Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 1, a pharmacokinetic/pharmacodynamic comparison with paroxetine in healthy men

We compared the effect of vortioxetine, paroxetine and placebo after three days of dosing on sleep architecture. This was a randomised, double-blind, four-way crossover, placebo-controlled, multiple-dose study in 24 healthy young men. Subjects received 20mg vortioxetine, 40mg vortioxetine, 20mg paroxetine or placebo for three consecutive days in four different periods with at least three weeks between them. Polysomnography and blood sampling for pharmacokinetic analysis were performed on the pre-dose night and nights 1 and 3 of dosing in each period. Plasma concentrations of vortioxetine and paroxetine during the polysomnography measurement were used to estimate SERT occupancies using published relationships in healthy subjects. All three active treatments significantly increased REM onset latency and decreased time spent in REM sleep. In the pharmacokinetic/pharmacodynamics analysis significant relationships were found between REM onset latency and time spent in REM sleep and vortioxetine/paroxetine exposure. The relation between REM suppression parameters and SERT occupancy was significantly different between vortioxetine and paroxetine, despite the same SERT occupancy. This indicates that vortioxetine has a different clinical pharmacological profile from paroxetine, which may explain the differences in adverse effect profile of the two drugs, for instance the lower incidence of nausea, weight gain and sexual dysfunction with vortioxetine

정상인에서 아리피프라졸 단회투약 자료를 이용한 조현병 환자의 항정상태 뇌 수용체 점유율 모델링 연구

학위논문(박사) -- 서울대학교대학원 : 의과대학 협동과정 임상약리학전공, 2021.8. 권준수.Background: While embarked from a serendipitous discovery, antipsychotic medications antagonising brain dopamine D2 receptor (D2R) have actively been developed. Recently, compounds possessing unique pharmacodynamic (PD) properties such as D2R partial agonist aripiprazole were developed as antipsychotics. Yet, despite unmet need for newer therapeutics in psychiatry, their development has been dampened by several difficulties in clinical trials. To facilitate drug development, strategies that employ healthy volunteers instead of patients has been suggested. Since few relevant studies have been conducted, we aimed to develop and validate a model predicting steady-state D2R occupancy by aripiprazole in patients with schizophrenia using data from a single-dosing study in healthy volunteers. Methods: Data were collected from a single-dosing study with 18 healthy volunteers which conducted serial pharmacokinetic (PK) samplings and [11C]raclopride positron emission tomography (PET) scans to obtain brain D2R occupancy after administering 2-30 mg aripiprazole. Steady-state D2R occupancy in patients with schizophrenia taking 2-30 mg aripiprazole was simulated using PK and PD parameters estimated from healthy volunteers. The simulated D2R occupancy was compared to the actual occupancy measured in 8 patients taking aripiprazole for 2 years on average, and measures to correct the difference was employed to better predict the actual occupancy. Results: Data from the single-dosing healthy volunteer study overestimated the steady-state D2R occupancy in the patients. The discrepancy in PD response was addressed with introduction of tolerance compartment in the PD modelling. Conclusion: The finding suggests that certain compounds such as aripiprazole behave distinctively at steady-state in patient with schizophrenia than single-dosing state in healthy individuals. The difference may be attributed to receptor internalisation and up-regulation following interaction of D2R with aripiprazole. The finding implies that although single-dosing studies could be used to inform steady-state in patients, considerations should be given to potential change of physiology due to characteristics of each drug and pathology of each illness to predict drug response more reliably.연구배경: 조현병 등 정신질환 치료에 주로 사용되는 항정신병약물을 대개 도파민 D2 수용체 길항제이나, 최근 들어 D2 수용체 부분적 효현제인 아리피프라졸 등 독특한 약력학적 특성을 가지는 항정신병약물들이 개발되고 있다. 그러나 정신과학 분야의 임상적 특성으로 인해 정신질환 신약 개발에 어려움이 가중되어, 이를 해결하기 위해 일부 임상시험을 정신질환 환자 대신 건강자원자에서 수행할 수 있는지에 대한 논의가 있어왔다. 본 연구에서는 이를 확인하기 위해 아리피프라졸을 단회투약한 건강자원자 자료를 바탕으로 조현병 환자에서 항정상태 아리피프라졸 D2 수용체 점유율을 예측하는 모델을 만들고 검증하고자 한다. 방법: 2-30 mg 아리피프라졸을 단회 투약한 건강자원자 18명을 대상으로 약동학적 채혈과 [11C]raclopride 양전자방출단층촬영을 통해 각각 아리피프라졸 혈중농도 및 D2 수용체 점유율의 예측모델 수립을 위한 자료를 수집했고, 2-30mg 아리피프라졸을 평균 2년의 장기간 투약한 조현병 환자 8명을 대상으로 같은 방법을 통해 모델 검증을 위한 자료를 수집했다. 예측모델을 이용해 시뮬레이션한 D2 수용체 점유율을 실제 조현병 환자에서 D2 수용체 점유율 값과 비교하고, 차이가 있는 경우 차이를 보정하여 실제 수용체 점유율을 더 잘 예측하는 모델을 수립했다. 결과: 건강자원자에서 단회 투약한 자료를 이용해 수립한 예측모델은 조현병 환자에서 항정상태 D2 수용체 점유율을 실제 값보다 높게 예측했다. 이 약력학적 반응의 차이를 약력학 모델에 내성 구획을 도입하여 보정했다. 결론: 본 연구의 결과에 따르면 아리피프라졸 등 특정 약물은 건강자원자에서 단회투약 했을 때와, 조현병 환자에서 항정상태에 도달했을 때 서로 다른 효과를 나타냄을 시사한다. 이러한 효과의 차이는 약물로 인한 D2 수용체 내재화 또는 상향조절의 결과로 추측할 수 있다. 따라서 건강자원자의 단회투약 자료로 환자의 항정상태를 예측할 수 있지만, 정확한 약물 반응 예측을 위해 각각 약물의 작용기전 및 질병 여부에 따른 인체의 생리적 변화를 고려하는 것이 권장된다.Chapter 1. Introduction 1 Chapter 2. Methods 7 Chapter 3. Results 11 Chapter 4. Discussion 15 Chapter 5. Conclusion 23 References 24 Tables 30 Figures 33 Abstract in Korean 48박

