The Journal of Clinical Pharmacology最新文献

Methoxyethyl etomidate hydrochloride (ET-26) is a novel intravenous general anesthetic designed to address the clinical limitations of etomidate. This Phase I clinical trial assessed the pharmacokinetics, pharmacodynamics, drug–drug interaction (DDI) potential, and safety of ET-26 in 68 healthy subjects across three sequences, evaluating interactions with rifampin (CYP2C19/3A4 inducer), fluconazole (CYP2C19/3A4 inhibitor), and omeprazole/midazolam. ET-26 pharmacokinetic analyses showed that compared with administration of ET-26 alone, co-administration of rifampin resulted in a 10% decrease in the geometric mean ratio (GMR) of the AUC_0-∞ for ET-26 (GMR 90.0%, 90% CI 85.4%-94.8%), while co-administration fluconazole increased the AUC_0-∞ by 18.5% (GMR 118.5%, 90% CI 111.4%-126.2%). ET-26 slightly increased the AUC_0-∞ by 18.5% for omeprazole (GMR 118.5%, 90% CI 111.4%-126.1%) and 11.1% for midazolam (GMR 111.1%, 90% CI 104.9%-117.8%). The 90% CI for key parameters largely fell within no-effect boundaries, indicating no clinically significant DDIs. Pharmacodynamic assessments showed consistent sedation profiles across sequences, with mild additive effects with midazolam. Safety evaluations identified treatment-emergent adverse events such as injection site pain and myoclonus, more frequent with fluconazole. No serious adverse events were observed. These findings suggest ET-26 exhibits a favorable safety and pharmacokinetic profile with no significant DDIs observed in clinical, supporting its potential as a safer alternative to etomidate for general anesthesia.

Autism spectrum disorders are characterized by some difficulties with social interactions and communication, atypical patterns of behavior, and unusual reactions to emotions. Studies have found promising results regarding the effects of cannabis on autism. We conducted a systematic review of randomized clinical trials on the effects of cannabis derivatives and their analogs for autism. This review was developed according to the Cochrane Handbook for Systematic Reviews of Interventions and reported according to PRISMA 2020. The protocol was prospectively published in the PROSPERO database (CRD42023468300). We included randomized controlled trials with autism-diagnosed participants treated with any cannabis derivate or its analogs for therapeutic purposes. Two reviewers assessed titles and abstracts independently and potentially eligible full texts were assessed to confirm eligibility. After that, they extracted data using a standardized worksheet. Searches retrieved 1264 references, only 11 RCTs were included, four with available results for children/adolescents with autism. Five different cannabis presentations were tested. One trial pointed that cannabis may improve global assessment symptoms, but for other outcomes results were uncertain. No included study assessed quality of life. The certainty of evidence ranged from very low to low certainty for the assessed outcomes. Cannabis whole plant extract may improve global assessment symptoms, but the different cannabis presentations, outcome assessments and very low certainty of evidence from the included studies make it difficult to draw conclusions about cannabis for people with autism. This scenario of uncertainties impacts directly clinical practice and decision making.

Impaired awareness of hypoglycemia (IAH) impacts 25%-30% of individuals with type 1 diabetes mellitus (T1D), potentially leading to severe outcomes due to reduced symptom perception. Naloxone, a mu-opioid receptor antagonist, shows promise as a preventive measure against IAH. This study explored intranasal (IN) naloxone as a potential therapy to preserve counterregulatory and symptom responses to hypoglycemia following exercise in T1D patients. Participants included adults with T1D for 2-20 years. The study aimed to develop a population pharmacokinetic (PopPK) model of IN naloxone and assess exposure–response relationships. The study was conducted as a single-center, single-blinded, placebo-controlled crossover study. It involved collecting blood samples at 12 intervals before, during, and after exercise. Plasma naloxone concentrations were analyzed using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Utilizing nonlinear mixed effects modeling, the PopPK model simulated individual naloxone maximum concentrations (C_max) and total area under the curve (AUC) to evaluate exposure–response relationships. A two-compartment model with combined zero- and first-order absorption best described the naloxone's pharmacokinetics. Allometric scaling based on weight was applied to volume and clearance parameters, with a combined additive and proportional error model describing residual unexplained variability. Clearance and volume estimates were: central: 6.82 L/min/70 kg and 171 L/70 kg, peripheral: 2.97 L/h/70 kg and 278 L/70 kg. The absorption rate constant and zero-order absorption duration were 0.0272 min⁻¹ and 7.33 min, respectively. While a strong correlation was observed between simulated exposures (C_max and AUC), no statistically significant correlation was found between exposures and responses. This is the first PopPK model of IN naloxone in T1D offering insights for future clinical pharmacokinetic studies.

