Journal of clinical pharmacology最新文献

{"title":"In Silico Modeling for Ex Vivo Placental Transfer of Morphine.","authors":"Harvey Ho,&nbsp;Shengjie Zhang,&nbsp;Ken Kurosawa,&nbsp;Koji Chiba","doi":"10.1002/jcph.2105","DOIUrl":"https://doi.org/10.1002/jcph.2105","url":null,"abstract":"<p><p>Morphine may be administered in pregnant women as an analgesic agent. The transplacental pharmacokinetics (PK) of morphine varies during pregnancy because of physiological and metabolic changes. In this work, we use a multi-compartment model to simulate ex vivo human placental transfer studies of morphine. The computational model is based on a recently published model for metformin with both passive and active transport kinetics. Modifications were made to incorporate morphine-specific transfer parameters. Parameters for the PK models were determined via the nonlinear regression method. In addition, the Latin hypercube sampling (LHS) method was used for the global parameter analysis of the model. Simulation results show good agreement between the model and observed fetal and maternal morphine concentrations. In addition, the lower efflux of morphine from fetal to maternal plasma reflects reduced P-glycoprotein (P-gp) transport as pregnancy progresses, which leads to slower clearance of morphine in the maternal plasma. The LHS analysis also indicates the more significant roles played by the passive diffusion parameters than the active transport parameter on the fetal/maternal morphine concentrations. In conclusion, we used an in silico model to investigate the transplacental properties of morphine and to predict the in vivo transplacental properties of morphine when PK parameters change.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"140-146"},"PeriodicalIF":2.9,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/03/83/JCPH-62-140.PMC9543479.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40358632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive Value of C-Reactive Protein and Albumin for Temporal Within-Individual Pharmacokinetic Variability of Voriconazole in Pediatric Patients Undergoing Hematopoietic Cell Transplantation.","authors":"Takuto Takahashi,&nbsp;Mutaz M Jaber,&nbsp;Angela R Smith,&nbsp;Pamala A Jacobson,&nbsp;James Fisher,&nbsp;Mark N Kirstein","doi":"10.1002/jcph.2024","DOIUrl":"https://doi.org/10.1002/jcph.2024","url":null,"abstract":"<p><p>Voriconazole is a widely used antifungal agent in immunocompromised patients, but its utility is limited by its variable exposure and narrow therapeutic index. Population pharmacokinetic (PK) models have been used to characterize voriconazole PK and derive individualized dosing regimens. However, determinants of temporal within-patient variability of voriconazole PK were not well established. We aimed to characterize temporal variability of voriconazole PK within individuals and identify predictive clinical factors. This study was conducted as a part of a single-institution, phase I study of intravenous voriconazole in children undergoing hematopoietic cell transplantation (NCT02227797). We analyzed voriconazole PK study data collected at week 1 and again at week 2 after the start of voriconazole therapy in 59 pediatric patients undergoing HCT (age <21 years). Population PK analysis using nonlinear mixed effect modeling was performed to analyze temporal within-individual variability of voriconazole PK by incorporating a between-occasion variability term in the model. A 2-compartment linear elimination model incorporating body weight and cytochrome P450 2C19 phenotype described the data. The ratio of individual voriconazole clearance between weeks 1 and 2 ranged from 0.11 to 3.3 (-9.1 to +3.3-fold change). Incorporation of covariate effects by serum C-reactive protein and albumin levels decreased between-occasion variability of clearance as compared to the model without them (coefficient of variation, 41.2% and 59.5%, respectively) and improved the model fit (P < .05). As significant covariates on voriconazole PK, C-reactive protein and albumin concentrations may potentially serve as useful biomarkers as part of therapeutic drug monitoring.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"855-862"},"PeriodicalIF":2.9,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39888124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-Drug Interactions in People Living With HIV at Risk of Hepatic and Renal Impairment: Current Status and Future Perspectives.","authors":"Nicolas Cottura,&nbsp;Hannah Kinvig,&nbsp;Sandra Grañana-Castillo,&nbsp;Adam Wood,&nbsp;Marco Siccardi","doi":"10.1002/jcph.2025","DOIUrl":"https://doi.org/10.1002/jcph.2025","url":null,"abstract":"<p><p>Despite the advancement of antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV), drug-drug interactions (DDIs) remain a relevant clinical issue for people living with HIV receiving ART. Antiretroviral (ARV) drugs can be victims and perpetrators of DDIs, and a detailed investigation during drug discovery