Clinical Pharmacology & Therapeutics最新文献

The measurement of endogenous biomarkers in plasma and urine before and after administration of an investigational drug in a clinical study may provide an early indication of its drug-drug interaction (DDI) potential via a specific pathway. In the first international harmonized guideline on drug interaction studies, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M12, endogenous biomarkers have been recognized as an emerging approach in the transporter- and enzyme-based DDI risk assessment. Clinical Pharmacology Roundtable Conference 2024 held at Pharmaceuticals and Medical Devices Agency (PMDA) brought together experts from regulatory agencies, academia, and industries to discuss potential advantages and challenges of the biomarkers approach in drug development and regulatory decision making. This meeting report facilitates stakeholders involved in drug development in better understanding the utility of biomarker approaches and promotes early implementation of biomarker-informed DDI evaluation in regulatory use.

The use of partial residual plots (PRPs) was explored as a model diagnostic tool in Model-based Meta-Analysis (MBMA). Mathematical derivations illustrating the concepts were followed by an MBMA example using publicly available literature data of anti-depressive treatments with fluoxetine and venlafaxine. An E_max dose-response model was identified for venlafaxine while a constant drug effect combining all dose levels vs. placebo was identified for fluoxetine. The larger the mean baseline Hamilton Depression Rating (HAMD) score, the larger the expected drug effect (P = 0.0122), based on the likelihood ratio test. Mean baseline HAMD score (range) was 25.4 (23.5, 29.4) and 20.8 (15, 26) while mean placebo change from baseline (range) was -9.02 (-12.2, -4.8) and - 6.22 (-10.9, -1.3) for venlafaxine and fluoxetine, respectively. Average baseline HAMD score appeared larger for venlafaxine compared to fluoxetine, albeit a wider range for fluoxetine. Placebo response seemed lower but also more variable in fluoxetine compared to venlafaxine studies. Observed data points tended to deviate from model predictions when the mean baseline HAMD and placebo response values associated with those data points differed substantially from the corresponding values used for the model prediction. Normalizing observed data addressed this, providing a "like-to-like" comparison with model predictions in PRP when assessing the effect of one covariate (dose) after normalizing for other covariates/effects (placebo response and mean baseline). PRPs provide a robust integrated diagnostic tool in MBMA that uses all data to show the correlation between response and any covariate while controlling for other covariates included in the model.

Recent advances have significantly enhanced our understanding of the role of membrane transporters in drug disposition, particularly focusing on their influence on pharmacokinetics, and consequently, pharmacodynamics. The relevance of these transporters in clinical pharmacology is well acknowledged. Recent research has also underscored the critical role of membrane transporters as targets in human diseases, including their involvement in rare genetic disorders. This review focuses on transporters for water-soluble B vitamins, such as thiamine, riboflavin, and biotin, essential cofactors for metabolic enzymes. Mutations in transporters, such as SLC19A3 (thiamine), SLC52A2, and SLC52A3 (riboflavin), and SLC5A6 (multiple B vitamins including pantothenic acid and biotin) are linked to severe neurological disorders due to their role in the blood–brain barrier, which is crucial for brain vitamin supply. Current treatments, mainly involving vitamin supplementation, often result in variable response. This review also provides a short perspective on the role of the transporters in the blood-cerebrospinal fluid barrier and highlights the potential development of pharmacologic treatments for rare disorders associated with mutations in these transporters.

Parathyroid carcinoma (PC) is a rare malignancy, often characterized by the unregulated secretion of parathyroid hormone. The sequelae of severe hypercalcemia together with direct complications from tumor dissemination in patients with advanced disease are usually fatal. Due to its rarity, formal studies to guide the diagnosis and management of parathyroid carcinoma are lacking. However, recent data from case reports, case series, and registry studies suggest the emergence of new and effective treatment approaches for this understudied disease. We reviewed existing literature on the diagnosis and management of parathyroid carcinoma. Our findings suggest that traditional approaches such as surgical resection for both localized and metastatic diseases continue to play an important role in patient management. For patients with unresectable disease, newer systemic treatment approaches, including the use of temozolomide and tyrosine kinase inhibitors, may offer clinical benefit.

In patients with heart failure (HF) who respond inadequately to loop diuretic therapy, BMS-986308, an oral, selective, reversible renal outer medullary potassium channel (ROMK) inhibitor may represent an effective diuretic with a novel mechanism of action. We present data from the first-in-human study aimed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) following single ascending doses of BMS-986308 in healthy adult participants. Forty healthy participants, aged from 20 to 55 years, and body mass index (BMI) from 19.8 to 31.6 kg/m² were assigned to 1 of 5 dose cohorts (1, 3, 10, 30, and 100 mg) and randomized (6:2) to receive BMS-986308 oral solution or matching placebo. Following administration, BMS-986308 was rapidly absorbed with a median time to maximum concentration (T_max) of 1.00 to 1.75 h and exhibiting a mean terminal half-life (t_1/2) of approximately 13 h. Dose proportionality was evident in BMS-986308 area under the concentration-time curve (AUC), while maximum concentration (C_max) was slightly greater than dose-proportional. We observed that urine output (or diuresis; mL) and urinary sodium excretion (or natriuresis; mmol) increased in a dose-dependent manner, starting at a minimum pharmacologically active dose of 30 mg. The largest mean changes from baseline in diuresis and natriuresis occurred in both the 6- and −24 h post-dose period following administration of 100 mg (1683.0 mL and 2055.3 mL, and 231.7 mmol and 213.7 mmol, respectively; ***P < 0.001). Overall, single-dose BMS-986308 was found to be safe, well-tolerated, with an excellent PK profile, and substantial diuretic and natriuretic activity.