A critical aspect of drug development is evaluating pharmacokinetics (PK) and pharmacodynamics to assess how intrinsic (e.g., age, sex, comorbidities, and genomics) and extrinsic (e.g., drug–drug interactions [DDIs] and food interaction) factors influence drug exposure and response. These aspects guide dose selection and inform drug labeling by accounting for interindividual variability to ensure safe and effective use across complex patient populations. However, identifying the relationship of co-occurring factors, resembling complex patient populations, remains challenging. Herein, we analyzed drug labeling for therapeutic products approved by the Center of Drug Evaluation and Research at the US Food and Drug Administration from 2019 to 2023 to understand if intrinsic and extrinsic factors are considered simultaneously and how these factors influence prescribing recommendations. We characterized factors including pharmacogenomics (PGx), renal and hepatic function, age, pregnancy, body weight, comorbidities, and DDIs. Among 227 drug labelings, 93% independently assessed more than one factor and 2.6% evaluated the combined influence of two factors. Most drug labelings focused on single factors, with PK DDIs (70.0%), renal impairment (74.4%), and age (78.9%) frequently assessed. In rare disease indications, no significant differences in factor assessment frequency were observed. Of the six drug labelings that address simultaneously occurring factors, four addressed the interaction between PGx and PK DDIs. This analysis highlights a gap in evaluating co-occurring intrinsic and extrinsic factors in drug labeling, underscoring the need for integrated approaches during drug development to better guide clinical decision making for complex patient populations.

Racial and ethnic differences in drug disposition and response may have a significant impact on its risk-benefit balance. Therefore, it is important to examine whether an investigational drug has characteristics that make the pharmacokinetics (PK), safety, and efficacy likely to be affected by intrinsic and extrinsic ethnic factors based on ethnic sensitivity assessment. This assessment is recommended by the latest Japanese guideline (issued in December 2023) for Japanese phase 1 studies before participation in multi-regional clinical trials (MRCTs). To comprehensively understand characteristics and ethnic sensitivity of drugs that seem to have racial/ethnic differences in its disposition and response, we investigated 620 new molecular entities (NMEs) approved by the United States Food and Drug Administration (FDA) between 2008 and 2023. Of those, only 6.5% (40 NMEs) reported racial/ethnic differences in the PK (5.0%), safety (1.6%), and/or efficacy (0.6%) in the FDA drug labeling, with only one NME (0.16%) having a clinically significant PK difference which requires a reduced starting dose in East Asian patients. Additionally, 4.4% of 620 NMEs reported differences in the pharmacogenetics for drug-metabolizing enzymes. The comprehensive evaluation of characteristics and ethnic sensitivity of 40 NMEs with racial/ethnic differences in the PK, safety, and/or efficacy indicated two key findings. First, participation in MRCTs from various regions as early as possible is much more important than conduct of an additional phase 1 study in a specific region/country. Second, more attention and deeper evaluation of Asian PK would be needed for drugs with low bioavailability in the overall drug development.

Pulmonary hypertension (PH) is a chronic disorder characterized by increased pulmonary vascular resistance, leading to right ventricular failure and death. PH can develop in patients with chronic obstructive pulmonary disease (COPD), resulting in greater morbidity and mortality than either condition alone. Current treatment options for PH-COPD are limited, and systemic vasodilators often cause adverse effects. Frespaciguat (MK-5475), an inhaled soluble guanylate cyclase stimulator, is being studied for its potential to selectively reduce pulmonary vascular pressures with minimal systemic exposure. This study (NCT06777602, 5475-011) aimed to characterize the pharmacokinetics (PK), metabolism, elimination, safety, and tolerability of frespaciguat in healthy male participants following a single 100 µg intravenous dose of [¹⁴C]frespaciguat using a low radioactive dose. The PK of frespaciguat is characterized by moderate clearance and a short half-life of approximately 2 h. The drug is predominantly eliminated via the biliary–fecal route, with metabolism playing a major role. Frespaciguat and its metabolites were well tolerated, with no severe adverse events reported. The study demonstrated that frespaciguat is extensively metabolized, likely via enzymes involved in β-oxidation, and is primarily excreted in feces. The human mass balance and metabolism study suggests that frespaciguat's metabolism may be impacted by inhibitors of β-oxidation enzymes. These findings support the potential of frespaciguat as a targeted treatment for PH-COPD, offering a promising therapeutic approach with minimal systemic side effects.