and development is required to determine whether dose adjustments are necessary or coadministrations are contraindicated. Maintaining therapeutic ARV plasma concentrations is essential for successful ART, and changes resulting from potential DDIs could lead to toxicity, treatment failure, or the emergence of ARV-resistant HIV. The challenges surrounding DDI management are complex in special populations of people living with HIV, and often lack evidence-based guidance as a result of their underrepresentation in clinical investigations. Specifically, the prevalence of hepatic and renal impairment in people living with HIV are between five and 10 times greater than in people who are HIV-negative, with each condition constituting approximately 15% of non-AIDS-related mortality. Therapeutic strategies tend to revolve around the treatment of risk factors that lead to hepatic and renal impairment, such as hepatitis C, hepatitis B, hypertension, hyperlipidemia, and diabetes. These strategies result in a diverse range of potential DDIs with ART. The purpose of this review was 2-fold. First, to summarize current pharmacokinetic DDIs and their mechanisms between ARVs and co-medications used for the prevention and treatment of hepatic and renal impairment in people living with HIV. Second, to identify existing knowledge gaps surrounding DDIs related to these special populations and suggest areas and techniques to focus upon in future research efforts.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"835-846"},"PeriodicalIF":2.9,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39666812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Vancomycin Clearance Between Augmented Renal Clearance and Normal Renal Function in Critically Ill Infants: A Population Pharmacokinetics Study.","authors":"Guang-Ming Huang,&nbsp;Yue Qiu,&nbsp;Tao-Tao Liu,&nbsp;Jie-Jiu Lu","doi":"10.1002/jcph.2029","DOIUrl":"https://doi.org/10.1002/jcph.2029","url":null,"abstract":"<p><p>Augmented renal clearance presents as super-renal function with enhanced renal perfusion and glomerular hyperfiltration in many critically ill infants. This study was to compare vancomycin clearance (CL) between critically ill infants with augmented renal clearance and with normal renal function and to optimize the vancomycin dosage. Data were retrospectively obtained from infants treated in intensive care units. Population pharmacokinetics analysis was conducted using nonlinear mixed-effects model software. A total of 66 critically ill infants were included: 47 infants with augmented renal clearance and 19 infants with normal renal function. The median doses of vancomycin for infants with augmented renal clearance and with normal renal function were 48 and 47 mg/kg/day (P > .05), respectively. The median CL in infants with augmented renal clearance was increased 1.96-fold compared with infants who had normal renal function (0.98 versus 0.5 L/h, P < .001). Simulations indicated that the recommended dosage of 60, 70, 80, 90, and 100 mg/kg/day would be appropriate in critically ill infants with an estimated glomerular filtration rate (eGFR) of 130-149, 150-169, 170-189, 190-209, and >210 mL/min/1.73 m² , respectively. Doses of 70 and 75 mg/kg/day were recommended for infants with augmented renal clearance and gestational ages of 27-32.9 and 33-39 weeks, respectively. Doses of 70, 75, 80, and 90 mg/kg/day were recommended for infants with augmented renal clearance and weights of 2.0-2.9, 3.0-3.9, 4.0-4.9, and 5.0-6.0 kg, respectively. In conclusion, the typical vancomycin dosage is insufficient for critically ill infants with augmented renal clearance. Premature infants and infants of low weight with augmented renal clearance need individualized dosing regimens to obtain an adequate area under the serum concentration time curve over 24 h/minimum inhibitory concentration ratio.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"863-872"},"PeriodicalIF":2.9,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39925402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics and Exposure-Response Relationships of Astegolimab in Patients With Severe Asthma.","authors":"Naoki Kotani,&nbsp;Michael Dolton,&nbsp;Robin J Svensson,&nbsp;Jakob Ribbing,&nbsp;Lena E Friberg,&nbsp;Shweta Vadhavkar,&nbsp;Dorothy Cheung,&nbsp;Tracy Staton,&nbsp;Gizette Sperinde,&nbsp;Jin Jin,&nbsp;Wendy S Putnam,&nbsp;Angelica Quartino","doi":"10.1002/jcph.2021","DOIUrl":"https://doi.org/10.1002/jcph.2021","url":null,"abstract":"<p><p>Astegolimab is a fully human immunoglobulin G2 monoclonal antibody that binds to the ST2 receptor and blocks the interleukin-33 signaling. It was evaluated in patients with uncontrolled severe asthma in the phase 2b study (Zenyatta) at doses of 70, 210, and 490 mg subcutaneously every 4 weeks for 52 weeks. This work aimed to characterize astegolimab pharmacokinetics, identify influential covariates contributing to its interindividual variability, and make a descriptive assessment of the