British journal of clinical pharmacology最新文献

Aims: Linezolid is primarily used to treat of methicillin-resistant Staphylococcus aureus and multidrug-resistant tuberculosis infections. Thrombocytopenia due to linezolid usage is a concern, and therapeutic drug monitoring has been reported to be effective in its prevention. Plasma concentrations provide valuable information for treatment decisions; however, collecting plasma samples can be burdensome for both patients and healthcare providers. Therefore, there is interest in saliva as an alternative for monitoring, considering its potential to replace plasma samples.

Methods: Patients hospitalized at Hokkaido University Hospital and Hokkaido Spinal Cord Injury Center between April 2022 and July 2024, who received oral or intravenous linezolid treatment, were enrolled. The concentrations of linezolid were simultaneously measured in plasma and saliva samples. We determined the concentration profiles of linezolid in the saliva and examined the correlation between saliva and plasma linezolid concentrations.

Results: Eighteen patients receiving linezolid were enrolled. The average of saliva/plasma (S/P) concentration ratios of linezolid were 1.018. A strong correlation was found between the salivary and plasma concentrations of linezolid (R = .833, P < .001). Notably, in patients receiving intravenous administration of linezolid, the correlation was even more pronounced (R = .885, P < .001). Additionally, when focusing on the S/P ratio of the trough concentrations in the morning and at night, the S/P ratios at night were much closer to 1.0.

Conclusion: The concentrations of linezolid in plasma and saliva were similar, indicating their potential applicability in clinical settings. The monitoring of linezolid concentrations in saliva has been shown to be particularly suitable for patients receiving intravenous administration.

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Safety, pharmacokinetics and antiviral activity of ainuovirine as 10-day monotherapy in treatment-naïve adults with HIV-1

Su Bin¹, Wu Hao¹, Wei Xia¹, Zhang Li², Yun Xinming² and Qin Hong²

¹Beijing Youan Hospital Affiliated to Capital Medical University; ²Jiangsu Aidea Pharmaceutical Co., Ltd

Background: Ainuovirine (ANV) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of HIV-1 infection. This study aimed to evaluate the safety, pharmacokinetics and antiviral activity of short-term ANV monotherapy in antiretroviral treatment-naive adults with HIV-1.

Methods: A single-centre, open-label, dose-ranging study was conducted among 28 treatment-naive adults with HIV-1. Participants received ainuovirine monotherapy, at the dosage of 75, 150 or 300 mg, once daily, for 10 days.

Results: Baseline characteristics were similar across dose cohorts (75 mg, n = 8; 150 mg, n = 10; 300 mg, n = 10). Across all dose cohorts, all adverse events were rated as mild to moderate in severity. No serious adverse event was reported. ANV was readily absorbed, with the maximum concentration achieved at a median time of approximately 2–3 h after dosing. The ANV exposure (AUC and C_max) increased slightly greater than the dose proportionality after single dose (day 1). Plasma ANV concentration reached the steady state at day 10 of dosing. Saturated C_max,ss, AUC_max,ss, and C_min,ss were observed at 150 and 300 mg on day 10 after repeated dosing. The inhibitory quotient (IQ) was 69.6-fold (150 mg, C_min,ss = 153.0 ng/mL) for wild type (EC50 = 2.2 ng/mL), 10.0-fold for K103N mutant (EC50 = 15.3 ng/mL) and 6.9-fold for Y181C mutant (EC50 = 22.1 ng/mL), respectively. Mean changes in HIV RNA from baseline (log10 copies/mL [90%CI]) were −1.73 [−1.90, −1.57], −1.72 [−1.87, −1.57] and −1.66 [−1.80, −1.51], respectively, on day 11.

Conclusion: ANV demonstrated favourable safety and pharmacokinetics, and potent antiviral activity in treatment-naive adults with HIV-1. An once-daily dosing regimen of 150 mg was recommended for subsequent confirmatory efficacy trial.

Keywords: ainuovirine, anti-HIV treatment, viral kinetics

Aim: Therapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model.

Methods: We prospectively enrolled 63 stable adult kidney-transplanted patients and collected dense (12-h, n = 18) or sparse (4-h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography-mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM.

Results: Tacrolimus whole blood concentrations were well described using a two-compartment pharmacokinetic model with a lag-time and first-order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (R_C:PBMC), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non-expressors and NR1I2-25 385T allele expressors demonstrated higher R_C:PBMC ratios of 42.4% and 60.7%, respectively.

Conclusion: Tacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies.

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Absorption, distribution, metabolism and excretion of ainuovirine in healthy adults: A radiolabelled mass balance and biotransformation study

Miao Liyan¹, Jiang Bin¹, Sang Shibiao¹, Qin Hong² and Wu Yuechan²

¹The First Affiliated Hospital of Soochow University; ²Jiangsu Aidea Pharmaceutical Co., Ltd

Background: Ainuovirine (ANV) is a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. The absorption, distribution, metabolism and elimination of ANV was evaluated in a human radiolabelled mass balance and biotransformation study.

Methods: A single-centre, single-dose, non-randomized, open-label study was conducted, in which six healthy males received a single dose of oral suspension containing [14C]ANV at 150 mg/approximately 100 μCi on the first day in the study under fasting condition. Whole blood, plasma, urine and faecal samples were collected at the specific time points during the study. The data of pharmacokinetic (PK) parameters of the total radioactivity in plasma, concentration ratio of total radioactivity in whole blood to plasma and mass balance were obtained by measuring the total radioactivity of [14C]ANV in plasma, whole blood, urine and faeces. The main metabolic elimination pathways and characteristics of ANV in human body were obtained by analysing the radioactive metabolite profiles in plasma, urine and faeces; and the structure of major metabolites was identified using radioisotope and mass spectrometry.

Results: The time to maximum plasma total radioactivity (T_max) was 3.42 h; the mean maximum concentration (C_max) was 327 ng·eq./g; and the half-life of the total radioactivity terminal elimination phase (t½) was 43.5 h. Within 0–240 h, the mean cumulative excretion rate of total radioactivity was 101.64%. Specifically, the mean total excretion accounted for 28.10% of the administered dose in urine and 73.54% of the administered dose in faeces, suggesting that [14C]ANV was primarily excreted into faeces. The primary clearance pathway of [14C]ANV was mono-oxygenated to form M341, which was further glucuronidated, and metabolized by the liver, and excreted into faeces and urine. The secondary metabolic pathway was glucuronidation of the unchanged drug to form M501, which was excreted into urine.

Conclusions: Ainuovirine is primarily metabolized by the liver and excreted into faeces and urine, with a low plasma clearance, in the human body.

Keywords: ainuovirine, human immunodeficiency virus 1, mass balance, non-nucleoside reverse transcriptase inhibitor, pharmacokinetics