Journal of Clinical Pharmacology最新文献

Pharmaceutical companies have several options to evaluate drug-induced QT prolongation, often referred to as QT pathways, during clinical development. Current regulatory practices recommend achieving high clinical exposure (HCE) for conventional thorough QT (TQT) studies. An alternative to the TQT study, commonly known as the Q&A 5.1 pathway, recommends a two-fold HCE as the exposure margin for concentration-corrected QT (C-QTc) analysis. To assess the impact of these recommendations, we analyzed the exposure margins of 166 new active substances approved in Japan since 2015. Among these, 28.3% of substances in conventional TQT studies (n = 92) did not achieve HCE, and 50.0% of substances in the C-QTc analysis (n = 22) did not achieve two-fold HCE. In the integrated risk assessment, C-QTc analysis, often incorporated into first-in-human studies, is recommended to cover HCE for substances showing no QT prolongation risks in both in vitro and in vivo non-clinical studies, and we analyzed whether the C_max achieved in single-ascending dose (SAD) and multiple-ascending dose (MAD) studies reached HCE. The result showed that 51.1% and 47.7% of substances did not achieve HCE in SAD and MAD studies, respectively. Our findings highlight the need for dose-ascending strategy targeting two-fold therapeutic exposure to ensure HCE. Insufficient exposure may lead to failure to waive the TQT study, and delays in development timelines. To address these challenges, we propose strategies for optimizing early clinical study designs to meet the exposure recommendations and reduce the risk of additional requirements from the regulatory authorities at a later stage.

Street medicine is a point-of-care, mobile approach that services the needs of unhoused individuals who are otherwise unable to access medical care in traditional settings. The prevalence of injection drug use combines with the pipeline of illicit substances, to produce a constellation of severe, potentially life-threatening dermatological disorders unique to this population. This review applies principles of clinical pharmacology to clarify the mechanisms underlying the dermatological toxicity of xylazine, desomorphine, and 3,4-methylenedioxymethamphetamine (MDMA).

How infusion fluids are distributed and eliminated is of importance to how much and how fast they should be administered. This manuscript applies population pharmacokinetic modeling to intravenous infusions of crystalloid fluid, which is a common therapy in hospital care and mandatory during surgery. The analysis was based on the hemodilution and urine output measured during and after 262 infusions of 1647 ± 461 mL (mean ± SD) of fluid over 30 min in adults. The result shows that distribution of fluid from the plasma to the interstitial fluid space occurred twice as fast during general anesthesia as compared to the conscious state. The increased rate ensures adequate nutritional flow to the cells despite decreased flow in the macrocirculation, which is a characteristic of general anesthesia. This increased capillary leakage of fluid was coupled with an even greater reduction of the urinary output and accumulation of fluid in both the fast-exchange interstitial fluid space and a remote "third fluid space," the latter of which apparently serves as an overflow reservoir. During the first hour of the experiments, 88% more fluid resided extravascularly in the presence of general anesthesia than in the awake state. General anesthesia increased the half-life from 1.8 to 16.6 h, showing marked impairment in the handling of infused crystalloid fluid.

Pediatric asthma exacerbations represent a significant cause of emergency department use and hospitalizations. Despite available treatment options, many children's exacerbations are refractory to standard therapies and require adjunct treatments. The Intravenous Magnesium: Prompt use for Asthma in Children Treated in the Emergency Department study investigated the pharmacology of intravenous magnesium sulfate (IVMg) in treating pediatric asthma exacerbations. Specifically, the objectives of the study included (1) externally validating a previously published population pharmacokinetic model and (2) linking serum magnesium concentrations with outcomes including asthma severity score (efficacy) and hypotension (safety). Data were obtained from 49 children prospectively treated with IVMg (placebo, 50 or 75 mg/kg) after presenting to the pediatric emergency department with an acute asthma exacerbation. Reductions in Pediatric Respiratory Assessment Measure scores were associated with both total and ionized serum magnesium area under the concentration-time curve (AUC_{0-2 h}). Despite frequent study-specific blood pressure monitoring, hypotension was uncommon in IVMg-treated participants (n = 2/31), and no concentration dependence was observed. The findings signal that IVMg may be an efficacious and safe option for treating moderate-severe pediatric acute asthma exacerbations in the ED. Importantly, this study is the first to suggest a serum exposure target (total serum magnesium AUC_{0-2 h} >63.1 mg h/L) reflective of effective IVMg dosing in pediatric acute asthma. While further study in a larger clinical trial is needed to refine and validate this exposure target, these findings support the continued study of IVMg therapy as an adjunct therapeutic option in the setting of pediatric asthma exacerbations.