exposure-response relationships. A population pharmacokinetic model was developed using data from 368 patients in the Zenyatta study. Predicted average steady-state concentration was used in the subsequent exposure-response analyses, which evaluated efficacy (asthma exacerbation rate) and biomarker end points including forced expiratory volume in 1 second, fraction exhaled nitric oxide, blood eosinophils, and soluble ST2. A 2-compartment disposition model with first-order elimination and first-order absorption best described the astegolimab pharmacokinetics. The relative bioavailability for the 70-mg dose was 15.3% lower. Baseline body weight, estimated glomerular filtration rate, and eosinophils were statistically correlated with pharmacokinetic parameters, but only body weight had a clinically meaningful influence on the steady-state exposure (ratios exceeding 0.8-1.25). The exposure-response of efficacy and biomarkers were generally flat with a weak trend in favor of the highest dose/exposure. This study characterized astegolimab pharmacokinetics in patients with asthma and showed typical pharmacokinetic behavior as a monoclonal antibody-based drug. The exposure-response analyses suggested the highest dose tested in the Zenyatta study (490 mg every 4 weeks) performed close to the maximum effect, and no additional response may be expected above it.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"905-917"},"PeriodicalIF":2.9,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/57/f1/JCPH-62-905.PMC9303772.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39647542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary on Pharmacologically Meaningful Half-Life.","authors":"Nick Holford","doi":"10.1002/jcph.2051","DOIUrl":"https://doi.org/10.1002/jcph.2051","url":null,"abstract":"Chaiken and Pai have proposed that there is a need for a pharmacologically meaningful half-life in order to provide a single descriptor to account for the duration of pharmacologic effect and dosing interval.1 Although they show in their introductory remarks that they are aware of pharmacometrics and systems biology, they have also clearly illustrated the limitations of a single parameter to describe the relationship between concentration and effect. A description of the time course of drug effect, and hence the duration, requires, at a minimum, a description of the time course of concentration and the relationship between concentration and effect. The simplest pharmacokinetic model for the time course of concentration involves a bolus input, a single distribution volume (V), and a first-order elimination process, defined by clearance (CL). The simplest realistic pharmacodynamic model has a maximum effect (Emax) and the concentration at 50% of Emax (C50). Ignoring more realistic input processes and delays between plasma concentration and effect, this means that a minimum of four parameters are required (V, CL, Emax, and C50). Thus, even the simplest description that can account for the duration of pharmacologic effect requires four parameters it is logically impossible and scientifically incorrect to imagine that a single half-life parameter can be found to describe the complexity. This is illustrated in Figures 1–3, which show the dramatic change in the duration of drug effect with increasing initial concentration (equivalent to increasing dose). The pharmacokinetic and pharmacodynamic parameters rest unchanged only the dose has changed. There is no single half-life that can predict or explain these changes based on the simplest possible realistic description of drug effect. Instead of searching for the impossible by looking for a single half-life to describe complex drug effects, clinicians are advised to learn the basic principles Figure 1. Time course of concentration (blue) and effect (red) with a peak concentration equal to C50. The concentration half-life is about 7 time units. Concentrations are mainly lower than the C50, and thus the effect is approximately proportional to the concentration. The time course of the effect is similar to the time course of concentration, but does not follow the exponential decrease and therefore cannot be described with a half-life of effect.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"62 7","pages":"833-834"},"PeriodicalIF":2.9,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1c/bb/JCPH-62-833.PMC10138753.