Clinical therapeutics最新文献

Purpose: To study the pharmacokinetic characteristics of progesterone (GenSci070) in healthy Chinese postmenopausal women volunteers and to evaluate the bioequivalence and safety of GenSci070 and reference formulation.

Methods: In this randomized, open-label, single-center, single-dose, 2-period, 2-sequence, 2-way crossover study, 50 postmenopausal healthy women were recruited and received a single subcutaneous injection of test (GenSci070) or reference formulation 25 mg, respectively. Plasma progesterone concentrations were measured using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated by noncompartmental analysis method using Phoenix WinNonlin 8.3.1 software to evaluate the bioequivalence. The safety profile was evaluated by adverse events, physical examination, vital signs, laboratory tests, 12-lead ECG, etc. FINDINGS: The geometric mean ratios (90% CIs) for C_max, AUC_0-t, and AUC_0-∞ of the test and reference formulations were 92.70% (87.29%-98.44%), 96.26% (94.02%-98.55%), and 95.46% (93.27%-97.71%), respectively. They were all within the acceptable bioequivalence range of 80% to 125%. Thirty-one treatment-emergent adverse events occurred in 22 participants (44.0%) who received test formulation and 21 treatment-emergent adverse events occurred in 16 participants (32.0%) who received reference formulation, all events were mild.

Implications: The water-soluble progesterone injection (GenSci070) demonstrated bioequivalence to the marketed progesterone injection (Lubion) and exhibited a good safety profile in this study.

Purpose: Despite implementation of therapeutic drug monitoring (TDM) for voriconazole, the incidence of hepatotoxicity remains high. The albumin-bilirubin (ALBI) score may be useful for estimating voriconazole-induced hepatotoxicity. This pilot study aimed to investigate whether the ALBI score could estimate voriconazole-induced hepatotoxicity during TDM implementation.

Methods: This single-center, retrospective cohort study included 134 patients. The primary outcome was voriconazole-induced hepatotoxicity. The cutoff value of the ALBI score was determined using a receiver operating characteristic curve. The cumulative risk of hepatotoxicity was evaluated using Kaplan-Meier curve analysis with a log-rank test for the cutoff value and ALBI grade. Moreover, the group of patients with the trough concentration of voriconazole 1-4 μg/mL was also investigated.

Findings: The incidence of hepatotoxicity was 13.4% (18/134). The cutoff value of the ALBI score was -1.91 (sensitivity, 0.611; specificity, 0.655; area under the curve, 0.615). The cumulative risk of hepatotoxicity was significantly higher in the ALBI score ≥-1.91 group than in the ALBI score <-1.91 group (P = 0.024) and patients with higher ALBI grades tended to be at higher risk (P = 0.080). The cumulative risk tended to be higher with ALBI ≥-1.91 in the trough concentration 1-4 μg/mL group; however, no significant difference was found (P = 0.134).

Implications: The pilot study indicated that the ALBI score ≥-1.91 may be an indicator for voriconazole-induced hepatotoxicity even when TDM is conducted. Because this study was a single-center and small cohort design, further studies should be conducted using a large datasets and translational research.

Purpose: To determine the incidence of therapeutic target attainment using a three-times per week protocol for vancomycin therapy given during the last hour of intermittent hemodialysis (HD).

Methods: A single-center retrospective cohort study was conducted of patient medical records in a remote dialysis center from January 2017 to July 2023. Adult patients with chronic kidney disease stage 5 on ≥3 months of intermittent HD who had received a course of vancomycin therapy with ≥1 serum vancomycin concentration recorded were included. Demographic and dosing data were collected. Clinician adherence with the dosing protocol and attainment of the therapeutic target (trough concentration within 15-20 mg/L) following the loading and maintenance doses were assessed. Factors associated with target nonattainment following the loading dose were analyzed, and the 48- and 72-h maintenance dosing intervals were analyzed for target nonattainment.

