Intravenous Infusion In Healthy Volunteers Research Articles

Phase I Pharmacokinetics Study of Drug for Infusion «Areplivir» (INN: Favipiravir) (LLC "PROMOMED RUS", Russia)

Introduction. The novel coronavirus infection COVID-19 (Coronavirus Disease 2019) is caused by an enveloped, positive-sense, single-stranded ribonucleic acid (RNA) virus SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2). Favipiravir is the antiviral drug recommended for etiotropic treatment of COVID-19. Parenteral therapy has advantages over the other routes of the drug administration: there are no interaction with food and digestive enzymes, may be used for patients with diseases of the digestive system and unconscious patients. For parenteral drug administration of favipiravir the drug "Areplivir" has been registered in Russia.Aim. The aim is pharmacokinetics study of drug "Areplivir", a lyophilisate for the preparation of a concentrate for the infusion solution (the manufacturer is JSC "Biokhimic", LLC "Promomed RUS" as registration certificate holder) by intravenous infusion in healthy volunteers in a phase I pharmacokinetics study.Materials and methods. The clinical and analytical phases of the pharmacokinetic study as well as pharmacokinetic analyses have been performed as part of a clinical trial of the drug "Areplivir" in different doses, a lyophilisate for the preparation of a concentrate for the infusion solution (LLC "Promomed RUS", Russia). Chromatographic separation and detection were carried out on a LC-2040C high-performance liquid chromatograph (Shimadzu Corporation, Japan) with a built-in UV detector, a low-pressure four-component gradient pump, a degasser, an autosampler, a column thermostat and a controller. The pharmacokinetic parameters were calculated with the Boomer pharmacokinetic analysis add-in for Microsoft Excel (Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, CA 92606, USA). Descriptive pharmacokinetic statistics were calculated with Microsoft Excel (Microsoft Corporation, USA). Correlation and Regression Analysis were conducted with IBM SPSS Statistics (version 23.0), IBM, USA.Results and discussion. For single dose administration of 400, 800, 1600 and 1800 mg in 4 cohorts of 5 volunteers pharmacokinetic parameters were calculated. For Cmax and an administered dose the strong correlation coefficient on the Chaddock scale (r = 0,98; p = 0,02; r – Pearson correlation coefficient; p – the reached significance value) and the determination coefficient (R2 = 0,96; F = 45,97; p = 0,02; R2 – determination coefficient; F – the actual value of the Fisher's criterion) were statistically significant. For AUC0-t and an administered dose the strong correlation coefficient on the Chaddock scale (r = 0,97; p = 0,03) and the determination coefficient (R2 = 0,94; F = 33,54; p = 0,03) were statistically significant. The obtained results show the linearity of Cmax and an administered dose and the linearity of AUC0-t and an administered dose (400–1800 mg).Conclusion. According to the concentrations of favipiravir from the analytical phase of the pharmacokinetic study the pharmacokinetic parameters were calculated, averaged pharmacokinetic profiles in linear and log-linear scales were plotted after single dose administrations of the drug "Areplivir" in different doses, a lyophilisate for the preparation of a concentrate for the infusion solution (LLC "Promomed RUS", Russia). The linearity of Cmax and a single administered dose and the linearity of AUC0-t and a single administered dose of the drug "Areplivir" have been demonstrated for doses of 400 to 1800 mg. The results justified the study of multiple dose administration of "AREPLIVIR" and the subsequent phases of clinical trials.

An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers.

Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2-80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2-59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

The Engineered Antibiotic Peptide PLG0206 Eliminates Biofilms and Is a Potential Treatment for Periprosthetic Joint Infections.