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9416409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medication Optimization Using Pharmacogenomic Testing in a Complex Mental Health Population Prescribed Psychiatric Polypharmacy.","authors":"Amanda Ernst Wood,&nbsp;Deepika Agrawal,&nbsp;Alison P Deem,&nbsp;Terri L Dupper Knoper,&nbsp;Rosa F Merino,&nbsp;Hylton E Molzof,&nbsp;Laurie E Maus,&nbsp;Floreen Kim,&nbsp;Zohra Lodin,&nbsp;Sonia Lim","doi":"10.1002/jcph.2032","DOIUrl":"https://doi.org/10.1002/jcph.2032","url":null,"abstract":"<p><p>The use of polypharmacy has become significantly more common over the past two decades, increasing the risk of drug-drug interactions and adverse drug reactions. Pharmacogenomic (PGx) assays have the purported benefit of being able to predict an individual's response to a specific medication based on genetic markers, which may facilitate the development of optimized medication regimens for patients prescribed polypharmacy. This 12-week pilot study examined the impact of the PGx results on the clinical management of Veterans who were prescribed psychiatric polypharmacy. Psychiatric medication providers were given access to the PGx assay results, including notification of drug-drug-gene interactions computed from an algorithm decision tool, to assist with medication management decisions. Veteran outpatients (N = 53) prescribed polypharmacy (mean = 13.15 medications) were enrolled into the study. In 92.4% of cases, providers changed medications at baseline, with 83% of providers indicating that they changed their original medication plan based on the PGx results. Clinical improvement over the 12-week treatment phase was seen in depression (F(1.63, 45) = 5.45, P = .01, η²  = .11) and mental health quality of life (F(2.00, 45) = 4.16, P < .05, η²  = .16). Adverse drug effects were unchanged or improved over time. Rates of polypharmacy remained unchanged. The results suggest that medication changes based on the PGx assay may be beneficial in a complex patient population prescribed polypharmacy.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"898-904"},"PeriodicalIF":2.9,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39858011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Will the Pharmacologically Meaningful Half-Life Please Stand Up?","authors":"Philip Chaikin,&nbsp;Sudhakar M Pai","doi":"10.1002/jcph.2036","DOIUrl":"https://doi.org/10.1002/jcph.2036","url":null,"abstract":"In the 21st century, much emphasis in the field of clinical pharmacology has been placed on pharmacometrics and systems biology—the mathematical modeling of complex biologic processes. These principles have been applied to clinical trial simulations, prediction of drug– drug interactions using physiological pharmacokinetic models, optimization of dosing regimens, modeling of disease state progression, and Bayesian forecasting of clinical trial outcomes. Although these approaches have undoubtedly contributed to advances in drug development and individualized dosing, it seems appropriate to revisit certain basic principles of clinical pharmacology that are relevant to pharmacotherapy. Drug elimination half-life is directly related to distribution volume, an equilibrium concept, and is inversely related to total body clearance, which in turn depends on variables such as blood flow to eliminating organs and intrinsic clearance, as described elsewhere.1,2 The clinical pharmacology literature cites different descriptors of half-life: distribution and elimination half-lives, effective half-life, and the so-called context-sensitive half-life. Distribution and elimination half-lives usually pertain to initial and terminal loglinear portions of concentration–time profiles, respectively. For certain drugs with multicompartment pharmacokinetic characteristics, there can also be a (gamma) terminal phase half-life that is reflective of binding and dissociation from a receptor complex or very slow release from a deep peripheral compartment. Effective half-life pertains to drug accumulation following repeated dosing, and context-sensitive half-life to duration of administration. As a result of the kinetics of drug distribution to effect sites, it is important to recognize that for various drugs, the clinically or pharmacologicallymeaningful half-life does not always equate to the elimination half-life. This is contrary to the belief of many clinicians, where the assumption is that the longer the elimination half-life, the longer the duration of pharmacologic effect. The aim of this commentary is to illustrate, by way of relevant examples, the necessity of use of an appropriate descriptor of half-life (vide supra), and not solely the elimination half-life, to account for the duration of pharmacologic effect and dosing interval for individual drugs or within drug classes. In fact, the elimination half-life is irrelevant to the duration of pharmacologic effect in numerous instances and is affected by the absorption rate constant (for oral dosing), sampling interval and duration, and assay sensitivity (among other aspects). For the purpose of this discussion, it is considered that the underlying rate processes are first order and that the duration of drug action correlates with the pharmacologically relevant half-life and accumulation at appropriate receptors in the biophase. Although elimination and terminal halflife can also be relevant to drug toxicity, an in-dep","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"829-832"},"PeriodicalIF":2.9,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39606930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining