The Journal of Clinical Pharmacology最新文献

As illegally made fentanyl and congeners continue to drive overdose deaths in the US, experts have called for stronger and longer-lasting antagonists. A randomized, 4-period, 2-treatment crossover replicate-design study in healthy moderately-experienced opioid users (n = 24) evaluated the reversal of opioid-induced respiratory depression (OIRD) by intramuscular (IM) nalmefene 1.5 mg administered by auto-injector delivering a formulation developed for faster onset, compared to intranasal (IN) naloxone 4 mg. Fentanyl infusions were administered to induce a 50% reduction in minute ventilation (MV). Reversal of OIRD, pharmacokinetics, and safety were investigated under steady-state fentanyl agonism. For the primary endpoint, nalmefene demonstrated superiority at 5 min with an MV increase of 4.59 L/min, more than twice the 1.99 L/min increase for naloxone (P < .0001). Nalmefene superiority was also demonstrated at 10, 15, 20, and 30 min, while non-inferiority was demonstrated at 2.5 and 90 min. The time-course of mean antagonist concentrations correlated with increases in mean MV, peaking at approximately 5-10 min following nalmefene compared to 20-30 min following naloxone. Decreases in transcutaneous CO₂ (TCO₂) followed a similar time-course with a slight delay. At each threshold of percent reversal (25%-100%), nalmefene consistently showed a faster time to onset than naloxone. Both antagonist treatments were tolerated with no serious adverse events. This study shows that nalmefene 1.5 mg IM administered by auto-injector achieved a faster onset, higher magnitude, and longer duration of reversal of OIRD compared to naloxone 4 mg IN and represents another option for the treatment of opioid overdose.

Valbenazine improved chorea in individuals with Huntington's disease compared to placebo in a phase 3, placebo-controlled study (KINECT-HD). Population pharmacokinetics (PK) and exposure–response (E–R) analyses focused on understanding the PK characteristics of valbenazine and its active metabolite, [+]-α-dihydrotetrabenazine ([+]-α-HTBZ), and their correlation with clinical efficacy measured by the total maximal chorea (TMC) score. Consistent with previous analyses, a two-compartmental population PK model adequately described valbenazine and [+]-α-HTBZ plasma disposition, generating reliable individual-predicted exposure levels for sequential E–R analysis. The distributions of individual-predicted steady-state exposures of valbenazine and [+]-α-HTBZ were found to largely overlap between patients with tardive dyskinesia and those with Huntington's disease (HD) chorea. The relationship between the change from baseline in TMC score and [+]-α-HTBZ systemic exposure were effectively characterized by a nonlinear E_max model, with negligible impact from selected covariates. The predicted E–R curve closely aligns with the observed data, exhibiting a negative slope that indicates an increasing clinical response with escalating doses of 40, 60, and 80 mg/day. Predicted efficacy appears to reach a plateau at 80 mg once daily (QD), suggesting minimal additional benefit beyond this dosage. Together, results from the population PK model and E–R analyses reinforce the evidence base for valbenazine efficacy in reducing chorea severity, as demonstrated by the notable decrease in TMC scores compared to baseline. They also endorse the selection of dosing regimens ranging from 40 to 80 mg QD for the treatment of chorea in patients with HD.

We previously developed a population pharmacokinetic (PopPK) model for meropenem in pediatric intensive care unit patients accounting for effect of body size, maturation, and kidney function on clearance. This study aimed to extrapolate meropenem exposure to neonates and young infants using the pediatric PopPK model and to validate the predictions using external data. An independent dataset was obtained from the regulations.gov website, which included 176 neonates and young infants (up to 3 months old) with a total of 767 plasma meropenem concentrations. After normalizing the estimated glomerular filtration rate (eGFR) using a maturation factor, the PopPK model was applied to this dataset and the concordance between the model predictions and observed concentrations was visually assessed using goodness-of-fit (GOF) plots and prediction-corrected visual predictive check. Median prediction error (MDPE) evaluated bias and median absolute prediction error (MDAPE) evaluated precision of the predictions. GOF plots indicated no apparent bias or model misspecification. Individual-level predictions showed an MDPE of 1% and an MDAPE of 18.3%, both within commonly accepted thresholds for bias (<±20%-30%) and precision (<30%-35%), respectively. The findings support the model's application for simulations when neonatal eGFR is normalized using a maturation factor and for model-informed precision dosing in clinical practice for neonates and infants.