Antimicrobial peptides (AMPs) have recently gained attention for their potential to treat diseases related to bacterial and viral infections, as many traditional antimicrobial drugs have reduced efficacy in treating these infections due to the increased prevalence of drug-resistant pathogens. PLG0206, an engineered cationic antibiotic peptide that is 24 residues long, has been designed to address some limitations of other natural AMPs, such as toxicity and limited activity due to pH and ion concentrations. Nonclinical studies have shown that PLG0206 is highly selective for targeting bacterial cells and is not toxic to human blood cells. Antibiofilm experiments demonstrated that PLG0206 is effective at reducing both biotic and abiotic biofilm burdens following direct biofilm contact. PLG0206 has rapid and broad-spectrum activity against both Gram-positive and Gram-negative bacteria that are implicated as etiologic agents in periprosthetic joint infections, including multidrug-resistant ESKAPE pathogens and colistin-resistant isolates. A recent first-in-human study demonstrated that PLG0206 is well tolerated and safe as an intravenous infusion in healthy volunteers. Studies are planned to determine the efficacy of PLG0206 in patients for the treatment of periprosthetic joint infections. This review summarizes the chemistry, pharmacology, and microbiology of PLG0206 and explores its current preclinical, clinical, and regulatory status.

Pharmacokinetic Properties of S-oxiracetam After Single and Multiple Intravenous Infusions in Healthy Volunteers.

As a chiral drug, oxiracetam (ORT) can exist in two different isomeric forms: S-oxiracetam (S-ORT) and R-oxiracetam (R-ORT). S-ORT has emerged as a promising nootropic drug with the potential to treat brain injury and the resulting loss of neural function, memory and mental impairment as assessed by studies in various animal models. However, limited data are available on the pharmacokinetics of S-ORT in humans, so the present study was designed to evaluate the safety and pharmacokinetic profile of S-ORT in healthy volunteers. In part 1, subjects were intravenously administered single ascending dose (2.0, 4.0 and 8.0 g) S-ORT. In part 2, subjects were treated at a single intravenous infusion dose of 3.0 g S-ORT or 6.0 g racemic ORT using a two-sequence, two-period crossover design. In part 3, subjects were intravenously injected with 4.0 g S-ORT once a day for 7 days. Blood and urine samples were collected to evaluate the pharmacokinetic parameters and urine excretion rate. The safety profile of the drug was also evaluated throughout the study. Fifty-two subjects (30 in part 1, 12 in part 2, 10 in part 3) completed the study; only one subject displayed a mild adverse event, which possibly was treatment related, and no serious adverse event occurred. In part 1 for a single dose of 2.0, 4.0 and 8.0 g, the maximum concentration (Cmax) values were 111.28±18.99, 230.76±29.16 and 352.67±42.94 μg/ml, respectively; the values of area under the plasma concentration-time curve (AUC) from time zero to the time of last quantifiable concentration (AUC0-t) were 267.09±59.66, 524.50 ±72.87 and 822.68±95.21 μg·h/ml, respectively; the AUC from 0 h to infinity (AUC0-∞) values were 274.72±61.65, 536.06±78.13 and 832.07±96.91 μg·h/ml, respectively. The urine excretion rate of the unchanged drug was approximately 60%. After consecutive administration of S-ORT for 7 days, the accumulation index was 1.05±0.08. The plasma drug concentration-time curves for both S-ORT and R-oxiracetam (R-ORT) were almost identical. S-ORT was well tolerated, and no serious adverse events occurred in 2.0, 4.0 and 8.0 g in single- and 4.0 g in multiple-dose studies. S-ORT showed dose linearity with increasing doses and no drug accumulation after 7 days of continuous administration was observed.

