The Journal of Clinical Pharmacology最新文献

This study assesses the use of population pharmacokinetics (PopPK) in supporting pediatric dosing of novel biological drug products. The labeling for biologic drug products approved by the US Food and Drug Administration (FDA) from 2002 until 2021 was reviewed to identify those with a pediatric indication. For the drugs with a pediatric indication, the dosing regimen(s) based on age groups, dosing strategy, the use of PopPK to support the dose, and the types of pediatric clinical trials were reviewed. Data were collected from FDA's review documents and product labels on the Drugs@FDA website, and as needed, more clinical trial details were collected from PubMed and clinicaltrials.gov. The role of PopPK analyses in dosing was captured when mentioned in the label or review as playing a role in selecting the approved pediatric dose and/or in verifying the adequacy of the studied dose to support labeling. Between 2002 and 2021, FDA approved 169 biological products, and 78 of 169 (46%) products have an approved indication for which the label contains dosing recommendations for pediatric use. For the 78 products approved in pediatrics, there was a total of 180 clinical trials that included pediatric patients. Phase 3 pediatric trials commonly supported pediatric approval and dosing for the reviewed products (64%, 50/78 products; 56.1%, 101/180 trials). PopPK analyses were reported to play a critical role in dose selection, prediction, and verification for 40 of the 78 products (51%), including informing pediatric dosing in the absence of pediatric data (e.g., drugs approved under animal rule), comparing exposures to the exposure range observed in adults, and informing alternative dosing strategies in certain age or body weight groups. PopPK analyses have been applied in a variety of ways to inform pediatric dosing and support extrapolation from adult data or other pediatric age groups for biologics. Understanding and learning from these past cases on the use of pharmacometrics tools to support pediatric dosing of biological products can inform future pediatric development programs.

This study aims to meticulously map the bibliometric landscape of drug-drug interactions (DDIs) in clinical research. This represents the first use of bibliometric analysis to comprehensively highlight the evolutionary trends and core themes in this critical field of pharmacology. An exhaustive bibliometric search was performed within the Web of Science Core Collection, aiming to comprehensively gather literature on DDIs in clinical settings. A combination of sophisticated analytical tools including DIKW, VOSviewer, and Citespace was utilized for an in-depth exploration of bibliometric patterns and trends. Of the 3421 initially identified articles, 2622 were considered relevant. The analysis revealed a marked escalation in DDIs publications, with a peak observed in 2020. Five principal thematic clusters emerged: Safety and Adverse Reactions, Drug Metabolism and Efficacy, Disease and Drug Treatment, Research Methods and Practices, and Special Populations and Combined Medication. Key insights included the escalating significance of drug metabolism in pharmacokinetics, heightened focus on cardiovascular and antiviral therapeutics, and the advancing frontier of personalized medicine. Additionally, the analysis underscored the necessity for strategic attention to vulnerable populations and innovative methodological approaches. This study calls for the global harmonization of research methods in DDIs clinical investigations, advocating for the integration of personalized medicine paradigms and the implementation of cutting-edge computational analytics. It highlights the imperative for inclusive and collaborative research approaches to adeptly address the intricate challenges of contemporary pharmacotherapy.

This parallel-group, open-label Phase I study evaluated the effect of mild to moderate hepatic impairment on pharmacokinetics (PK), pharmacodynamics (PD), and safety of a single oral dose of SHR4640. Participants with mild or moderate hepatic impairment were enrolled, with each cohort consisting of eight individuals, alongside eight well-matched controls with normal hepatic function. The participants were administered 10 mg SHR4640, and blood samples were collected for PK evaluation over 72 h. Additionally, serum uric acid (sUA) levels were measured to assess PD changes. Safety was evaluated through adverse events, laboratory tests, vital signs, and electrocardiograms. The C_max of SHR4640 decreased by 15.0% in the mild hepatic impairment group (geometric least squares means of the ratios [GMR] = 0.850, 90% CI: 0.701-1.03) and by 17.5% in the moderate hepatic impairment group (GMR = 0.825, 90% CI: 0.681-1.00). These reductions were not statistically significant compared to the normal hepatic function group. AUC_0-t and AUC_0-inf were similar across all groups, indicating that overall exposure to the drug was not clinical significantly affected by hepatic impairment. Apparent clearance and volume of distribution of SHR4640 showed no association with the severity of hepatic impairment as measured by the Child–Pugh score. There were no significant differences in the changes in sUA levels from baseline across different levels of hepatic function. SHR4640 is well tolerated in participants with mild or moderate hepatic impairment. Mild and moderate hepatic impairment did not have a clinically relevant impact on PK, PD, and safety of SHR4640. SHR4640 can be used in patients with mild to moderate hepatic impairment without the need for dose adjustment.