Gepirone, an antidepressant drug, is biotransformed into two principal metabolites [1-(2-pyrimidinyl)-piperazine (1-PP) and 3′-OH-gepirone] primarily by CYP3A enzymes. Metabolism of gepirone in the presence of ketoconazole, a potent inhibitor of human CYP3A activity, was studied in vitro in human liver microsomes. The clinical pharmacokinetic interaction of ketoconazole (as a maximal chemical inhibitor of CYP3A isoforms) with single doses of gepirone was evaluated in a Phase 1 study in human volunteers (N = 24). In vitro coincubation of gepirone with increasing concentrations of ketoconazole produced extensive inhibition of 1-PP and 3′-OH-gepirone formation, with IC₅₀ values in the range of 0.026 µM to 0.162 µM. These inhibitory values are substantially lower than clinically encountered systemic concentrations of ketoconazole, thereby predicting extensive in vivo increases in gepirone exposure when coadministered with ketoconazole. In the clinical pharmacokinetic study, ketoconazole produced large increases in gepirone exposure by factors of 5.92- to 7.80-fold. Appearance of 1-PP in the systemic circulation decreased by factors of 0.56 to 0.97, while appearance of 3′-OH-gepirone increased by 1.70- to 2.43-fold. The clinical findings are consistent with the in vitro results, and underlie the labeling recommendation that gepirone not be coadministered with “strong” CYP3A inhibitors.

This study aims to compare the efficacy and safety of different 5-HT3 receptor antagonists as monotherapy for nausea and vomiting in patients undergoing surgery or chemotherapy. A thorough search of various electronic databases was conducted to determine the randomized controlled trials comparing the efficacy and safety of different 5-HT3 receptor antagonists as monotherapy for preventing nausea and vomiting in patients undergoing surgery or chemotherapy. Primary outcomes included nausea, vomiting, and adverse events. A network meta-analysis was performed to compare each outcome. Seventeen trials were included in this study. For the control of nausea, palonosetron was the optimal choice among 5-HT3 receptor antagonists (surface under the cumulative ranking curve, SUCRA = 86.95%), regardless of whether the patients were undergoing surgery (SUCRA = 82.04%) or chemotherapy (SUCRA = 71.63%). As for controlling vomiting, palonosetron was still the optimal choice among different 5-HT3 receptor antagonists (SUCRA = 80.87%). In surgical patients, granisetron was the most effective in controlling vomiting (SUCRA = 88.04%). When considering the drug doses, palonosetron 0.25 mg was the optimal regimen for controlling both nausea and vomiting. In terms of safety, palonosetron 0.25 mg and granisetron 3 mg were the safest regimens among different 5-HT3 receptor antagonists. Among the various 5-HT3 receptor antagonists, palonosetron at a dosage of 0.25 mg emerged as the optimal choice for chemotherapy patients, while granisetron at a dosage of 3 mg proved to be the best option for surgical patients, taking into account both efficacy and safety. The study protocol was registered with PROSPERO (CRD42024552117).

In addition to antiretroviral therapy (ART), people with HIV often take medications to treat comorbidities. It is therefore important to assess these medications for potential drug-drug interactions, which may affect the safety and efficacy of ART. Three phase I studies were conducted in adult participants without HIV. The pharmacokinetics (PK) and safety of bictegravir (administered alone or as bictegravir/emtricitabine/tenofovir alafenamide fumarate [TAF]) were assessed when co-administered with inducers (rifampin, rifabutin, and rifapentine) or inhibitors (atazanavir ± cobicistat, darunavir + cobicistat, and voriconazole) of cytochrome P450 3A4 (CYP3A4), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), and/or P-glycoprotein (P-gp). PK parameters were compared using analysis of variance to calculate geometric least-square mean ratios and 90% confidence intervals. Overall, 172 participants were enrolled. CYP3A4 inhibition (voriconazole) moderately increased bictegravir exposure (61% increase in area under the concentration-time curve extrapolated to infinity [AUC_inf]), whereas dual CYP3A4 and UGT1A1 inhibition (atazanavir) led to a 315% increase in AUC_inf. P-gp inhibition had a minimal effect on bictegravir exposure. Induction of CYP3A4, UGT1A1, and/or P-gp by rifampin, rifabutin, and rifapentine led to decreases in bictegravir exposure and/or trough concentration (C_trough). Bictegravir and bictegravir/emtricitabine/TAF were well tolerated alone and in combination with other drugs. Inhibition of CYP3A4 or UGT1A1 alone is unlikely to cause clinically meaningful changes in bictegravir exposure; only potent inhibitors of both pathways are expected to significantly affect bictegravir PK. Induction of CYP3A4 with/without UGT1A1 significantly influenced bictegravir PK, although C_trough remained above the protein-adjusted 95% effective concentration. These findings should be considered when co-administering medications with bictegravir.