Journal of Clinical Pharmacology最新文献

Fezolinetant is a non-hormonal, selective neurokinin 3 receptor antagonist approved in multiple countries including the United States, in Europe, and in Asia for the treatment of moderate to severe vasomotor symptoms in menopausal women. Fezolinetant is primarily metabolized by CYP1A2 and was found to be a sensitive substrate for CYP1A2 metabolism based on a clinical DDI study with strong CYP1A2 inhibitor, fluvoxamine. Therefore, coadministration with CYP1A2 inhibitors or inducers (such as smoking) could lead to changes in fezolinetant exposure. A physiological-based pharmacokinetic (PBPK) model was built for fezolinetant using the Simcyp simulator software with in vitro and in vivo data. The final verified model was used to predict fezolinetant exposure following coadministration with mexiletine (moderate CYP1A2 inhibitor), ciprofloxacin (moderate CYP1A2 inhibitor), and cimetidine (weak CYP1A2 inhibitor). Depending on the dosing regimen of the inhibitor and the meal status, coadministration with a weak CYP1A2 inhibitor, such as cimetidine, was predicted to increase fezolinetant C_max by 1.30 to 1.36 and AUC_inf by 1.61 to 2.01 fold. A moderate CYP1A2 inhibitor, such as mexiletine, was predicted to increase fezolinetant C_max by 1.36 to 1.59 fold and AUC_inf by 3.38 to 4.61 fold. Another moderate CYP1A2 inhibitor, ciprofloxacin, was predicted to increase fezolinetant C_max by 1.39 to 1.49 fold and AUC_inf by and 1.99 to 2.33 fold. The results of the PBPK analysis supported global labeling language statements for fezolinetant.

The standard dose of enoxaparin for therapeutic anticoagulation is 1 mg/kg every 12 h in patients with a creatinine clearance (CrCl) greater than 30 mL/min. Besides pregnancy, obesity, and renal impairment, literature on other risk factors for supratherapeutic anti-Xa levels is sparse. The objective of this retrospective study was to determine novel risk factors for supratherapeutic anti-Xa levels and further inform empiric enoxaparin dosing. We included adult patients with CrCl greater than 30 mL/min that received 1 ± 0.09 mg/kg of enoxaparin every 12 h. The primary outcome was the correlation between blood urea nitrogen (BUN) and anti-Xa levels. The associations between other clinical factors and supratherapeutic anti-Xa levels were also evaluated. Secondary outcomes included the incidence of major bleeding and breakthrough thrombosis in patients who had supratherapeutic levels versus those who did not. A total of 732 patients were included in the final analysis. A small correlation was detected between BUN and anti-Xa levels (Pearson correlation coefficient 0.25, P <. 001). However, multivariate analyses revealed that only female sex, body mass index, number of enoxaparin doses prior to the initial anti-Xa level, concomitant corticosteroid administration, and lower CrCl were associated with an increased risk of supratherapeutic levels (P <. 05) when controlling for other factors. There were no significant differences in the incidence of major bleeding or breakthrough thrombosis in patients with supratherapeutic, therapeutic, or subtherapeutic levels. In this study, we identified potential risk factors for supratherapeutic anti-Xa levels in patients without severe renal impairment that may be clinically relevant when empirically dosing therapeutic enoxaparin.

This study aimed to assess the associations between recent cannabis use and 49 biochemical biomarkers in a representative sample of American adults, using data from the 2009-2018 National Health and Nutrition Examination Survey. A phenotype-wide association study (PheWAS) was conducted to uncover new biomarkers linked to cannabis use. The analysis included 19,926 adults aged 18-59, with a mean age of 38.93 years (50.8% women), and 36.7% reporting recent cannabis use. Metabolic associations included higher high-density lipoprotein (HDL) cholesterol (3.51 mg/dL, 95% CI [2.50, 4.62]) and lower glycohemoglobin (-0.09%, 95% CI [-0.15, -0.04]) and glucose (-2.39 mg/dL, 95% CI [-4.07, -0.70]). Hematological findings included higher hemoglobin (0.09 g/dL, 95% CI [0.02, 0.16]), mean erythrocyte volume (1.46 fL, 95% CI [1.12, 1.80]), mean erythrocyte hemoglobin (0.46 pg, 95% CI [0.32, 0.60]), erythrocyte volume fraction (0.31%, 95% CI [0.11%, 0.50%]), and lower erythrocyte counts (-0.04 million cells/µL, 95% CI [-0.07, -0.02]). Serum chemistry associations included higher bicarbonate (0.20 mmol/L, 95% CI [0.06, 0.35]) and lower chloride (-0.47 mmol/L, 95% CI [-0.69, -0.24]). Associations were also observed with 25 hydroxyvitamin-3 (OHD3) (2.38 nmol/L, 95% CI [0.55, 4.22]) and epi-25OHD3 (0.40 nmol/L, 95% CI [0.15, 0.65]), and an inverse association with globulin (-0.03 g/dL, 95% CI [-0.06, -0.01]). Sensitivity analyses confirmed the robustness of these associations. Recent marijuana use is associated with diverse and complex phenotypes, several of which have not been previously evaluated. Further validation studies are warranted, this approach offers an opportunity to understand a comprehensive range of potential effects of marijuana use.