TAVO101 is a humanized anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody under clinical development for the treatment of atopic dermatitis (AD) and other allergic inflammatory conditions. The crystallizable fragment region of the antibody was engineered for half-life extension and attenuated effector functions. This Phase 1, double-blinded, randomized, placebo-controlled study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of TAVO101 in healthy adult subjects in seven ascending dose cohorts. Subjects received a single intravenous administration of TAVO101 or placebo with a 195-day follow-up. TAVO101 was safe and well tolerated. The incidences and severities of treatment-emergent adverse events were mostly mild and comparable between the active and placebo groups, with no trends of dose relationship. There were no severe adverse events, deaths, or treatment-related withdrawals. TAVO101 exhibited a linear pharmacokinetic profile, low clearance, and a median elimination half-life of 67 days in healthy subjects. All TAVO101-treated subjects tested negative for anti-drug antibodies. To support development in AD, TAVO101 was studied in an oxazolone-induced AD model in hTSLP transgenic mice and demonstrated efficacy. This long-acting anti-TSLP antibody has the potential for stronger and sustained allergic inflammatory disease control. The results from this study warranted further clinical development of TAVO101 in patients.

Cenerimod is a sphingosine-1-phosphate receptor 1 modulator that reduces tissue availability of circulating lymphocytes. The compound is in Phase 3 development for the treatment of systemic lupus erythematosus. Its pharmacokinetic properties are characterized by slow absorption and multiphasic elimination with a long terminal half-life (t_½), potentially caused by enterohepatic circulation (EHC). In this trial in healthy participants, oral cenerimod 0.5 and 4 mg once daily was administered for 50 days, followed by oral administration of activated charcoal (ie, 50 mg every 12 h for 11 days, starting 24 h after the last cenerimod dose), to investigate the potential EHC of cenerimod and assess whether elimination of cenerimod can be accelerated. The multiple-dose pharmacokinetics, pharmacodynamics, safety, and tolerability of cenerimod were also evaluated. For both doses, peak plasma concentrations were reached 6 and 7 h after dosing. Cenerimod accumulated approximately eightfold and (near) steady-state conditions were reached after 50 doses, resembling clinically meaningful exposure to cenerimod. The t_½ following 0.5 and 4 mg of cenerimod was 767 and 799 h (ie, 32 and 33 days) and 720 and 780 h (ie, 30 and 33 days) with or without administration of charcoal, respectively, indicating no statistically significant difference. Therefore, charcoal did not accelerate cenerimod elimination suggesting that there is no EHC of cenerimod. A reversible, dose-dependent decrease in total lymphocyte count was observed. No safety concerns were identified; administration of charcoal was well tolerated.

Dexamethasone is a synthetic glucocorticoid approved for treating disorders of various organ systems in both adult and pediatric populations. Currently, approved pediatric dosing recommendations are weight-based, but it is unknown whether differences in dexamethasone drug disposition and exposure exist for children with obesity. This study aimed to develop a population pharmacokinetic (PopPK) model for dexamethasone with data collected from children with obesity. Dexamethasone was given as either IV or oral/enteral administration, and a salt factor correction was used for dexamethasone sodium phosphate injection. A PopPK analysis using dexamethasone plasma concentration versus time was performed using the software NONMEM. A virtual population of 1000 children with obesity across three age groups was generated for dosing simulations. Data from 59 study participants with 82 PK plasma samples were used in the PopPK analysis. A one-compartment model with first-order absorption and the inclusion of total body weight as a covariate characterized the data. No other covariates were included in the PopPK model. Single and multiple IV dose(s) of 0.5 and 1 mg/kg every 8 h resulted in 68% or more of virtual children with obesity attaining simulated exposures that were within exposure ranges previously reported in adult studies. In conclusion, this was the first study to characterize dexamethasone's PopPK in children with obesity. Simulation results suggest that virtual children with obesity receiving oral doses of 0.5 and 1 mg/kg had generally comparable dexamethasone exposures as adult estimates. Additional studies are needed to characterize the dexamethasone's target exposure in children.

Introduced by the Hatch-Waxman Amendments of 1984, 505(b)(2) applications permit the US Food and Drug Administration to rely, for approval of a new drug application, on information from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. This pathway is designed to circumvent the unnecessary duplication of studies already conducted on a previously approved drug. It can lead to a considerably more efficient and expedited route to approval compared to a traditional development path. Model-informed drug development refers to the utilization of a diverse array of quantitative models in drug development to streamline the decision-making process. In this approach, diverse quantitative models that integrate knowledge of physiology, disease processes, and drug pharmacology are employed to address drug development challenges and guide regulatory decisions. Integration of these model-informed approaches into 505(b)(2) regulatory submissions and decision-making can further expedite the approval of new drugs. This article discusses some applications of model-informed approaches that were used to support 505(b)(2) drug development and regulatory actions. Specifically, various quantitative models such as population pharmacokinetic and exposure-response models have been employed to provide evidence of effectiveness, guide dosing in subgroups such as subjects with hepatic or renal impairment, and inform policies. These case study examples collectively underscore the significance of model-informed approaches in drug development and regulatory decisions associated with 505(b)(2) submissions.

