Overall pharmacokinetics during prolonged treatment of healthy volunteers with digoxin andβ-methyldigoxin

Summary Five healthy volunteers received digoxin 0.4 mg or -methyldigoxin 0.4 mg i. v., daily for 14 days, in a randomized cross-over arrangement. By monitoring minimal plasma concentrations during multiple dosing, it was found that the steady state pharmacokinetics of digoxin and -methyldigoxin could be estimated even better by a one-compartment than by a two-compartment model. The following mean parameters were calculated: the half life of digoxin of 1.54±0.31 days was significantly shorter than the half life of 2.29±0.34 days for -methyldigoxin. The distribution volume of 807±187 liters for digoxin was not significantly larger than the 735±227 liters for -methyldigoxin. Renal digoxin clearance of 191±25 ml/min was significantly higher than both the renal clearance of -methyldigoxin of 111±23 ml/min and also the creatinine clearance, which indicates tubular secretion of digoxin. There was a 2.8-fold accumulation of -methyldigoxin injected once a day, which was significantly higher than the 1.8-fold accumulation of digoxin.Abbreviations of parameters D dose - EST estimated disposition rate constant (day^–1) semilog curve fit - KTOT total disposition rate constant (day^–1) NONLIN fit - KREN renal disposition rate constant (day^–1) NONLIN fit - VOL volume of distribution (liters) NONLIN fit - CTOT total clearance (ml/min) - CREN renal clearance (ml/min) - BMIN body stores (µg) before next dose in steady state - CCR creatinine clearnace (ml/min) - CR/CT fraction renally excreted - CR/CCR renal drug clearance versus creatinine clearance - T/2 half life (days) - BMIN/D extent of accumulation This study was supported by Bundesministerium für Jugend, Familie und Gesundheit, Federal Republic of Germany.     

Pharmacokinetics of nisoldipine in Chinese healthy volunteers

AIM: To study PK profile of nisoldipine (Nis, imported) in 8 Chinese healthy volunteers. METHODS: Single-dose of Nis was given po. A selective RP-HPLC method was established to determine phasma concentrations of Nis.     

Bioequivalence study of fusidicacid suspension in healthy volunteers

依诺沙星分散片的人体相对生物利用度研究@韩仰$Institute of Clinical Pharmacology, Xiangya Medical College, Central South University!Changsha 410078,Hunan,China @谭志荣$Institute of Clinical Pharmacology, Xiangya Medical College, Central South University!C     

Drug–drug interaction of rabeprazole and clopidogrel in healthy Chinese volunteers

Purpose

This study was aimed to determine the impact of rabeprazole (RBRZ) on the antiplatelet efficacy of clopidogrel (CPG) in healthy Chinese volunteers, and further to predict the effect of CYP2C19 genetic polymorphism on the efficacy of rabeprazole and clopidogrel.

Methods

The open-label, two period cross-over study was conducted in 20 healthy Chinese subjects with different CYP2C19 genotypes receiving clopidogrel, rabeprazole or the two drugs, respectively. All the volunteers were divided into two groups, poor metabolizers (PMs) and extensive metabolizers (EMs), depending on CYP2C19 genotypes. Blood samples were collected at baseline and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h after administration. The plasma concentrations of rabeprazole and clopidogrel were analyzed by LC-MS/MS and ADP-induced platelet aggregation was detected by the optical turbidimetric method.

Results

There were no significant differences in the mean plasma concentration–time curves of clopidogrel (CPG), the inactive metabolite clopidogrel carboxylic acid (CPG-CA), the active metabolite clopidogrel-MP-Derivative (MP-AM), and rabeprazole (RBRZ) according to the co-administration of CPG and RBRZ. There were no major changes in the pharmacokinetics of CPG and RBRZ. The maximal ADP-induced platelet aggregation (2 μmol/L) was decreased in EMs compared with PMs.

Conclusion

Co-administration of rabeprazol and clopidogrel did not affect the antiplatelet efficacy of clopidogrel. The CYP2C19 genetic polymorphism may impact the efficacy of clopidogrel.     