Findings: A total of 98 vancomycin courses (67 patients) were available for analysis. Only 38% of the loading doses were prescribed as per protocol. Following the loading dose, 25% of trough concentrations achieved the therapeutic target concentration (15-20 mg/L), 25% returned a supra-therapeutic concentration (>20 mg/L) and 50% were sub-therapeutic (<15 mg/L). When compared with those achieving target, sub-therapeutic concentrations were associated with a lower loading dose (median 16.6 vs 20.0 mg/kg, P < 0.002), and supra-therapeutic concentrations had a shorter dosing interval between the loading dose and first maintenance dose (median 31.5 vs 39.0 h, P = 0.06). Of the 201 maintenance trough concentrations collected, 65% were therapeutic, 21% were sub-therapeutic and 14% were supra-therapeutic, with an overall median trough concentration of 17.3 mg/L. As the treatment duration increased, an increase was seen in the number of dose adjustments required to achieve the target trough concentration. The 48-h dosing interval was associated with more supra-therapeutic concentrations and the 72-h interval was associated with more sub-therapeutic concentrations (df = 2, P = 0.022).

Implications: We have identified a high rate of target nonattainment for HD patients on a three times a week vancomycin dosing regimen. We recommend a loading dose of 20 to 25 mg/kg irrespective of the indication and a better-defined dosing interval after the loading dose. A higher maintenance dose should be prescribed when the time to next dialysis session is 72 h. Further pharmacokinetic studies are needed to assess factors influencing target concentration attainment following the maintenance doses and to determine an optimal dosing regimen.

Purpose: Sudden sensorineural hearing loss (SSHL) is an abrupt hearing loss, often of unknown cause. Apheresis is a treatment option aimed at improving blood hemorheology by removing pathogenic blood components. There are currently no previous meta-analyses on its efficacy. Therefore, the aim of this study was to evaluate the efficacy of apheresis in achieving total, complete, and partial remission of SSHL, as well as remission outcomes based on the type of apheresis used.

Methods: A systematic search was performed in PubMed, Scopus, Web of Science, and the Cochrane Library until March 2024. Random-effects models were used to calculate pooled estimates of treatment success rates (TSR) and their respective 95% CI to analyze the efficacy of apheresis in the remission of SSHL. Subgroup analyses were performed by type of apheresis (HELP-apheresis and rheopheresis).

Findings: The systematic review included 12 studies (10 in the meta-analysis) involving 786 adults with SSHL. The effect of apheresis showed significant total remission (TSR: 0.55; 95% CI: 0.47, 0.64), complete remission (TSR: 0.21; 95% CI: 0.11, 0.30), and partial remission (TSR: 0.43; 95% CI: 0.37, 0.48). Subgroup analysis revealed significant remission rates for HELP-apheresis (TSR: 0.58; 95% CI: 0.52, 0.64) and rheopheresis (TSR: 0.51; 95% CI: 0.30, 0.72).

Implications: These findings support apheresis as an equally or more effective treatment for SSHL, particularly in cases where corticosteroid therapy fails. However, due to the unknown etiology of SSHL, further clinical trials with larger, diverse populations are essential to confirm these results.

Purpose: This systematic review was conducted to determine which type of oral medication for obesity provides the best weight loss effect.

Methods: This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guideline. For this systematic review, we used 3 databases for journal searches: PubMed, ScienceDirect, and Scopus. This study only included randomized controlled trials or open-label clinical trials. There was no year limit used in the journal search for this systematic review.

Findings: Eighteen randomized controlled trials, with a total population of 12,259 patients, were included. Of 18 studies, 15 were used for network meta-analysis. Based on the results of the network meta-analysis, weight loss was found in phentermine/topiramate (mean difference [MD], -3.28; 95% CI, -4.47 to -2.09), semaglutide (MD, -2.92; 95% CI, -4.38 to -1.46), phentermine (MD, -2.31; 95% CI, -3.82 to -0.81), naltrexone/bupropion (MD, -1.68; 95% CI, -2.87 to -0.49), topiramate (MD, -1.67; 95% CI, -2.86 to -0.48), and orlistat (MD, -1.44; 95% CI, -2.32 to -0.55). There were no significant differences among the groups. However, compared with placebo, all oral obesity therapies provide better benefits in weight loss (MD, -2.12; 95% CI, -2.64 to -1.59; P ≤ 0.00001).

