The Journal of Clinical Pharmacology最新文献

{"title":"Patients in Clinical Trials are Sub-Optimally Protected for Drug–Drug Interactions: A Call for Action","authors":"David Burger PhD, Loek de Jong PhD, Daphne van Dijk MSc, Catherijne A. J. Knibbe PhD, Rob ter Heine PhD, Elise Smolders PhD, Munir Pirmohamed PhD","doi":"10.1002/jcph.6168","DOIUrl":"10.1002/jcph.6168","url":null,"abstract":"<p>It is essential that patients in clinical trials of investigational medicinal products are protected from harm. However, some of the advances made to improve medication safety in routine clinical care have only sparsely trickled down to clinical trials. For instance, in routine care, drug–drug interaction data from the approved product information<span><sup>1, 2</sup></span> is incorporated in prescribing and dispensing software to generate an automatic alert when a drug–drug interaction may occur. In contrast, drug–drug interaction management with investigational medicinal products is performed manually by the study physician or pharmacist based on instructions in the study protocol.</p><p>In our experience, instructions for drug–drug interaction management in clinical studies with unlicensed investigational medicinal products are highly variable, often outdated, and/or incomplete. To our knowledge, this problem has not yet been investigated in a systematic manner. We decided to focus on investigational medicinal products with CYP3A-related drug–drug interaction management.</p><p>Between January 1, 2022, and March 1, 2023 we reviewed phase 2/3 study protocols of ongoing clinical trials in adults with unlicensed investigational medicinal products being small molecules, supported by the Pharmacy at RadboudUMC, Nijmegen, the Netherlands. Unlicensed investigational medicinal products not being small molecules (i.e., large proteins and antibodies) are usually not (or minimally) susceptible to drug interactions and were therefore not part of this investigation. Investigational medicinal products that were already licensed for other indications were also excluded.</p><p>For each unlicensed investigational medicinal product, we recorded the clinical development phase, the drug–drug interaction profile of the product known at the time of writing the study protocol (substrate/inhibitor/inducer), the list of prohibited medications when mentioned, and the relevant sources that were described. The unlicensed investigational medicinal product name/number and name of sponsor were not recorded in order to guarantee confidentiality.</p><p>In order to facilitate the analysis and interpretation of the data, we decided to focus on unlicensed orally administered investigational medicinal products with CYP3A-related drug–drug interaction management (n = 12) as this was by far the largest group of medications where drug–drug interaction management was described.</p><p>The 12 unlicensed investigational medicinal products were equally divided between clinical development phases 2 and 3. All were multinational studies. These included nine CYP3A substrates, three CYP3A inhibitors, and two CYP3A inducers.</p><p>Figure 1 shows the number of CYP3A inducers that were listed as prohibited co-medication in case the unlicensed investigational medicinal product was a CYP3A substrate (nine study protocols). This number varied between 0 and 26 agents per protocol, with the highe","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"654-657"},"PeriodicalIF":0.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Results of the ACTION-Galactosemia Kids Study to Evaluate the Effects of Govorestat in Pediatric Patients with Classic Galactosemia","authors":"Evan Bailey MD,&nbsp;Han Phan MD,&nbsp;Ayesha Ahmad MD,&nbsp;Janet Thomas MD,&nbsp;Elizabeth G. Ames MD,&nbsp;Amanda B. Pritchard MD,&nbsp;Shane C. Quinonez MD,&nbsp;Stella Wang MS, MPH,&nbsp;Caleb Dayley MS,&nbsp;Andrew Salt MS,&nbsp;Christina Pick MS,&nbsp;Abe Durrant MS,&nbsp;Samuel Johnson MS,&nbsp;Jessie Nicodemus-Johnson PhD,&nbsp;Samuel P. Dickson PhD,&nbsp;Riccardo Perfetti MD, PhD,&nbsp;Suzanne B. Hendrix PhD,&nbsp;Shoshana Shendelman PhD","doi":"10.1002/jcph.6170","DOIUrl":"10.1002/jcph.6170","url":null,"abstract":"<p>To evaluate the pharmacodynamic effects and clinical outcomes of orally administered once-daily govorestat (AT-007), a central nervous system penetrant aldose reductase inhibitor, the double-blind placebo-controlled ACTION-Galactosemia Kids study (NCT04902781) randomly assigned 47 participants (2-17 years old) with Classic Galactosemia to 18 months of govorestat or placebo (2:1) treatment. Mean change in galactitol was compared between the treatment groups at each post-baseline timepoint using a t-test, with a mixed