The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) oversee pharmaceutical regulations, including orphan drugs targeting rare diseases with limited patient populations. Post-marketing studies are crucial for monitoring safety and efficacy, with post-marketing requirements (PMRs) mandated by the regulatory agencies to ensure compliance. This study aims to compare PMR statuses, objectives, and pivotal trial characteristics of orphan drugs approved by the FDA (n = 154) and EMA (n = 79) from 2008 to 2018, shedding light on regulatory differences and their impact on drug development. Contrary to expectations, our analysis found no significant disparity in the proportion of orphan drugs with and without PMRs approved by both the FDA (48.1%) and EMA (55.7%). Safety concerns surrounding orphan drugs post-approval, attributed partly to pivotal trial design, underscore the need for robust post-marketing surveillance. While the FDA primarily focuses on post-marketing safety (36.1%), the EMA places a higher emphasis on both efficacy and safety (47.1%), reflecting distinct approaches to PMR management between the two regulatory bodies. The observed trend of delayed PMRs at the EMA (47.1%) highlights the importance of effective cooperation between regulators and pharmaceutical companies to ensure the timely completion of PMRs and enhance drug safety.

Data published on the oral clavulanic acid pharmacokinetics in the pediatric population is lacking. This research aimed to describe clavulanic acid disposition following oral and intravenous administration and to provide insights into clavulanic acid exposure based on threshold concentrations for (pre-)term neonates and infants. This pooled population pharmacokinetic study combined four datasets for analysis in NONMEM v7.4.3. Clavulanic acid exposure was simulated using the percentage of time above the threshold concentrations (%fT > C_T). Multiple dosage regimens and amoxicillin/clavulanic acid dosage ratios were evaluated. The cohort consisted of 89 (42 oral, 47 intravenous) subjects (403 samples) with a median (range) postnatal age 54.5 days (0-365), gestational age 37.4 weeks (23.0-41.7), and current bodyweight 3.9 kg (0.6-9.0). A one-compartment model with first-order absorption best described clavulanic acid pharmacokinetics with postnatal age as a covariate on the inter-individual variability of clearance. Oral bioavailability was 24.4% in neonates up to 10 days of age. An oral dosing regimen 90 mg/kg/day amoxicillin/clavulanic acid (4:1 ratio) resulted in 40.2% of simulated patients achieving 100% fT > C_T,2mg/L. An amoxicillin/clavulanic acid ratio of 4:1 is preferred for neonatal oral regimens due to the higher exposure along the entire %fT > C_T range (0-100%) as ratios higher than 4:1 might result in inadequate exposure. Our results highlight substantial exposure differences (%fT > C_T) when using threshold concentrations of 1 mg/L vs. 2 mg/L. This first population pharmacokinetic model for clavulanic acid in neonates may serve as a foundational step for future research, once more precise clavulanic acid targets become available.

In 2019, Indiana University launched the Precision Health Initiative to enhance the institutional adoption of precision medicine, including pharmacogenetics (PGx) implementation, at university-affiliated practice sites across Indiana. The overarching goal of this PGx implementation program was to facilitate the sustainable adoption of genotype-guided prescribing into routine clinical care. To accomplish this goal, we pursued the following specific objectives: (i) to integrate PGx testing into existing healthcare system processes; (ii) to implement drug–gene pairs with high-level evidence and educate providers and pharmacists on established clinical management recommendations; (iii) to engage key stakeholders, including patients to optimize the return of results for PGx testing; (iv) to reduce health disparities through the targeted inclusion of underrepresented populations; (v) and to track third-party reimbursement. This tutorial details our multifaceted PGx implementation program, including descriptions of our interventions, the critical challenges faced, and the major program successes. By describing our experience, we aim to assist other clinical teams in achieving sustainable PGx implementation in their health systems.

The availability of clinical trial data, advocacy, and increased funding has facilitated the implementation of pharmacometrics in Africa, resulting in the establishment of additional training programs for pharmacometricians. This study conducted a systematic review to evaluate the progress made from the implementation of pharmacometrics in clinical drug development and its adoption into drug approval by regulatory authorities in Africa. We performed a comprehensive literature search using major databases such as PubMed and Google Scholar. The study included articles published until 2024, with no lower cutoff. Articles were excluded if not addressing the research question or of pharmacometrics studies done outside Africa with no collaboration with African researchers (study setting). For the review, a total of 121 articles were included for analysis. Among the reported pharmacometrics approaches, Population pharmacokinetics modeling approaches are the most used (95 (78.5%)). South Africa and Uganda researchers have the most research output in pharmacometrics in Africa (82 (89.1%) and 7 (7.61%), respectively), with the University of Cape Town (South Africa) producing the highest (71 (78.8%)) of all article in Africa. The most studied conditions are TB (43 (35.5%)), HIV (33 (27.3%), TB and HIV (22 (18.2%)), and malaria (12 (9.92%). Pharmacometrics is gaining momentum in Africa, and the progress made since inception will significantly improve the safety and efficacy of therapeutic agents used to treat HIV, TB, and other emerging conditions.