Population pharmacokinetics of buprenorphine following a two-stage intravenous infusion in healthy volunteers

The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only. Twenty-three healthy male volunteers aged 21-40 years received 0.6 mg buprenorphine by means of an i.v. infusion over a 150-min period. The plasma concentration-time profiles up to 24 h post-administration of the infusion were subjected to population pharmacokinetic modelling using NONMEM: software. A three-compartment model best described the plasma concentration-time course. Body weight was found to be a significant covariate for elimination clearance in a linear fashion. Inter-individual variability (coefficient of variation) was estimable for apparent clearance (CL, 23.5%), central distribution volume (V(1), 81.8%), peripheral distribution volume 1 (V(2), 23.7%) and inter-compartmental clearances between V(1) and V(2) (Q(2), 34.8%). Models using parameters derived from previous published data obtained after an i.v. bolus of buprenorphine were found to overestimate the measured buprenorphine concentrations during the course of the i.v. infusion and to underpredict those following the end of the infusion. Most parameters describing the disposition of buprenorphine in the volunteers showed only moderate inter-subject variability. However, the parameters differed from those previously reported for i.v. bolus administration. We conclude that pharmacokinetic parameter estimates obtained from the appropriate study in accordance to the mode of administration should be used in the design of dose regimens of buprenorphine.

Identification of metabolites of [14C]zonampanel, an α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist, following intravenous infusion in healthy volunteers

This study determined the pharmacokinetics, metabolism and excretion of an α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist zonampanel monohydrate (YM872) after intravenous infusion of [14C]YM872 at 1 mg kg−1 h−1 for 2 h to four healthy male volunteers. Mean pharmacokinetic parameters of unchanged YM872 were 0.78 h for terminal half-life, 25.9 l h−1 for total clearance, 22.9 l h−1 for renal clearance, and 15.6 l for volume of distribution at steady-state. Urinary excretion of radioactivity accounted for 94.9% of the dose, and faecal excretion for only 0.5% of the dose. Measurement of YM872 concentrations by a high-performance liquid chromatography (HPLC)-ultraviolet method and radiometric HPLC metabolite profiling revealed that almost all of [14C]YM872 was excreted unchanged in the urine and that unchanged [14C]YM872 was the major circulating [14C] component in the plasma. Two minor metabolites, H1 and H2, detected in the urine and identified as the same chemical structures as those of the rat urinary metabolites, have a hydroxyamino group and an amino group, respectively, which were probably formed by reduction of the nitro group of YM872. These results show that virtually all of the administered YM872 remains unchanged, with urinary excretion representing the major elimination pathway. The high renal clearance implies tubular secretion of this drug.

Pharmacokinetics and pharmacodynamics of aztreonam administered by continuous intravenous infusion

The pharmacodynamic parameter that appears to correlate best with a successful therapeutic outcome with beta-lactam antibiotics is the length of time the serum antibiotic concentration remains above the minimum inhibitory concentration (MIC) for the infecting pathogen. By maximizing this parameter, continuous administration of beta-lactam and related antibiotics by intravenous infusion could represent the optimal mode of drug administration. The pharmacokinetic and pharmacodynamic properties of ceftazidime administered by continuous intravenous infusion have been evaluated previously. Aztreonam is a monobactam antibiotic with similar pharmacokinetic and microbiologic activity to that of ceftazidime. This study evaluated the pharmacokinetic and pharmacodynamic characteristics of aztreonam administered as a continuous intravenous infusion in healthy volunteers against multiple clinical isolates. Five men and 3 women received 6 g of aztreonam administered by continuous intravenous infusion over 24 hours. Blood samples were collected before the infusion and at 0.5, 1 through 8, 12, 18, and 24 hours after the start of the infusion. Pharmacokinetic parameters were determined by standard equations. In vitro susceptibility testing was performed using National Committee for Clinical Laboratory Standards guidelines for 4 clinical isolates of gram-negative bacteria (2 each of Escherichia coli and Pseudomonas aeruginosa). Serum inhibitory titers (SITs) were determined in duplicate for each clinical isolate at 0 and 24 hours. The subjects' mean (D) age was 29.3 .4 years; mean weight, 74.6 4.0 kg; and calculated mean creatinine clearance, 107 3 mL/min. For the pharmacokinetic parameters, mean (D) values were as follows: steady-state serum concentration, 40.9 .8 μg/L; halflife, 1.5 .4 hours; elimination rate constant, 0.50 ±0.13 hours −1; steady-state volume of distribution, 0.18 .04 L/kg; and total body clearance, 6.1 .2 L/h. The MICs were 0.0625 and 0.125 μg/mL against the 2 E coli isolates and 4 μg/mL against both P aeruginosa isolates. The median SITs against the E coli isolates were 1:256 and 1:512, and against the P aeruginosa isolates were 1:8 and 1:16. At steady state, 11 subjects had serum concentrations of aztreonam ≥4 times the MIC for each organism. These findings suggest that further clinical study of the administration of aztreonam by continuous intravenous infusion is warranted.