Oral nicotine pouches (NPs), although addictive and not risk-free, have potential application for a tobacco harm reduction approach. This study aims to further characterize their ability to deliver nicotine effectively. This randomized seven-way crossover PK study in healthy oral pouch consumers evaluated 11 and 20 mg NPs used for 10, 20, and 30 min, and for 30 min with expulsion of saliva. Used pouches were analyzed for extracted nicotine, flavor components, and sweeteners. The C_max and AUC_{0–4 h} increased with nicotine strength and usage time (18.9–21.6 and 26.7–33.6 ng/mL; 24.6–43.0 and 36.4 to 65.6 h ng/mL for the 11 and 20 mg NPs, respectively). Extracted nicotine was greater for the 11-mg than for the 20-mg NP, (10 min, 28.0% vs. 22.4%; 20 min, 35.8% vs. 29.6%; 30 min, 43.7% vs. 36.9%, respectively). Only 1.8% of the nicotine measured in the reference NPs was detected in saliva collected over the 30 min use period. Use of 20-mg NP for 30 min resulted in the extraction of 30.1% flavor components and 17.3% sweeteners, but only 0.16% and 3.4% of the amount measured in the reference NPs were detected in saliva, respectively. Thus, very little nicotine, flavor components, and sweeteners were swallowed during NP use. This study shows NPs can deliver nicotine effectively to satisfy smokers’ nicotine desire. Nicotine delivery to the consumer increases with the duration of use. Our findings suggest that smokers who switch completely to an NP can obtain their accustomed amount of nicotine during normal product use.

International Standard Registered Clinical Trial number: ISRCTN12265853.

This study reviews the main points of saliva as a therapeutic drug monitoring (TDM) matrix, its advantages and limitations, the methods of saliva sample collection and testing, the types of drugs in saliva TDM, and the methods of establishing saliva population pharmacokinetic (Pop PK) models, as well as summarizes the experiences and limitations, to provide references to carry out related studies. The PubMed database was systematically searched for studies on the topic of saliva as a matrix for drug TDM. The literature was screened according to the established inclusion and exclusion criteria, and relevant data were extracted and summarized. The systematic review ultimately screened 112 articles involving relevant studies on 73 drugs, of which studies on 53 drugs supported saliva as a matrix for TDM; studies on 13 drugs did not support it; and the results of studies on seven drugs were inconsistent, with conflicting results regarding whether they supported salivary TDM or not. The study steps for Pop PK modeling based on saliva concentrations are summarized, and representative drugs for which Pop PK models incorporating both plasma and saliva concentrations have been established are listed. Saliva TDM, as a new exploration and attempt, has been confirmed to be feasible for some drugs in the current study, and is expected to be applied to the clinic in the future; Pop PK modeling based on saliva TDM for precision drug delivery has only been initially attempted for some drugs, and its application has yet to be verified in clinical studies.

This study aimed to identify the potential associations between intravitreal administration of anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies (ranibizumab, aflibercept, and brolucizumab) and cardiovascular or cerebrovascular adverse events using the Japanese Adverse Drug Event Reporting (JADER) database. We conducted a disproportionality analysis using the JADER database from April 2004 to December 2024 to evaluate the cardiovascular and cerebrovascular adverse events associated with intravitreal administration of ranibizumab, aflibercept, and brolucizumab. Time-to-onset distribution and post-onset outcomes were also analyzed. Disproportional signals were observed for cerebral and myocardial infarction associated with ranibizumab and aflibercept, but not with brolucizumab. Time-to-onset analysis showed earlier onset patterns for ranibizumab than for aflibercept, with Weibull shape parameters indicating an early failure-type distribution. Post-event outcome analysis revealed some events resulting in sequelae or death, although many reports had unknown outcomes. This study identified the potential cardiovascular and cerebrovascular safety signals associated with intravitreal administration of ranibizumab and aflibercept. Although brolucizumab showed no significant disproportionality, interpretation requires caution because of limited data. Our findings underscore the importance of continued pharmacovigilance and hypothesis-driven investigations to ensure the safe use of anti-VEGF therapies.

Piperacillin/tazobactam is the first-line treatment for pneumonia in elderly patients. However, there are differences in dosing regimens and infusion times among different centers. We aimed to evaluate the population pharmacokinetics of piperacillin in elderly patients with pneumonia and optimize the dosing regimens. This was a prospective pharmacokinetic (PK) study of piperacillin/tazobactam in elderly patients with pneumonia using an opportunistic sampling design. The blood concentration of piperacillin was determined by high-performance liquid chromatography. A population PK model was constructed using NONMEM software, and its predictive performance was further validated in a separate test cohort. The final population PK model was used for dose optimization. A total of 151 blood samples from 73 patients were used to develop a population PK model, and 60 concentrations of therapeutic drug monitoring from 22 patients were used for model validation. A one-compartment model with first-order elimination was established. Covariate analysis showed that eGFR was the only covariate. Monte Carlo simulation results showed that for pathogens with MIC values of 8 and 16 mg/L, the dosing regimen (4000 mg every 6/8 h administered 30 min) used in this study resulted in PTAs of 23.5%-64.3%. The PTAs of the dosing regimen 4000 mg every 6 h administered by 4-h infusion for patients with different levels of renal function exceeded 90% (90.7%-99.8%), except for patients with eGFR ≥ 50 mL/min/1.73 m².