model for repeated measures (MMRM) analysis as a sensitivity analysis. Changes from baseline in clinical outcomes were compared between treatment groups also using a t-test with two different MMRM models as sensitivity models, one including baseline clinical outcome score. The pharmacodynamic effect of govorestat was assessed by correlating galactitol level at 3 months with change from baseline in clinical measures at 18 months using a Pearson correlation. Govorestat treatment resulted in a rapid and sustained reduction in plasma galactitol. Govorestat treatment stabilized or improved clinical measures of behavior, daily living skills, adaptive skills, cognition, tremor, and fine motor skills, which declined over time in the placebo group. Govorestat treatment did not demonstrate a benefit compared with placebo on speech outcomes or gross motor skills, which improved in both treatment groups over 18 months. Govorestat was safe and well tolerated, with adverse events well balanced between the active and placebo groups. Aldose reductase inhibition with govorestat represents a potential opportunity to lower galactitol and improve clinical outcomes in children with Classic Galactosemia.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"575-587"},"PeriodicalIF":0.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6170","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro Evaluation of CYP-Mediated Metabolism of Fezolinetant and Pharmacokinetic Interaction Between Fezolinetant and Fluvoxamine in Healthy Postmenopausal Smokers and Nonsmokers","authors":"Megumi Iwai PhD,&nbsp;Jace Nielsen Pharm D,&nbsp;Mayuko Miyagawa MS,&nbsp;Melanie Patton BSc,&nbsp;Peter L. Bonate PhD,&nbsp;Xuegong Wang MD, PhD,&nbsp;Tomasz Wojtkowski MS,&nbsp;Angela Sinn MD,&nbsp;Jiayin Huang PhD","doi":"10.1002/jcph.6157","DOIUrl":"10.1002/jcph.6157","url":null,"abstract":"<p>Fezolinetant is an oral, nonhormonal, neurokinin 3 receptor antagonist treatment option for moderate to severe vasomotor symptoms associated with menopause. An in vitro study using human recombinant cytochrome P450 (CYP) enzymes and human liver microsomes showed that fezolinetant is metabolized to its major but inactive metabolite, ES259564, predominantly through CYP1A2, with minor contributions from CYP2C9 and CYP2C19. The clinical impact of CYP1A2 inhibition and induction on single-dose pharmacokinetics of fezolinetant was assessed in an open-label, single-sequence, phase 1 study in healthy postmenopausal women, where the impact of fluvoxamine, a strong CYP1A2 inhibitor, and smoking, a moderate CYP1A2 inducer, were evaluated. In total, 18 participants, 9 of whom were smokers, were enrolled. Fezolinetant pharmacokinetics were evaluated after a single 30-mg dose on Day 1 and Day 7. Fluvoxamine 50 mg was administered as a single dose on Days 3 and 10 and twice daily from Days 4 to 9. Fluvoxamine increased geometric mean ratio of fezolinetant maximum plasma concentrations (C_max) and area under the curve from time of dosing extrapolated to infinity (AUC_inf) to 182% and 939%, respectively, while ES259564 C_max decreased to 20.1% with no significant change in AUC. In smokers versus nonsmokers, when fezolinetant was administered alone, fezolinetant C_max and AUC_inf decreased to 71.7% and 48.3%, respectively, while ES259564 C_max increased to 130.2% and AUC_inf decreased to 81.8%. A single oral 30-mg dose of fezolinetant was considered safe and well tolerated when co-administered with fluvoxamine in healthy postmenopausal women.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"508-519"},"PeriodicalIF":0.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Limited Sampling Strategy for Predicting the Area under Plasma Concentration–Time Curve of Nadolol in Healthy Subjects","authors":"Shingen Misaka PhD,&nbsp;Yuko Maejima PhD,&nbsp;Kenju Shimomura MD, PhD","doi":"10.1002/jcph.6164","DOIUrl":"10.1002/jcph.6164","url":null,"abstract":"<p>Nadolol is a hydrophilic β-adrenoceptor blocker with a relatively long half-life and negligible metabolism. It is a substrate of P-glycoprotein and organic anion transporting polypeptide 1A2, and may serve as an in vivo probe drug for the assessment of drug–drug and food–drug interactions mediated by these transporters. In the present study, we aimed to develop limited sampling strategy (LSS) models for predicting the area under the plasma concentration–time curve (AUC_0-∞) of nadolol. Plasma concentration data (C_t) in healthy volunteers reported in four previous studies were randomly divided into a training dataset for model development (n = 15) and a test dataset for model validation (n = 16). By multiple linear regression analysis, we confirmed that four out of the