Belumosudil is an oral selective rho-associated coiled-coil containing protein kinase 2 inhibitor, approved as a treatment for chronic graft-versus-host disease. Prior clinical studies demonstrated that coadministration with strong CYP3A4 inducers or proton pump inhibitors requires dose modification of belumosudil. In vitro assessments suggested that belumosudil may inhibit uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), P-glycoprotein (P-gp), organic anion transporting polypeptide 1B1 (OATP1B1), and breast cancer resistance protein (BCRP), resulting in drug-drug interactions (DDIs). This three-part clinical DDI study (NCT05806567) was conducted to assess the effect of multiple doses of belumosudil (200 mg daily) on the single-dose pharmacokinetics of raltegravir (UGT1A1-sensitive substrate), dabigatran etexilate (P-gp-sensitive substrate), and rosuvastatin calcium (OATP1B1/BCRP-sensitive substrate). Although there was no marked change in raltegravir exposure after coadministration with belumosudil, exposure to the glucuronide metabolite was decreased by 39.6% (area under the curve from time 0 to the time of last measurable concentration [AUC_0-last]) and 42.4% (maximum observed concentration [C_max]), suggesting that belumosudil is an in vivo inhibitor of UGT1A1. There was an approximate 2-fold increase in C_max, AUC_0-last, and AUC from time 0 extrapolated to infinity (AUC_0-inf) for dabigatran etexilate, suggesting a potential and clinically relevant DDI for belumosudil and sensitive P-gp substrates. C_max and AUC_0-last for rosuvastatin calcium increased by 3.6-fold and 4.6-fold, respectively, suggesting a clinically relevant interaction with drugs that are substrates of OATP1B1 or BCRP. There was no impact of coadministration with raltegravir, dabigatran etexilate, or rosuvastatin calcium on belumosudil pharmacokinetics, and belumosudil was well tolerated.

Tacrolimus, a critical immunosuppressant in organ transplantation, is available in immediate-release (IR-T) and extended-release (ER-T) formulations. While ER-T improves patient adherence, clinical studies have not demonstrated superior outcomes compared to IR-T. However, the underlying reasons for this discrepancy remain unclear. This study aimed to evaluate tacrolimus exposure under non-adherent dosing behaviors with IR-T and ER-T and to provide insights for selecting the optimal tacrolimus formulation. Monte Carlo simulations were conducted to assess the proportion of target attainment (%PTA) and deviation time (DT) from the therapeutic range in scenarios involving delayed or missed doses, based on published population pharmacokinetic models. The influence of renal function, the post-transplantation period, and hematocrit levels on %PTA and DT were also analyzed. Our findings revealed that patients on ER-T exhibited lower %PTA and longer DT than those on IR-T when doses were delayed or missed, reflecting poorer "forgiveness." This observation elucidates the lack of clinical superiority observed for ER-T in previous studies. Furthermore, fast metabolizers experienced worse forgiveness with ER-T, exacerbating the challenge of maintaining therapeutic levels. Additionally, a web-based dashboard was developed to calculate the %PTA and DT for individual patients and to provide formulation recommendations tailored to their dosing behaviors and clinical characteristics. In conclusion, adherence and forgiveness play a crucial role in the success of pharmacotherapy. This study highlights the significance of pharmacokinetic modeling and simulation in providing evidence-based recommendations for selecting the optimal tacrolimus formulation.