Evaluation of the development of acute tolerance to the psychomotor effects of midazolam following intravenous infusions in healthy volunteers

AbstractThe effect on digit‐symbol substitution (DSST) of duration and extent of exposure to midazolam was studied in seven healthy male volunteers. Individual pharmacokinetic and pharmacodynamic parameters were estimated after a 7·5 mg intravenous bolus dose of midazolam. Subjects then received, in a double‐blind crossover design, loading doses of midazolam and steady‐dose infusions to provide (A) 25 per cent of maximal effect (Emax) for 6h, (B) 50 per cent of Emax for 3 h, (C) 75 per cent of Emax for 2 h, and (D) 0 per cent of Emax (placebo). Infusions A‐C were designed to yield a similar area under the effect curve (AUEC) during the infusion. DSST was assessed during the infusion and after a 3·75 mg IV midazolam challenge dose given at 6 h after infusion start. Actual decrements in DSST scores during infusions were 40·2 per cent, 60·7 per cent, and 86·8 per cent at 1 h for infusions A‐C, respectively. The degree of tolerance was assessed by calculating an effect ratio: ER = peak challenge dose DSST decrement/challenge dose Cmax. ER's for treatments A‐C and were 69·9 per cent, 79·3 per cent, and 68·4 per cent, respectively, of the control value; treatment A and CER's were significantly different from control. There were no significant differences among infusions A‐C in ER or AUEC. These results show that, in subjects who are relatively sensitive to the effects of midazolam, tolerance develops acutely to the effects of midazolam and suggest that tolerance is dependent on both the time and extent of exposure.

Dose dependent pharmacokinetics of nitroglycerin after multiple intravenous infusions in healthy volunteers.

Evaluation of the pharmacokinetics of nitroglycerin has been hindered in the past by the lack of specific and sensitive analytical procedures, and the unavailability of parenteral nitroglycerin and infusion sets which did not adsorb nitroglycerin. The purpose for this present study was to determine the pharmacokinetic parameters of nitroglycerin and the dinitrate metabolites after multiple intravenous infusions of nitroglycerin in healthy volunteers. Six volunteers received variable infusion rates of nitroglycerin. Generally, at 0, 40, 80, and 120 min, the infusion rates were adjusted to 10, 20, 40, and 10 micrograms/min, respectively. Plasma samples were drawn and analyzed for nitroglycerin and its 1,2- and 1,3-dinitrate metabolites using capillary GC. Steady-state nitroglycerin plasma concentrations attained at 10, 20, 40, and 10 micrograms/min were 0.44 +/- 0.31, 1.32 +/- 0.71, 4.23 +/- 1.50 and 1.04 +/- 0.43 ng/ml, respectively. As the infusion rate was increased, the steady-state concentrations increased disproportionately. When the dose was decreased from 40 to 10 micrograms/min, the steady-state nitroglycerin concentrations were always higher than those at the initial low infusion rate. Thus, in the majority of subjects, a hysteretic type of response was present. The hysteresis observed in the dose versus steady-state concentration curve may be explained by either end-product inhibition or saturable binding of nitroglycerin to blood vessels. The clearance values (5.5 to 711/min) were very high and far exceed the maximum possible hepatic clearance suggesting that nitroglycerin is metabolized by organs other than liver. Clearance was not directly related to plasma concentrations but was found to decrease to a constant value (approximately 11 +/- 6 l/min) as nitroglycerin concentrations initially increased.