Exidavnemab is a monoclonal antibody (mAb) with a high affinity and selectivity for pathological aggregated forms of α-synuclein and a low affinity for physiological monomers, which is in clinical development as a disease-modifying treatment for patients with synucleinopathies such as Parkinson's disease. Safety, tolerability, pharmacokinetics, immunogenicity, and exploratory biomarkers were assessed in two separate Phase 1 single ascending dose studies, including single intravenous (IV) (100 to 6000 mg) or subcutaneous (SC) (300 mg) administration of exidavnemab in healthy volunteers (HVs). Across the two studies, a total of 98 Western, Caucasian, Japanese, and Han Chinese HVs were enrolled, of which 95 completed the study. Exidavnemab was generally well tolerated. There were no serious adverse events or safety issues identified in laboratory analyses. Headache, asymptomatic COVID-19, back pain, and post lumbar puncture syndrome were the most frequently reported treatment-emergent adverse events. Following IV infusion, the pharmacokinetics of exidavnemab was approximately dose linear in the range 100-6000 mg. The terminal half-life was approximately 30 days, and the exposure was comparable across Western, Caucasian, Japanese, and Han Chinese volunteers. The absolute SC bioavailability was ∼71%. Cerebrospinal fluid exposure relative to serum after single dose was within the range expected for mAbs (approximately 0.2%). The anti-drug antibody rates were low and there was no effect of immunogenicity on the pharmacokinetics or safety. Dose-dependent reduction of free α-synuclein in plasma was observed. In summary, exidavnemab was found to have an excellent pharmacokinetic profile and was well tolerated in HVs, supporting the continued clinical development.

A novel dual PI3K α/δ inhibitor, TQ-B3525, has been developed for the targeted treatment of lymphoma and solid tumors. TQ-B3525 is primarily metabolized by CYP3A4 and FOM3, while also serving as a substrate for the P-glycoprotein transporter. The aim of this study was to anticipate the drug–drug interaction (DDI) of TQ-B3525 and its two metabolites with CYP3A4 enzyme potent inducer (rifampicin) and CYP3A4/P-gp inhibitor (itraconazole) utilizing a physiologically based pharmacokinetic (PBPK) modeling approach. Clinical data from healthy and cancer patient adults were employed to construct and evaluate the PBPK model for TQ-B3525, M3, and M8-3. Models involving rifampicin combined with midazolam, itraconazole combined with midazolam or digoxin were utilized to showcase the robustness of evaluating DDI effects. The simulated drug exposure of TQ-B3525, M3, and M8-3 in healthy and patient adults were consistent with clinical data, and the mean fold error values were within the acceptable ranges. The simulated results of positive substrates correspond to those reported in the literature. Co-administration with rifampicin reduces C_max and AUC of TQ-B3525 to 76.1% and 46.0%, while increasing the levels of M3 and M8-3. With itraconazole, C_max and AUC of TQ-B3525 rise to 131% and 204%, but decrease substantially for M3 and M8-3. PBPK model simulation results showed that the systemic exposure of TQ-B3525 was significantly affected when co-administered with CYP3A4/P-gp inducers and inhibitors. This indicates that the combination with strong inducers and inhibitors should be carefully avoided or adjust the dosage of TQ-B3525 in clinic.

Roux-en-Y gastric bypass (RYGB) involves creating a small stomach pouch, bypassing part of the small intestine, and rerouting the digestive tract. These alterations can potentially change the drug exposure and response. Our primary aim was to assess the impact of RYGB on the pharmacokinetics of simvastatin lactone (SV) and its active metabolite, simvastatin hydroxy acid (SVA). Ultimately, we aimed to optimize dosing for this understudied population by employing a population pharmacokinetic–pharmacodynamic link approach. The study comprised patients who had undergone RYGB surgery and individuals without a previous history of RYGB. All participants received a single oral dose of simvastatin. Plasma concentration data were analyzed with a nonlinear mixed-effect modeling approach. A parent–metabolite model with first-order absorption, 2-compartments for SV and 1-compartment for SVA, linear elimination, and enterohepatic circulation best described the data. The model was linked to the turnover pharmacodynamic model to describe the SVA inhibition on LDL-cholesterol production. Our simulations indicated that following RYGB surgery, the exposure to SV and SVA decreased by 40%. Consequently, for low-intensity statin patients, we recommend increasing the dose from 10 to 20 mg in post-RYGB patients to maintain a comparable response to that of non-operated subjects. Moderate-intensity statin patients should require increasing doses to 40 or 60 mg or the addition of a non-statin medication to achieve similar therapeutic outcomes. In conclusion, individuals post-RYGB exhibit diminished exposure to SV and may benefit from increasing the dose or adjunctive therapy with non-statin drugs to attain equivalent responses and mitigate potential adverse events.