Efanesoctocog alfa is a first-in-class high-sustained factor VIII (HSF) replacement therapy for treatment of hemophilia A. This article presents population pharmacokinetics (PopPK) of efanesoctocog alfa and repeated time-to-event (RTTE) analysis of bleeding episodes in adults/adolescents (≥12 years of age) and children (<12 years). The final PopPK dataset contained pooled data from 277 patients (4405 post-dose factor VIII [FVIII] activity records) from two Phase 1/2a studies (NCT03205163; EudraCT 2018-001535-51), and three Phase 3 studies, XTEND-1 (NCT04161495), XTEND-Kids (NCT04759131), and XTEND-ed (NCT04644575). The PopPK model developed was a linear one-compartment model including body weight effect on clearance and volume of central compartment; Asian race was identified as a statistically significant covariate on clearance. The final PopPK model adequately described the FVIII activity-time profiles in adults, adolescents, and children with once-weekly (QW) efanesoctocog alfa 50 IU/kg, consistent with experience in XTEND-1 and XTEND-Kids. Bleeding episodes in participants in XTEND-1 and XTEND-Kids were characterized by an RTTE model with a Weibull base hazard and effect of FVIII activity modeled by a power effect. The RTTE model showed the probability of being bleed-free in 1 year with efanesoctocog alfa 50 IU/kg QW regimen was >70% across all age groups, consistent with the observed clinical outcomes in the Phase 3 trials of highly effective protection from bleeding episodes in patients with severe hemophilia A, which validates the model's prediction of the long-term bleed hazard.

Sarilumab (interleukin-6 receptor inhibitor) is approved in the United States and Europe for polymyalgia rheumatica (PMR). This study characterized sarilumab pharmacokinetics (PK) and assessed the influence of intrinsic and extrinsic factors on PK in patients with PMR and giant cell arteritis (GCA). Exposure-responses analyses were conducted to evaluate the PK-pharmacodynamic (PD) relationships of sarilumab with key efficacy and safety endpoints in patients with PMR (NCT03600818). Population (Pop) PK analysis was conducted using pooled PK data from two phase III studies including 58 patients with PMR and 40 with GCA (NCT03600805). This Pop PK model was developed by re-estimating parameters from a previous rheumatoid arthritis (RA) model. The main source of intrinsic PK variability in patients with PMR was body weight, with decreasing weight causing increased sarilumab exposure. The population mean apparent clearance for patients with PMR was lower than for patients with RA due to higher albumin, lower creatinine clearance, and lower C-reactive protein (CRP) in PMR than in RA. Individual exposures at steady state overlapped among patients with PMR, GCA, and RA. PK-PD relationships showed that greater sarilumab C_trough in patients with PMR were associated with increasing total sIL-6Rα and decreasing CRP. There was a slight increase in patients achieving sustained remission at Week 52 and a decrease in absolute neutrophil count with increasing sarilumab C_trough plateauing at 20-25 mg/L. The PD effect of sarilumab plateaued at C_trough of 20-25 mg/L for target saturation, efficacy, and safety endpoints, supporting a dosage of 200 mg every 2 weeks for PMR.

Resilience is a critical leadership competency directly linked to engagement, sustainable innovation, and productivity. This Commentary presents resilience concepts using the Benatti Resiliency Model^®, which comprises five inter-related dimensions: Well-being, Self-awareness, Brand, Connection, and Innovation. Trust is discussed as a critical leadership competency, with three levels: self-trust, trust in relationships at the team level, and community trust. The concept of Ikigai, representing the intersection of what one loves, what one is good at, what the world needs, and what one can be paid for, is discussed as a framework for self-awareness, brand development, development planning, and mentoring. Time and energy management using the Eisenhower matrix is highlighted as a strategy to build resilience, manage stress, enhance productivity, and prevent burnout. Taken together, the strategies discussed in this commentary are intended to unlock the transformative potential of resilience for sustainable innovation and impact within and beyond the dynamic and interdisciplinary field of clinical pharmacology, ultimately enabling professional success and personal fulfillment.

Dose selection is a critical process within pediatric drug development and dose-ranging studies are integral to establish a reasonable dose. The objective of this analysis was to examine the dose-ranging trials utilized in pediatric drug development and to determine (1) the dose-ranging strategies that were used in all available pediatric dose-ranging studies, (2) the success of achieving pediatric labeling in those submissions to the US Food and Drug Administration, and (3) ethical aspects of providing a prospect of direct benefit to pediatric patients in dose-ranging studies. Of the 275 programs that previously surveyed pediatric drug development programs from 2012 to 2020, it was determined that dose-ranging studies were used for 97 (35.3%) programs. The three categorizations of these 97 programs included the parallel dose design (n = 66; 68%), the dose-escalation design (n = 18; 18.6%), and the crossover design (n = 13; 13.4%). In the 66 that used a parallel design, 41 of these products were approved for use in pediatric patients. In 13 out of the 41 drugs (31.7%) approved for pediatric use using parallel dose ranging, the lowest parallel dose (patient on the dose for the entire study) was lower than the approved dose. Dose ranging remains an important strategy for optimizing dosing, but ethical considerations and the need to optimize benefit for individual patients should drive decisions about dosing approaches in pediatric patients. The inclusion of adaptive designs is one possible approach to optimizing dose-ranging studies for pediatric patients.