eight models using two time points and all models using three time points met the acceptable criteria. In particular, the three time point models using (C₃, C₆, and C₂₄) and (C₄, C₈, and C₂₄) showed better predictive performances with r² values of 0.983 and 0.980, respectively. In drug interaction studies of nadolol with itraconazole, rifampicin, grapefruit juice, and green tea extract, both LSS models accurately predicted the AUC_0-∞ with percent mean absolute error ≤11% and percent root mean square error ≤12%. In addition, using digitized pharmacokinetic data of nadolol, both LSS models were further validated by predicting the AUC_0-∞ in different doses. The results suggest that the LSS models using three time points allow a reliable prediction of AUC_0-∞ of nadolol in healthy individuals.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"621-627"},"PeriodicalIF":0.0,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meta-Analysis of Exposure-Adverse Event Relationships for Antibody–Drug Conjugates","authors":"Cheng Wang PhD,&nbsp;Linda Irons PhD,&nbsp;Holly Kimko PhD,&nbsp;Dhaval K. Shah PhD","doi":"10.1002/jcph.6160","DOIUrl":"10.1002/jcph.6160","url":null,"abstract":"<p>Antibody–drug conjugates (ADCs) have become a vital class of therapeutics in oncology because of their ability to selectively deliver potent drug molecules to tumor cells. However, ADC-associated toxicities cause high failure rates in the clinic and hinder their full potential. Due to the complex structure and pharmacokinetics of ADCs, it is challenging to identify the drivers of their toxicities. Here, quantitative analysis was performed to correlate the incidence of clinical adverse events (AEs) with nine different commonly measured exposure parameters collected from study-level summary data. We considered ADC analytes for different classes of ADCs, to identify ADC analytes that are strongly associated with the AEs for ADCs. Published clinical exposure and safety data for any grade and grade ≥3 AEs from 40 publications across six ADCs and three payloads were collected and analyzed. Exposure-AE relationships were quantified using logit models, and the strength of the correlations and rank order were determined. The analysis suggests that deruxtecan ADC-related toxicities correlated most strongly with the exposure of the free payload; monomethyl auristatin E (MMAE) ADC-related toxicities correlated with the free MMAE area under the curve; and pyrrolobenzodiazepine ADC-related toxicities correlated with no specific analyte but the dose. These findings agree with the published literature and support the notion that AE profiles are often shared by ADCs that deliver the same cytotoxic payload. The exposure–AE relationships presented here, together with identification of the most informative ADC analytes, may facilitate more focused mechanistic studies on the drivers of clinical AEs and could support dosing decisions during clinical development of ADCs.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"486-498"},"PeriodicalIF":0.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Training the Next Generation of Pediatric Clinical Pharmacologists: Insights and Trainee Perspectives Over 10 Years","authors":"Rachel L. Randell MD, MSCR,&nbsp;Rose Gelineau-Morel MD,&nbsp;Sydney Thomas PhD,&nbsp;Daniel Gonzalez PharmD, PhD,&nbsp;J. Steven Leeder PharmD, PhD,&nbsp;Christoph P. Hornik MD, PhD, MPH","doi":"10.1002/jcph.6155","DOIUrl":"10.1002/jcph.6155","url":null,"abstract":"<p>The limited number of researchers with expertise necessary toaddress treatment gaps for children presents an ongoing challenge. The NationalInstitutes of Health established a national Pediatric Clinical Pharmacology T32Training Program in 2012 to train a multidisciplinary, collaborative pediatricclinical pharmacology workforce. We surveyed all current T32 trainees andgraduates since inception to identify strengths and opportunities to enhanceworkforce development. A total of 85 out of 155 (55%) responded, with themajority of respondents being female gender (61%), white race (75%), andworking in academia (75%). Nearly all (97%) reported using clinicalpharmacology in their current position, with 88% planning to remain in clinicalpharmacology in the long term, reinforcing current training efforts. Lifestylefactors and student debt appeared to influence career decisions. Mentors werecritical for introduction and future success in the field. Time and fundinglimitations were perceived as barriers to successful training. There was also apressing need to improve diversity. For workforce development, we suggestsupporting: (1) trainees' lifestyle, by offsetting financial pressures ofresearch training and expanding the geographic footprint of pediatric clinicalpharmacology training; (2) mentorship, by identifying mentors in the field andproviding dedicated support for mentorship; (3) efficiency, by evaluatingcurrent training activities and focusing on activities that maximizeopportunities for future funding; and (4) diversity, by examining barriers todiversity in the workforce in general and expanding early enrichmentopportunities.