Pharmacokinetic effects of proton pump inhibitors on the novel PARP inhibitor fluzoparib: a single-arm, fixed-sequence trial in male healthy volunteers.

Purpose To assess the pharmacokinetic (PK) effect of proton pump inhibitors on the novel poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor fluzoparib, and observe the safety of its co-administration with omeprazole. Patients and methods Sixteen male healthy volunteers (HVs) were enrolled in a single-center, single-arm, open-label, fixed-sequence study. HVs took fluzoparib (100 mg, p.o.) after meal consumption on day-1, took omeprazole 40 mg (p.o.) under a fasting condition from day-5 to day-9, and took fluzoparib (100 mg, p.o.) after meal consumption on day-9. Blood samples were collected at predetermined timepoints for PK analyses. Safety was assessed via clinical laboratory tests. The study was registered with the Clinical Trials Registry on 30 September 2019 (NCT04108676). Results The peak plasma concentrations (Cmax) after fluzoparib administration was 2395.17 ± 418.27 ng/mL, the area under the curve (AUC) within 72 h (AUC0 - 72 h) was 26669.09 ± 7320.12 h·ng/mL, and AUC0-∞ was 26897.44 ± 7573.61 h·ng/mL. The Cmax after co-administration of fluzoparib and omeprazole was 2489.43 ± 423.72 ng·mL, AUC0 - 72 h was 30300.49 ± 8350.08 h·ng/mL, and AUC0-∞ was 30678.74 ± 8595.55 h·ng/mL. The geometric mean ratio of Cmax, AUC0 - 72 h and AUC0-∞ was 104.0% (90%CI: 94.8-114.0%), 113.6% (104.2-123.9%) and 104.1% (104.5-124.6%). The number of HVs with adverse reactions was identical (eight) for administration of fluzoparib and co-administration of fluzoparib and omeprazole. Conclusions The proton pump inhibitor omeprazole did not have a significant influence on the PK behavior of fluzoparib, and its safety profile was good upon co-administration with omeprazole. (NCT04108676, 30 September 2019).

Population pharmacokinetics study of dexmedetomidine in Chinese adult patients during spinal anesthesia.

OBJECTIVES: The objectives of this study were to construct a population pharmacokinetics model for dexmedetomidine used in Chinese adult patients with spinal anesthesia and to identify the key factors affecting the pharmacokinetics of dexmedetomidine. METHODS: A total of 34 subjects (elderly group: n = 15; young group: n = 19) undergoing spinal anesthesia received dexmedetomidine with a loading dose of 0.5 µg×kg(-1) for 10 minutes, followed by a maintenance dose of 0.5 µg×kg-1×h(-1) for 50 minutes. Blood samples were collected until 10 hours after dosing. Laboratory and respiratory parameters, and dexmedetomidine concentrations were measured. A population pharmacokinetic model for dexmedetomidine was constructed using a nonlinear mixed effects model (NONMEM). RESULTS: Pharmacokinetics of dexmedetomidine can be described by a three-compartment model. The respective typical values for clearance (CL), V1, V2, Q2, Q3, and V3 were 0.883 L×min(-1), 17.6 L, 51.5 L, 2.37 L×min(-1), 0.517 L×min(-1), and 44.00 L. Alanine aminotransferase (ALT), age, and body weight were key factors affecting CL, V1, and V2, respectively. CONCLUSIONS: A three-compartment model can be used to describe the pharmacokinetics processing of dexmedetomidine for Chinese adult patients during spinal anesthesia. The population pharmacokinetic of dexmedetomidine was generally in line with results from previous studies.

Pharmacokinetic and pharmacodynamic study of dexmedetomidine in elderly patients during spinal anesthesia.

OBJECTIVE: The application of dexmedetomidine in patient sedation is generally accepted, though its clinical application is limited because of the lack of information detailing the specific properties among diverse populations of patients. The aim of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine between elderly and young patients during spinal anesthesia. METHODS: 34 subjects (elderly group: n = 15; young group: n = 19) with spinal anesthesia were enrolled in the present study following the inclusion/exclusion criteria detailed below. All subjects received intravenous infusion of dexmedetomidine with a loading dose of 0.5 µg x kg⁻¹ for 10 minutes and a maintenance dose of 0.5 µg x kg⁻¹ x h⁻¹ for 50 minutes. Plasma concentrations of dexmedetomidine were detected by the HPLC-MS/MS method and pharmacokinetic parameters were calculated using WinNolin software. RESULTS: There was no significant difference between the elderly and young subjects in major pharmacokinetic parameters. There was a marked gender difference in the Cmax (peak plasma concentration) and tmax (time to reach Cmax) between genders in elderly subjects, though in this cohort the other pharmacokinetic parameters were not significantly different. In the young subjects there were no noteworthy variations between genders in pharmacokinetic parameters. There was no significant difference between the two groups in BISAUC(0-t) (the area under the bispectral index-time curve from time 0 to t hours), BISmin (the minimum value of the bispectral index after drug delivery), and or tmin-BIS (bispectral index for the minimum value of time). SBP (systolic blood pressure), DBP (diastolic blood pressure), HR (heart rate), and SpO2(pulse oxygen saturation) developed substantive differences in a time-dependent manner, but there were no statistically significant differences in these four indicators in the time*group at three time points (1 hour, 2 hours, and 3 hours after drug administration); while SBP was significantly different between the groups, this differential declined in a time-dependent manner, and there were no significant attendant differences in the D-value. The observed values and D-values of DBP and HR were similar in the groups, but the observed value and D-value of SpO2did differ. There were 14 drug-related adverse events in the young group, and 26 drug-related adverse events in the elderly group, a 46% differential. The percentage of patients who requiring intervention during surgery was 68.75% (11/16) in the elderly group and 36.84% (7/19) in the young group, with no significant difference between the two groups once age was factored in (p = 0.06). None of the pharmacodynamic indices, however, correlated with the key pharmacokinetic parameters (Cmax, AUC(0→t), AUC(0→∞)) of dexmedetomidine. CONCLUSIONS: The clearance of dexmedetomidine in elderly patients showed a declining trend compared to young patients. Interventions in the elderly group were more frequent than in the young group, and the elderly group showed significant adverse effects. It is suggested that elderly patients who use dexmedetomidine may benefit from a different dose. However, further research with a larger population size is required to confirm these findings.

Evaluation of the highly variable agomelatine pharmacokinetics in Chinese healthy subjects to support bioequivalence study.

OBJECTIVES: We aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy. METHODS: A single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples. RESULTS: The intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for Cmax and AUC0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%). CONCLUSIONS: Agomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies. TRIAL REGISTRATION: ChiCTR.org ChiCTR-TTRCC-13003835.