Journal of Clinical Pharmacology最新文献

This study aimed to develop a prostatic pharmacokinetic model of ceftazidime and suggest more effective dosing strategy for the bacterial prostatitis, based on a site-specific pharmacokinetic and pharmacodynamic perspective. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-h infusion of 1.0 g or 2.0 g ceftazidime before transurethral resection of the prostate. Plasma and prostate samples were premeditatedly collected after the administration and the concentrations were measured by high-performance liquid chromatography. The prostate tissue/plasma ratio in area under the drug concentration-time curve was approximately 0.476. The prostatic population pharmacokinetic model incorporated creatinine clearance (CL_cr) into ceftazidime clearance was developed, and adequately predicted prostate tissue concentrations by diagnostic scatter plots and visual predictive checks. Aiming for a bactericidal target of 70% of time above minimum inhibitory concentration (T > MIC) in prostate tissue, 2.0 g twice daily achieved ≥90% expected probability against main pathogens like Escherichia coli and Proteus species in patients regardless of renal function (CL_cr = 60 and 90 mL/min). However, since the expected probability of attaining the bactericidal target of 0.5-h infusion dosing regimen did not achieve 90% against Pseudomonas aeruginosa in patients with CL_cr = 60 and 90 mL/min, 4-h infusion dosing regimen of 2.0 g three times daily (6 g/day) might be required for empirical treatment. Based on site-specific simulations, the present study provides more effective dosing strategy for bacterial prostatitis.

Loratadine is metabolized to desloratadine. Both of them have been used for allergy treatment in children. Anatomical, physiological, and biological parameters of children and clearance of drugs vary with age. We aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model to simultaneously predict the pharmacokinetics of loratadine and desloratadine in children. Following validation using 11 adult data sets, the developed PBPK model was extrapolated to children. Plasma concentrations following oral loratadine or desloratadine to children of different ages were simulated and compared with six children data sets. After scaling anatomy/physiology, protein binding, and clearance, pharmacokinetics of the two drugs in pediatric populations were satisfactorily predicted. Most of the observed concentrations fell within the 5th-95th percentile range of the simulations in 1000 virtual children. The predicted area under the concentration-time curve (AUC) and C_max fell within 0.5-2.0-fold range of the observations. Oral doses of loratadine or desloratadine for children of different ages were simulated based on similar AUCs following 10 mg of loratadine or 5 mg of desloratadine for adults. Pediatric PBPK model was successfully developed to simultaneously predict plasma concentrations of loratadine and desloratadine in children of all ages. The developed pediatric PBPK model may also be applied to optimize pediatric dosage.

Toll-like receptor (TLR)7 is a pattern recognition receptor that critically contributes to the pathogenesis of systemic lupus erythematosus (SLE). DS-7011a is an anti-TLR7 monoclonal antibody that prevents TLR7 from signaling. The aim of this first-in-human, double-blind, randomized, and placebo-controlled study was to evaluate the safety, pharmacokinetics, immunogenicity, and pharmacodynamics of single ascending intravenous (IV) and subcutaneous (SC) doses of DS-7011a in healthy subjects (HS) (NCT05203692). On day 1, 80 HS received DS-7011a or placebo 6:2 in 10 cohorts (7 treated IV and 3 SC) of 8 each and were followed for 8 weeks until day 57. Safety was evaluated by recording treatment-emergent adverse events (TEAEs), pharmacokinetics by measuring plasma DS-7011a, immunogenicity by measuring plasma anti-drug antibodies (ADAs), and pharmacodynamics by evaluating the suppression of interleukin-6 production ex vivo in whole blood. DS-7011a was safe and well tolerated across all cohorts. TEAEs were mostly mild in severity and not drug-related. DS-7011a exposure increased with the dose but was not dose proportional, as the elimination of lower doses was accelerated by target-mediated drug disposition. Terminal half-life was about 15-17 days and T_max upon SC administration was about 5 days. DS-7011a induced ADAs in about half of HS but with no impact on clinical findings and pharmacokinetics. Pharmacodynamic (PD) response also increased with the dose and at the higher doses was of large extent (>90%), early onset, and lasting duration. DS-7011a showed favorable safety, pharmacokinetics, immunogenicity, and PD properties that support its development for the treatment of SLE.

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Previous research has demonstrated similar pharmacokinetic (PK) responses to single doses of obicetrapib between Japanese and White males, but the PK responses have not been established in Chinese individuals. The purpose of this randomized, parallel, open-label trial was to characterize the PK and pharmacodynamic (PD; CETP activity and plasma lipids) responses and safety of single doses (5, 10, or 25 mg; N = 36) and multiple doses (10 mg for 14 days; N = 12) of obicetrapib in healthy Chinese individuals. The maximum concentration and area under the drug concentration-time curve of obicetrapib from 0 h to infinity increased with dose after all single doses of obicetrapib. After 7 consecutive days of dosing, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol reached their minimum and maximum changes of 42% reduction and 108% increase, respectively. Primary PK and PD parameters after single- and multiple-dose administration of obicetrapib were similar to those in healthy white participants in previous studies. One participant in the 5 mg dose group experienced a treatment-emergent adverse event of decreased white blood cell and neutrophil counts, which resolved without intervention. In conclusion, these findings support the inclusion of Chinese individuals in the ongoing phase 3 clinical development program of obicetrapib.