Population Pharmacokinetic-Pharmacodynamic Modeling of Haloperidol in Patients With Schizophrenia Using Positive and Negative Syndrome Rating Scale

The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that quantifies the efficacy of haloperidol, accounting for the placebo effect, the variability in exposure-response, and the dropouts. Subsequently, the developed model was utilized to characterize an effective dosing strategy for using haloperidol as a comparator drug in future antipsychotic drug trials. The time course of plasma haloperidol concentrations from 122 subjects and the Positive and Negative Syndrome Scale (PANSS) scores from 473 subjects were used in this analysis. A nonlinear mixed-effects modeling approach was utilized to describe the time course of PK and PANSS scores. Bootstrapping and simulation-based methods were used for the model evaluation. A 2-compartment model adequately described the haloperidol PK profiles. The Weibull and E-max models were able to describe the time course of the placebo and the drug effects, respectively. An exponential model was used to account for dropouts. Joint modeling of the PKPD model with dropout model indicated that the probability of patients dropping out is associated with the observed high PANSS score. The model evaluation results confirmed that the precision and accuracy of parameter estimates are acceptable. Based on the PKPD analysis, the recommended oral dose of haloperidol to achieve a 30% reduction in PANSS score from baseline is 5.6 mg/d, and the corresponding steady-state effective plasma haloperidol exposure is 2.7 ng/mL. In conclusion, the developed model describes the time course of PANSS scores adequately, and a recommendation of haloperidol dose was derived for future antipsychotic drug trials

Blood-Brain Barrier Penetration of Zolmitriptan—Modelling of Positron Emission Tomography Data