Patient adherence is vital for Helicobacter pylori eradication. Simplifying therapy dosing schedules may promote patient adherence, enhance treatment success rates, and help mitigate the development of antibiotic resistance. We aimed to assess plasma and intragastric rifabutin, amoxicillin, and omeprazole concentrations comparing two dosing schedules of RHB-105 (every 8 h and a more flexible three-times daily schedule, at 8 a.m., 12 p.m., and 6 p.m.) using a validated physiologically based pharmacokinetic (PBPK) model. Leveraging in vitro and in vivo information on the pharmacokinetics of the three components of RHB-105, we developed mechanistic absorption PBPK models to predict plasma and intragastric concentration-time profiles for each component. There were only negligible differences in the area under the concentration-time curves (AUC) for plasma and the intragastric compartment, and maximal concentration (C_max) with only up to a 1.1-fold difference for rifabutin, amoxicillin, and omeprazole between dosing schedules. Overlapping 90% confidence intervals for both AUC and C_max support that overall exposures are comparable regardless of dosing every 8 h or three-times daily for all three drugs. Drug exposure was highly similar for rifabutin, amoxicillin, and omeprazole with each dosing schedule. Novel mechanistic absorption PBPK modeling supports the approval and use of the more flexible dosing schedule for RHB-105, simplifying patient experience and potentially increasing adherence.

The absorption and bioavailability of most tyrosine kinase inhibitors are affected by gastrointestinal pH as they are weak basic lipophilic drugs. Hence, concomitant use of acid reducing agents (ARAs) is frequently restricted. Particularly comedication of crystalline dasatinib (Sprycel) and proton-pump inhibitors (PPIs) should be avoided. Drug-drug interaction (DDI) studies with PPIs report approximately 40%-80% bioavailability reduction of dasatinib. Limitations in the design of these studies do not allow for assessing the near maximum DDI as timing of PPI dosing was either not reported or 22 h prior to dasatinib intake. We conducted a DDI study of crystalline dasatinib and omeprazole in healthy, fasted participants, investigating the impact of PPI comedication on dasatinib plasma exposure at a time point when the near maximum DDI effect is expected. Participants were administered omeprazole (day 2-5) to reach steady state. On day 6, a single dose of crystalline dasatinib was given. Crystalline dasatinib dosing alone on day 1 served as control (single dose). The dosing interval between omeprazole administration and crystalline dasatinib was 10 h (median [range: 9-10 h]). Dasatinib C_max and AUC_0-24 were reduced by 96% and 89% by omeprazole comedication. C_max was 224.6 ± 104.7 ng/mL (mean ± SD) and 8.0 ± 4.5 ng/mL (P < .0001) and AUC_0-24 was 797.6 ± 274.5 and 90.6 ± 38.1 h·ng/mL (P < .0001) without and with omeprazole. T_1/2 was 5.7 ± 1.5 h (mean ± SD) with crystalline dasatinib dosing alone and could not be reliably calculated with comedication. To ensure optimal patient outcome, it is vital to investigate bioavailability of pH-sensitive drugs at the maximal DDI effect of ARAs to understand the worst-case influence for efficient clinical management.

Cisplatin is a platinum-based chemotherapeutic drug used to treat many types of cancer. The aim of this study was to develop a population pharmacokinetic model that incorporates plasma unbound and bound platinum levels. Cancer patients undergoing their first or second cycle of cisplatin-containing chemotherapy (n = 33) were prospectively randomized to receive a 5-hydroxytryptamine (5-HT₃) antagonist (5-HT₃A) antiemetic (ondansetron, granisetron, or palonosetron) followed by blood collection over 10 days. Total and unbound platinum levels were quantified using inductively coupled plasma mass spectrometry. Plasma concentrations of bound and unbound platinum were used to develop a nonlinear mixed-effect pharmacokinetic model in Phoenix NLME (v8.3, Certara Inc.). A stepwise search was used to screen covariates that influenced pharmacokinetic parameters. A compartment for bound platinum was added to a two-compartment unbound platinum model to create a combined platinum model. The volume of the central compartment for unbound platinum (V1_u) was significantly impacted by previous cisplatin exposure and the intercompartmental clearance of unbound platinum (CL2_u) was significantly influenced by concomitant lorazepam use. The models also suggested ondansetron- and granisetron-treated subjects had a 331% and 114% increase, respectively, in circulating exposures to unbound platinum than palonosetron-treated subjects. The results suggest platinum pharmacokinetics are altered by concomitant 5-HT₃A antiemetic use, concomitant lorazepam use, and previous exposure to cisplatin. Ondansetron and granisetron co-treatment increased unbound platinum exposure compared to palonosetron co-treatment, suggesting that palonosetron may be a preferred 5-HT₃A to reduce the risk of cisplatin-induced kidney injury.

Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and could reduce the effectiveness of concomitant drugs that are metabolized by CYP3A4, such as midazolam. This study aimed to determine if repeat doses of mavacamten achieving clinically relevant exposures affected midazolam exposure. This was a single-center, open-label study in healthy participants. Participants received: on day 1, midazolam 5 mg; on days 2-3, mavacamten 25 mg; on days 4-16, mavacamten 15 mg; and on day 17, mavacamten 15 mg and midazolam 5 mg. Plasma concentrations of mavacamten, midazolam, and the midazolam metabolite 1'-hydroxymidazolam were measured. A physiologically based pharmacokinetic (PBPK) model was used to simulate the effect of mavacamten-mediated CYP3A4 induction on midazolam exposure by CYP2C19 phenotype. Thirteen adult participants were enrolled (46.2% were female; mean [SD] age: 34.0 [9.0] years). Compared with midazolam alone, midazolam coadministered with mavacamten decreased the maximum observed plasma concentration (C_max), area under the drug concentration-time curve (AUC) from time zero to infinity (AUC_0-inf), and AUC from time zero to last measurable concentration (AUC_0-last) for midazolam by 7%, 13%, and 24%, respectively; for 1'-hydroxymidazolam, AUC_0-inf and AUC_0-last increased by 20% and 11%, respectively. Ten participants experienced adverse events and the majority were mild in severity. The PBPK model predicted the clinical trial data well. The PBPK simulation assessed that the overall impact of mavacamten on midazolam C_max and AUC was predicted to be weak regardless of CYP2C19 phenotype. At clinically relevant exposures, mavacamten had a negligible effect on midazolam exposure.

JNJ-75220795 or ARO-PNPLA3 is an investigational small interfering ribonucleic acid agent conjugated with N-acetyl-d-galactosamine that targets the PNPLA3 gene, currently being developed for metabolic dysfunction-associated steatohepatitis (MASH). This study evaluated the pharmacokinetics (PK) profile of single subcutaneous doses of JNJ-75220795 in preclinical species as well as in human subjects with homozygous or heterozygous PNPLA3 I148M mutation in two phase 1 studies-a first-in-human study in the United States and a first-in-Japanese study in Japan. Preclinical PK in rats and non-human primates (NHP) showed a rapid systemic absorption and elimination following single subcutaneous doses. JNJ-75220795 was predominantly distributed to the liver with peak liver concentrations reached at 4 h and still detectable at 672 and 336 h in rats and NHPs, respectively, with an apparent liver-to-plasma area under the curve (AUC) ratio of 2800 in rats. Consistent with the preclinical findings, clinical PK showed rapid systemic absorption and clearance in humans with median peak concentrations at 3.0-9.0 h and mean short half-life of 3.4-6.2 h. Plasma PK exposure parameters including C_max and AUC increased approximately dose proportionally. Kidney had the second highest tissue exposure following the liver in rats. Renal excretion was a significant but minor elimination pathway as approximately 15%-25% of the administered dose was recovered in urine. Based on the overall data, JNJ-75220795 was primarily localized to the liver and exhibited sustained hepatic exposures, which confer prolonged pharmacodynamic effects in the target organ. The favorable PK profiles of single subcutaneous doses observed in the phase 1 studies support continued clinical development of JNJ-75220795 for the treatment of MASH.

Despite the tremendous effort in the oncology community, the success rate of anticancer development remained low at 30% to 40% from the Phase 3 study to the regulatory approval. The factors associated with the regulatory approval for market authorization have gained interest in the community to improve the success rate of drug development. Using the data from 208 Phase 3 studies for anticancer drugs, we explored the possible factors associated with the US Food and Drug Administration's (FDA's) approval by multivariate logistic regression analysis. The model incorporated 21 factors from therapeutic context, study design, and outcomes. The hazard ratio (HR) for overall survival (OS) showed a significant association with FDA approval (coefficient: -29.907, P < .001), and the age of control drugs in the market followed (coefficient: -2.581, P = .008). In the model, if the HR for OS changes from 0.75 to 0.85, the probability of FDA approval remarkably decreases from 79.6% to 16.4%. A 50% likelihood of FDA approval is predicted at HR 0.795 for OS. Furthermore, the P-value for the OS test and the width of the confidence interval on HR for OS showed a significant association with the probability of FDA approval. These findings consistently underscore the rigorous standard required for new anticancer drugs to obtain regulatory approval from the FDA.