Aripiprazole and Haloperidol: Focus on D2 Receptor.","authors":"Calogero Crapanzano,&nbsp;Pier Francesco Laurenzi,&nbsp;Chiara Amendola,&nbsp;Ilaria Casolaro","doi":"10.1002/jcph.2026","DOIUrl":"https://doi.org/10.1002/jcph.2026","url":null,"abstract":"Antipsychotic polypharmacy, defined as coprescription of 2 or more antipsychotics, is a common treatment for resistant schizophrenia. While one of the most frequently employed combinations is aripiprazole and clozapine, the clinical and pharmacological effects of coadministration of aripiprazole and haloperidol remains understudied and is far from an exhaustive characterization.1,2 From a pharmacological perspective, when aripiprazole is used in combination with haloperidol, 3 substances are competing to bind dopamine receptors: aripiprazole, haloperidol, and endogenous dopamine. Aripiprazole, a partial agonist of low intrinsic activity (57%), is characterized by stronger binding affinity towardD2 receptors (D2Rs) (Ki = 0.11 nM) and slower dissociation kinetics (koff = 31 min), when compared to both haloperidol (Ki = 0.57 nM, koff = 1min) and dopamine (Ki = 16 nM, koff = 24min).3–5 Chronic use of D2 antagonists such as haloperidol has been linked to compensatory up-regulation of D2R in the mesolimbic pathway that may increase the functional dopaminergic activity of D2 agonist aripiprazole; nevertheless, clozapine, a weak D2 antagonist, does not induce dopamine supersensitivity.1,2 Therefore, according to pharmacodynamics, when aripiprazole is added to a stable haloperidol treatment, it displaces the latter off D2R sites and exerts its partial agonist intrinsic activity, exposing the patient to a potential relapse of positive symptoms.3 On the other hand, aripiprazole may attenuate antipsychoticinduced adverse effects such as hyperprolactinemia and ameliorating negative symptoms.1,2 Conversely, the addition of haloperidol to aripiprazole may yield a stronger D2 blockade and subsequently an improvement of positive symptoms, while at same time potentially reduce some of the benefits of aripiprazole’s atypicality, namely, its activity on serotoninergic and dopaminergic transmission (dopamine D2/D3 partial agonism, serotonin 5-HT1A agonism, 5HT2A antagonism).1–3 While our discussion on this topic has been limited to speculative considerations, some of those are generalizable to combinations between antagonists with high affinity for D2R (eg, pimozide, fluphenazine) such as haloperidol may cause dopamine supersensitivity and D2R partial agonists (eg, cariprazine, brexpiprazole) such as aripiprazole may induce excessive dopaminergic activity via the high D2R density induced by long-term exposure to D2R antagonists.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"918"},"PeriodicalIF":2.9,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39929822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Empirical Analysis of Japan's Drug Development Lag Behind the United States.","authors":"Hiroshi Nakamura,&nbsp;Naohiko Wakutsu,&nbsp;Satoshi Murayama,&nbsp;Takeshi Suzuki","doi":"10.1002/jcph.2023","DOIUrl":"https://doi.org/10.1002/jcph.2023","url":null,"abstract":"<p><p>The \"drug lag\" (ie, the approval lag for new drugs) hinders patients' access to innovative new medicines. The drug lag was heavily debated in Japan from the late 2000s to the early 2010s. It consists of \"development lag\" (ie, the submission date lag for new drug applications) and \"review lag\" (ie, the difference in review periods). As the 2 lags have different causes and display significantly different recent trends in Japan, we focus on the development lag-in contrast with most previous literature-between Japan and the United States, based on a database we created for all new drugs from 2008 to 2018 using publicly available data sources. First, we found that Japan's development lag relative to the United States did not shrink in terms of the overall distribution rather than the median, which was the focus of most prior studies. Second, we examined the factors (product characteristics) that significantly affected the development lag and found that products that underwent multiregional clinical trials and those that were certified as \"breakthrough therapies\" in the United States had significantly shorter development lags with high robustness, whereas products receiving price premiums did not. Finally, we discussed the policy implications of these results. For instance, innovative new drugs that are presumed to receive price premiums require enhanced policy support for early application from the initial stages of clinical trials. It is also essential to promote information sharing regarding evaluations by foreign reviewing authorities for efficient use in the home country.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"847-854"},"PeriodicalIF":2.9,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39775364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}