Positron emissiontomography (PET) with the drug radiolabelled allows a direct measurement of brain or other organ kinetics, information which can be essential in drug development. Usually, however, a PET-tracer is administered intravenously (i.v.), whereas the therapeutic drug is mostly given orally or by a different route to the PET-tracer. In such cases, a recalculation is needed to make the PET data representative for the alternative administration route. To investigate the blood-brain barrier penetration of a drug (zolmitriptan) using dynamic PET and by PK modelling quantify the brain concentration of the drug after the nasal administration of a therapeutic dose. [11C]Zolmitriptan at tracer dose was administered as a short i.v. infusion and the brain tissue and venous blood kinetics of [11C]zolmitriptan was measured by PET in 7 healthy volunteers. One PET study was performed before and one 30min after the administration of 5mg zolmitriptan as nasal spray. At each of the instances, the brain radioactivity concentration after subtraction of the vascular component was determined up to 90min after administration and compared to venous plasma radioactivity concentration after correction for radiolabelled metabolites. Convolution methods were used to describe the relationship between arterial and venous tracer concentrations, respectively between brain and arterial tracer concentration. Finally, the impulse response functions derived from the PET studies were applied on plasma PK data to estimate the brain zolmitriptan concentration after a nasal administration of a therapeutic dose. The studies shows that the PET data on brain kinetics could well be described as the convolution of venous tracer kinetics with an impulse response including terms for arterial-to-venous plasma and arterial-to-brain impulse responses. Application of the PET derived impulse responses on the plasma PK from nasal administration demonstrated that brain PK of zolmitriptan increased with time, achieving about 0.5mg/ml at 30min and close to a maximum of 1.5mg/ml after 2hr. A significant brain concentration was observed already after 5min. The data support the notation of a rapid brain availability of zolmitriptan after nasal administratio

Ligand-receptor interaction modelling using PET imaging

A basic problem in the discovery and development of novel drugs to be used in the treatment of neurological and psychiatric disorders is the absence of relevant in vitro or in vivo animal models that can yield results which can be extrapolated to man. Drug research now benefits from the fast development of functional imaging techniques such as positron emission tomography (PET) which trace radiolabelled molecules directly in the human brain. PET uses molecules that are labelled with short-lived radionuclides and injected intravenously into experimental animals, human volunteers or patients. The current work provided novel knowledge in the ligand-receptor interaction between GR205171 and neurokinin 1 (NK1) receptor. GR205171 is a high affinity and selective NK1-receptor antagonist. Clinical studies were performed both in monkeys and humans to obtain information about the suitability of the ligand with regard to its affinity and penetration. The specific objectives of this thesis were to define an appropriate model for GR205171 tracer and to calculate receptor occupancy in the monkey and human brain, introducing also novel methodological approaches. The definition of a relationship between plasma drug concentration and receptor occupancy was another important aim of this work. In fact, the demonstration of quantitative relationships between drug binding in vivo from plasma concentration data and drug effects in patients can be used to validate targets for drug action, to correlate pharmacological and physiological effects, and to optimise clinical treatment. In conclusion, the modelling of GR205171 PET data, including different methodological approaches, demonstrated its utility in assessing NK1 receptor occupancy after drug challenge and its relationship with plasma concentration

A population approach to characterise amisulpride pharmacokinetics in older people and Alzheimer's disease

Introduction Current prescribing guidelines for the antipsychotic amisulpride are based largely on pharmacokinetic (PK) studies in young adults, and there is a relative absence of data on older patients, who are at greatest risk of developing adverse events. Methods This study aimed to develop a population PK model for amisulpride specifically in older people, by combining data from a richly sampled phase 1, single (50 mg) dose study in healthy older people (n = 20, 65–79 years), with a clinical dataset obtained during off label, low-dose (25–75 mg daily) amisulpride prescribing in older people with Alzheimer’s disease (AD) (n = 25, 69–92 years), as part of an observational study. Results After introducing a scaling factor based on body weight, age accounted for 20 % of the inter-individual variability in drug clearance (CL), resulting in a 54 % difference in CL between those aged 65 and those aged 85 years, and higher blood concentrations in older patients. Discussion These findings argue for the consideration of age and weight-based dose stratification to optimise amisulpride prescribing in older people, particularly in those aged 85 years and above