Bispecific T-cell engagers have revolutionized the treatment and management of hematological malignancies and more recently have started making similar strides for solid tumor indications, with opportunities to become best-in- class therapeutics for cancer. Xaluritamig is a novel bivalent XmAb® 2+1 T cell engager with two STEAP1 binding sites and one CD3 binding site being developed for solid tumors with the primary indication of metastatic castrate resistant prostate cancer (mCRPC). The First-In-Human (FIH) study showed promising anti-tumor activity in mCRPC patients, and the program is currently in late phase clinical development. Xaluritamig was administered as an intravenous infusion once weekly (QW) or once every other week (Q2W) in the dose escalation of the FIH study at dose levels ranging from 0.001 to 2 mg. Initial pharmacokinetic (PK) characterization of xaluritamig exhibited approximately dose-proportional increase in exposures over the dose levels explored, with an estimated terminal half-life of ≈9 days, assuming subjects had no anti-drug antibodies, calculated via the population PK model. The time at which maximum concentration (C_max) occurred was typically at the end of infusion (median ≈ 1 h), as expected with IV administration. Additionally, thorough dose-exposure-response analyses integrated observed data and model-based simulations of PK, key efficacy endpoints, and safety events to support the evaluation of the target doses 0.75 mg QW, 1.5 mg QW, and 1.5 mg Q2W in dose expansion. This work provides the framework for which modeling and simulations can be used to guide dose selection for dose expansion at an early stage of development adhering to the recent principles of Project Optimus.

To compare the pharmacokinetics, bioavailability, tolerability, and safety of a novel 4 mg rivastigmine nasal spray to 3 mg rivastigmine oral capsule, a single-dose, open-label, randomized, crossover study was conducted in 16 fasted healthy young men (18 to 55 years). Mean (SD) rivastigmine C_max was 8.39 (6.8) and 13.77 (10.7) ng/mL for oral and nasal, respectively. Rivastigmine AUC_0-inf was 19.6 (14.9) and 40.6 (24.4) ng h/mL for oral and nasal, respectively. The ratio of LS means (nasal test / oral reference; 90% C.I.) for rivastigmine C_max was 185.83% (134.22, 257.28) and for rivastigmine AUC_0-inf was 257.35% (197.26, 335.73). Rivastigmine t_max for nasal (0.7 h) was significantly lower than oral (1.2 h, P < .05), however, NAP226-90 t_max for nasal (1.9 h) and oral (1.8 h) were similar. NAP226-90 C_max was 3.93 (1.1) and 3.01 (0.8) ng/mL for oral and nasal, respectively. NAP226-90 AUC_0-inf was 22.9 (5.3) and 23.2 (5.1) ng h/mL for oral and nasal, respectively. Median NAP226-90 to rivastigmine AUC_0-inf ratio for nasal (0.55) was significantly lower than oral (1.38, P < .05) because nasal bypassed first-pass metabolism. Both single-dose treatments were safe and well tolerated. Nasal and throat irritation were mostly perceived as mild and transient following nasal administration. The 4 mg rivastigmine nasal spray had 1.5- and 2.0-fold higher dose normalized rivastigmine C_max and AUC_0-inf, respectively, and 2.5-fold lower NAP226-90 to rivastigmine AUC_0-inf ratio compared to 3 mg oral capsule. This nasal spray has good potential to improve the local and gastrointestinal tolerability of rivastigmine treatment in Alzheimer's and Parkinson's disease dementia patients.

Pharmacokinetic boosting can be a strategy to enhance osimertinib exposure and reduce treatment associated costs. The OSIBOOST trial demonstrated that it was feasible to boost low osimertinib plasma trough levels with cobicistat. The current study aims to establish the equivalent dose of cobicistat boosted osimertinib compared to osimertinib 80 mg once daily (QD) by population pharmacokinetic (popPK) modeling. A popPK model was developed on the pharmacokinetic data from the OSIBOOST study using NONMEM 7.4.4. Simulations were performed with cobicistat boosted osimertinib dosing regimens to evaluate their equivalence to the standard of osimertinib 80 mg QD. A dose level was assumed equivalent when the 90% confidence interval (CI) of the geometric mean ratios (GMR) for the area under the curve over 144 h (AUC_0-144h) and maximum osimertinib concentration (C_max) were in the acceptance range of 0.8-1.25. Cobicistat decreased osimertinib CL/F by 29.6% compared to osimertinib monotherapy (P < .0001). Osimertinib 80 mg 2 days on, 1 day off, boosted with cobicistat 150 mg QD was equivalent for osimertinib AUC_0-144h (GMR [90% CI] = 0.96 [0.94-0.98]) and C_max (GMR [90% CI] = 1.06 [1.04-1.08]) compared to osimertinib 80 mg QD monotherapy. However, this regimen was not equivalent for AZ5104 AUC_0-144h (GMR [90% CI] = 0.67 [0.66-0.68]) and C_max (GMR [90% CI] = 0.74 [0.73-0.76]). Theoretically, this reduced dose of cobicistat boosted osimertinib can potentially save approximately 33% in osimertinib treatment associated costs whilst maintaining adequate osimertinib exposure.