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.

We evaluated the influence of clinical, biochemical, and genetic factors on response in 142 patients diagnosed with rheumatoid arthritis, of whom 87 patients were treated with tocilizumab (61.26%) and 55 patients were treated with rituximab (38.7%;) according to the variables European League Against Rheumatism (EULAR) response, remission, low disease activity, and improvement in Disease Activity Score, 28 joints (DAS28) at 6, 12, and 18 months. A retrospective prospective cohort study was conducted. Patients carrying the FCGR3A rs396991-TT genotype treated with tocilizumab showed higher EULAR response (OR, 5.075; 95%CI, 1.20-21.33; P = .027) at 12 months, those who were naive for biological disease-modifying antirheumatic drugs (bDMARDs) at the beginning of treatment showed satisfactory EULAR response, higher remission, and greater improvement in DAS28 at 6 months. Younger age at start of tocilizumab treatment was associated with satisfactory EULAR response at 18 months and greater remission at 6 and 18 months. Subcutaneous tocilizumab administration was associated with higher remission at 6 months and improved low disease activity rate at 12 months. In patients treated with rituximab, carriers of the FCGR2A rs1801274-TT genotype had higher EULAR response at 6 months (OR, 4.861; 95%CI, 1.11-21.12; P = .035), 12 months (OR, 4.667; p = 0.066, 95%CI, 0.90-24.12; P = .066), and 18 months (OR, 2.487; 95%CI, 0.35-17.31; P = .357), higher remission (OR: 10.625; p = 0.044, CI_95% : 1.07, 105.47) at 6 months, and greater improvement in DAS28 at 12 months (B = 0.782; 95%CI, -0.15 to 1.71; P = .098) and 18 months (B = 1.414; 95%CI, 0.19-2.63; P = .025). The FCGR3A rs396991-G allele was associated with improved low disease activity rate (OR, 4.904; 95%CI, 0.84-28.48; P = .077) and greater improvement in DAS28 (B = -1.083; 95%CI, -1.98 to -0.18; P = .021) at 18 months. Patients with a lower number of previous biological therapies had higher remission at 12 months. We suggest that the FCGR3A rs396991-TT genotype, higher baseline value of DAS28, subcutaneous tocilizumab administration, younger age at the beginning of treatment, and being bDMARD naive are associated with better response to tocilizumab. In patients treated with rituximab, we found better response in those patients with the FCGR2A rs1801274-TT genotype, the FCGR3A rs396991-G allele, and lower number of previous biological therapies.

Evaluation of the effect of food on the pharmacokinetics of oral oncology drugs is critical to drug development, as food can mitigate or exacerbate toxicities and alter systemic exposure. Our aim is to expand on current US Food and Drug Administration (FDA) guidance and provide data-driven food-effect study design recommendations specific to the oncology therapeutic area. Data for recently approved small-molecule oncology drugs was extracted from the clinical pharmacology review in the sponsor's FDA submission package. Information on subject selection, meal types, timing of the study relative to the pivotal trial, and study outcomes was analyzed. The number of subjects enrolled ranged from 12 to 60, and the majority of studies (19 of 29) were conducted in healthy volunteers. Using AstraZeneca cost data, healthy volunteer studies were estimated to cost 10-fold less than cancer patient studies. Nine of 29 (31%) studies included meals with multiple levels of fat content. Analysis of a subset of 16 drugs revealed that final results for the food-effect study were available before the start of the pivotal trial for only 2 drugs. Conducting small food-effect studies powered to estimate effect, rather than confirm no effect, with only a standardized high-fat meal according to FDA guidance may eliminate unnecessary studies, reduce cost, and improve efficiency in oncology drug development. Starting food-effect studies as early as possible is key to inform dosing in pivotal trials.

A pediatric population pharmacokinetic model including covariate effects was developed using data from 2 clinical trials in pediatric patients with epilepsy (SP0847 and SP1047). Lacosamide plasma concentration-time data (n = 402) were available from 79 children with body weights ranging from 6 to 76 kg, and a balanced age distribution (6 months to <2 years: n = 14; 2 to <6 years: n = 22; 6 to <12 years: n = 25; 12 to <18 years: n = 18). A single-compartment population pharmacokinetic model with first-order absorption and elimination described the data adequately. Plasma clearance was modeled using allometric scaling on body weight with a freely estimated allometric exponent, while volume of distribution used a fixed theoretical allometric exponent. Covariate search identified a significant effect of enzyme-inducing antiepileptic drugs resulting in a 35% decrease in lacosamide average plasma concentration. No additional effects on clearance could be attributed to race, sex, age, or renal function. Different dosing adaptation schemes by body weight bands were simulated to approximate, in pediatric patients aged 4 to 17 years, the same average plasma concentration as in adult patients receiving the maximum recommended lacosamide daily dose.