Implications: Oral antiobesity drugs provide better weight loss than placebo. However, some side effects can be incurred by utilizing the drug for weight loss, especially related to the gastrointestinal system. Nonetheless, in clinical settings, consideration should be given to particular patients to reduce risk of side effects.

Purpose: Posaconazole is a broad-spectrum antifungal for treating and preventing invasive fungal infections (IFIs) in immunocompromised individuals, including children as young as 2 years. Available in delayed-release (DR) oral suspension, intravenous formulation, and older immediate-release (IR) formulation (off-label in younger children), dosing harmonization across age groups and formulations remains inconsistent. This inconsistency arises from the unique physiology of young children and posaconazole's pH-dependent absorption. Limited pharmacokinetic (PK) data for children under 2 years complicates dosing, as absorption, distribution, metabolism, and excretion processes are underdeveloped and age-dependent. This work aims to harmonize pediatric dosing for children aged 2 to 7 years and extend dosing guidance for those aged 6 months to 2 years using physiologically-based PK (PBPK) modeling.

Methods: An adult PBPK model was created using posaconazole's physicochemical properties and ADME characteristics with virtual populations from PK-Sim. Calibrated with single-dose data from healthy subjects, the model was verified by predicting PK following multiple doses in adults at risk for IFIs. The model was then scaled to children, accounting for developmental anatomy and physiology, including UGT1A4 ontogeny. The pediatric model was evaluated against observed data from children aged 2 to 7 years. Simulations were conducted to harmonize dosing across formulations and extend dosing to children as young as 6 months, acknowledging standard plasma concentration targets for treatment of IFIs (1000 ng/mL) as well as prophylaxis (700 ng/mL).

Findings: The pediatric model adequately captured observed PK data from literature following all three formulations. The IR oral suspension is impractical and likely subtherapeutic for most children under 7 years due to solubility limits. Intravenous doses of 11-13 mg/kg once daily (QD) may be optimal for treatment, and 8 to 9 mg/kg QD for prophylaxis, varying by age. Oral DR suspension doses of 12 to 14 mg/kg QD for treatment and 8.5 to 10 mg/kg QD for prophylaxis may be optimal, also age-dependent. Dividing the total daily dose by a factor of 0.7 and administering twice daily can achieve similar trough levels.

Implications: PBPK modeling for posaconazole bridges the gap between PK principles and clinical practice, potentially improving therapeutic outcomes and minimizing risks associated with inadequate dosing in pediatric patients.

Purpose: Injectable once weekly semaglutide for diabetes (OW sema) is a medication approved in 2017 for the treatment of patients with type 2 diabetes (T2DM). In clinical trials, OW sema has been shown to be effective at helping patients achieve glycemic targets. However, more data are needed to understand how patients who initiate treatment with OW sema are treated in the real world and to aid prescribers in making treatment decisions. This study characterized noninsulin antidiabetic medication use patterns among US patients with T2DM initiating treatment with OW sema.

Methods: In this retrospective, claims-based study, patients (15,588) were included if they had at least 1 claim for OW sema between January 1, 2018 and December 31, 2019, were at least 18 years old, were continuously enrolled in the health plan, and had at least 1 claim indicating a diagnosis of T2DM. All patients had at least 1 line of therapy (LOT) that started on the date of the first fill for OW sema. Data related to pre-index date demographics and clinical characteristics were collected, as were data on patient regimens and LOTs. The length of the LOT was calculated, and the top 10 noninsulin treatment regimens were reported in each LOT.

Findings: In the first LOT, OW sema monotherapy was the most common regimen. More than one third (36.5%) of patients had 1 LOT until the end of follow-up and most patients who had a second (52.1%) or third (72.0%) LOT continued it to the end of the study. Among the top 10 regimens, 42.2% of patients with a second LOT and 45.8% of patients with a third LOT had an LOT that included OW sema.

Implications: This study describes medication regimens within the first year of OW sema use. Among patients initiating OW sema, monotherapy was the most common regimen. These results provide insight into real-world usage patterns of this medication.