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"389-395"},"PeriodicalIF":0.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I Study of the Pharmacokinetics, Pharmacodynamics, and Safety of Liposomal Bupivacaine for Sciatic Nerve Block in the Popliteal Fossa for Bunionectomy","authors":"Daniel I. Sessler MD,&nbsp;Xiaodong Bao MD, PhD,&nbsp;David Leiman MD,&nbsp;Jia Song MS,&nbsp;Jason Chittenden PhD,&nbsp;Alexander Voelkner PhD,&nbsp;Alparslan Turan MD,&nbsp;Jeffrey Gadsden MD","doi":"10.1002/jcph.6159","DOIUrl":"10.1002/jcph.6159","url":null,"abstract":"<p>This trial assessed the pharmacokinetics, pharmacodynamics, and safety of liposomal bupivacaine given via ultrasound-guided popliteal sciatic nerve block with or without immediate-release bupivacaine hydrochloride in adults having bunionectomies. Forty-five adults were enrolled into four sequential cohorts: (1) liposomal bupivacaine 266 mg with bupivacaine hydrochloride 50 mg; (2) liposomal bupivacaine 133 mg with bupivacaine hydrochloride 50 mg; (3) liposomal bupivacaine 266 mg; or (4) bupivacaine hydrochloride 100 mg. Outcomes included pharmacokinetics (e.g., bupivacaine maximum plasma concentration [C_max]), onset and duration of motor and sensory nerve block, and safety. Liposomal bupivacaine admixed with bupivacaine hydrochloride produced biphasic bupivacaine plasma disposition profiles with two distinct peaks. Geometric mean C_max of the early peak ranged from 235 to 421 ng/mL and the geometric mean of the late C_max was ∼30%-50% lower than the early peak. Median time to sensory block onset was 18 to 29 min in all cohorts. Sensory blocks lasted about twice as long with liposomal bupivacaine (median, 119-167 h) than with bupivacaine hydrochloride alone (median, 67 h). There were no serious adverse events. In conclusion, liposomal bupivacaine provided prolonged sensory nerve block when given as popliteal sciatic nerve blocks with or without bupivacaine hydrochloride, and bupivacaine plasma concentrations were well below the lower bound of the toxicity threshold of 2000 ng/mL for all cohorts.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"441-451"},"PeriodicalIF":0.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacometric Analysis to Describe Pharmacokinetics and Exposure-Efficacy Response of Ivermectin in Adolescents Infected with Trichuris trichiura","authors":"David T. Ajayi PhD,&nbsp;Ochuko M. Orherhe MPhil,&nbsp;Goonaseelan (Colin) Pillai PhD,&nbsp;Samer Mouksassi PhD,&nbsp;Britta Steffens PhD,&nbsp;Dominic Bräm PhD,&nbsp;Viviane Sprecher MSc,&nbsp;Daniela Hofmann PhD,&nbsp;Michael Buettcher MD,&nbsp;Jean T. Coulibaly PhD,&nbsp;Said M. Ali MSc,&nbsp;Jennifer Keiser PhD,&nbsp;Marc Pfister PhD","doi":"10.1002/jcph.6158","DOIUrl":"10.1002/jcph.6158","url":null,"abstract":"<p>The efficacy of the combination therapy of albendazole and ivermectin against <i>Trichuris trichiura</i> infection is higher in Tanzania than in Côte d'Ivoire. This study therefore aimed to investigate the difference between the population pharmacokinetics (PK) at these study sites and to determine if an exposure-response analysis could explain the low efficacy of the combination therapy in Côte d'Ivoire. Twenty-four participants (aged 12-19 years) receiving single doses of ivermectin (200 µg/kg) and albendazole (400 mg) were included in the population PK modeling. A regression analysis was performed to investigate the relationship between the reduction of fecal whipworm eggs and different exposure metrics (peak concentration, area under the plasma drug concentration-time curve [AUC], and time above a certain threshold). The PK profile of ivermectin was best described by a one-compartment model, first-order absorption, and no delay in absorption, with the absorption rate constant estimated as 0.26 per h, an apparent volume of distribution of 162.43 L, and an apparent clearance of 7.82 L/h. In Tanzania, all patients showed a very high reduction in egg count independent of exposure. In Côte d'Ivoire, a relationship was found between higher ivermectin exposure and egg reduction, although not statistically significant. There was no significant difference between the PK profiles at both study sites, despite a difference in clinical outcome. Model-based simulations indicate that higher ivermectin doses such as 400 and 600 µg/kg may be associated with reduced egg count. Larger clinical studies are warranted to explore further the exposure-efficacy response relationship at 200 µg/kg and higher ivermectin doses in adults and children.