료가 주요우울장애에 효과가 있었으며, 미술치료와 결합치료로서 임상적 효과를 검증할 수 있는 기회였다.