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"433-440"},"PeriodicalIF":0.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Pain Medications in Modulating Peripheral Nerve Injury Recovery","authors":"JuliAnne E. Allgood BS,&nbsp;Logan Whitney BS,&nbsp;Jeffrey Goodwin BA,&nbsp;Brian S. H. Chong MS,&nbsp;Amanda Brooks PhD,&nbsp;Jessica Pullan PhD","doi":"10.1002/jcph.6156","DOIUrl":"10.1002/jcph.6156","url":null,"abstract":"<p>Peripheral nerve injuries (PNIs) are common, costly, and cause significant pain. Effective management of PNIs involves tailoring medications to the injury type as well as understanding the pharmacokinetics/pharmacodynamics to support nerve regeneration and reduce pain. Opioids act on opioid receptors to significantly reduce pain for many patients, but there are significant addiction risks and side effects. In addition, opioids may exacerbate pain sensitivity and affect nerve regeneration. Non-steroidal anti-inflammatory drugs or acetaminophen act on cyclooxygenase enzymes and are commonly used for nerve pain, with 34.7% of people using them for neuropathic pain. While effective for mild pain, they are often combined with opioids, gamma-aminobutyric acid (GABA) analogs, lidocaine, or corticosteroids for more severe pain. Corticosteroids, mimicking adrenal hormones like cortisol, treat PNI-related inflammation and pain. Their pharmacokinetics are complex, often requiring local injections in order to minimize systemic risks while effectively treating PNIs. Lidocaine, a common local anesthetic, blocks ion channels in the central nervous system (CNS) and peripheral nerves, providing strong analgesic and anti-inflammatory effects. If used improperly, lidocaine can cause neuronal toxicity instead of anesthetic effect. GABA acts as an inhibitory neurotransmitter in the CNS and its drug analogs like pregabalin and gabapentin can alleviate neuropathic pain by binding to voltage-gated Ca²⁺ channels, inhibiting neurotransmitter release. These pain medications are commonly prescribed for PNIs despite a limited guidance on their effects on nerve regeneration. This review will discuss these drug's mechanisms of action, pharmacokinetics/pharmacodynamics, and their clinical application to highlight their effect on the PNI recovery.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"411-423"},"PeriodicalIF":0.0,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure–Response Analysis of Tofacitinib in Active Psoriatic Arthritis: Results from Two Phase 3 Studies","authors":"Sujatha Menon PhD,&nbsp;Satoshi Shoji PhD,&nbsp;Shinichi Tsuchiwata MS,&nbsp;Lara Fallon PhD,&nbsp;Keith Kanik MD","doi":"10.1002/jcph.6147","DOIUrl":"10.1002/jcph.6147","url":null,"abstract":"<p>Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). These post hoc exposure–response (E–R) analyses of pooled data from two Phase 3 studies (NCT01877668 and NCT01882439) characterized the relationships between tofacitinib exposure and efficacy (American College of Rheumatology [ACR] criteria), and changes in hemoglobin (Hgb) in patients with PsA. Efficacy data for the proportion of patients receiving tofacitinib 5 or 10 mg twice daily, or placebo, achieving ACR ≥20%, ≥50%, or ≥70% response criteria (ACR20, ACR50, and ACR70, respectively) at Month 3, were modeled jointly using a four-category ordered categorical exposure–response model (ACR20 non-responder, ACR20 responder but not ACR50 responder, ACR50 responder but not ACR70 responder, and ACR70 responder). A maximum drug effect (E_max) model (using average concentrations of tofacitinib at steady state [C_avg]) adequately described the exposure–ACR response rate relationship. Model-predicted response rates for tofacitinib 5 and 10 mg twice daily were 51% and 58%, respectively, for ACR20; 29% and 36% for ACR50; and 15% and 20% for ACR70. The E–R relationship between tofacitinib exposure and changes in Hgb was assessed using an indirect response model, which generally predicted Hgb concentration–time profiles across treatments well. The proportions of patients experiencing a decrease in Hgb of &gt;2 g/dL were similar with tofacitinib 5 mg twice daily or placebo. These results were generally consistent with previous analyses in rheumatoid arthritis and psoriasis, and support the use of tofacitinib 5 mg twice daily for active PsA.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"369-377"},"PeriodicalIF":0.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}