Functional capacity in healthy volunteers before and following β-blockade with controlled-release metoprolol

The effects of the ₁-selective -adrenergic blocker metoprolol on physiological responses, exercise capacity and gas exchange parameters were measured in healthy men using different graded bicycle exercise protocols on separate days before and following administration of 200 mg controlled-release metoprolol. Eleven men performed in randomised order maximal cardiopulmonary exercise testing on 50-W/6-min stage, 50-W/3-min stage and ramp (15-W/min^–1) protocols. Peak heart rate and peak heart rate-blood pressure products were similar on all exercise protocols, and were significantly reduced by metoprolol. Submaximal and peak oxygen consumption were similar before and following -adrenoceptor blockade. Depending on the exercise protocol applied, an insignificant decrease of 4–10% in maximal cumulated exercise capacity (work-rate × time integral) was observed following administration of metoprolol. It is concluded that in healthy men evaluated with different exercise protocols the ₁-selective controlled-release -adrenoceptor blocker metoprolol does not influence exercise capacity despite a marked reduction of heart rate and rate-pressure product.     

Population pharmacokinetics and exposure–response modeling and simulation for evolocumab in healthy volunteers and patients with hypercholesterolemia

Evolocumab, a novel human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets low-density lipoprotein-cholesterol (LDL-C) receptors for the treatment of hyperlipidemia. The primary objective of this analysis was to characterize the population pharmacokinetics (popPK) and exposure–response relationship of evolocumab to assess if dose adjustment is needed across differing patient populations. Data were pooled for 5474 patients in 11 clinical studies who received evolocumab doses of 7–420 mg at various frequencies, either intravenously or subcutaneously. Evolocumab area under concentration–time curve from 8 to 12 weeks (AUC_wk8–12) was simulated for individuals using the popPK model and was used to predict the LDL-C response in relation to AUC_wk8–12. Evolocumab was eliminated through nonspecific (linear) and target-mediated (nonlinear) clearance. PopPK parameters and associated variabilities of evolocumab were similar to those of other monoclonal antibodies. The exposure–response model predicted a maximal 66% reduction in LDL-C from baseline to the mean of weeks 10 and 12 for doses of evolocumab 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. After inclusion of statistically significant covariates in an uncertainty-based simulation, LDL-C reduction from baseline at the mean of weeks 10 and 12 was predicted to be within 74% to 126% of the reference patient for all simulated patient groups. Evolocumab had nonlinear pharmacokinetics. The range of responses based on intrinsic and extrinsic factors was not predicted to be sufficiently different from the reference patient to warrant evolocumab dose adjustment.     

Urinary γ-hydroxybutyrate concentrations in 1126 female subjects

γ-Hydroxybutyrate (GHB) and its metabolic precursor γ-butyrolactone (GBL) are often implicated in cases of drug-facilitated sexual assault (DFSA), although definitive confirmation of GHB/GBL ingestion is complicated by GHB's endogenous nature and rapid elimination following ingestion. Multiple studies have attempted to establish a discriminant limit (generally 10 mg/L) above which urinary GHB concentrations can be considered consistent with GHB/GBL consumption. To supplement the currently available data, a rapid gas chromatography-mass spectrometry method was developed and validated for the analysis of GHB (following acidic conversion to GBL) and used to analyze urine samples collected from 1126 women (mean = 0.84 mg/L, median = 0.68 mg/L, range = 0.00-5.5 mg/L). GHB concentrations were shown to be independent of urinary pH (within the range 4.6-9.3), age (within the range 18-35 years), body mass index (within the range 13.8-36.3), and race. Adjusting GHB concentrations with respect to urinary specific gravity had little effect on the mean value (0.91 mg/L) and range (0.0-7.76 mg/L), although a statistically significant trend of increasing GHB concentration with specific gravity could be observed. Our results can be taken to offer further support for the 10 mg/L discriminant limit for GHB administration in antemortem urine samples.     

Pharmacokinetics and bioequivalence of two brands of metformin 500 mg tablets in Iranian healthy volunteers

The aim of this study was to evaluate the pharmacokinetics (PK) and bioequivalence (BE) of two metformin tablets. For in vitro evaluation, weight variation, assay and dissolution tests were performed. A randomized, single dose, two-period, cross over study in healthy male fasting volunteers was designed. A 2-week washout period separated the two periods. For analysis of PK parameters blood sampling was performed before and after drug administration in various time points up to 12 h. Metformin concentration in plasma was determined using a developed high performance liquid chromatography method. Both formulations passed the assay, content uniformity, and dissolution tests acceptance value. PK parameters, representing the rate and the extent of metformin absorption were calculated and analyzed for two formulations. The 90 % CI obtained by analysis of variance for the ratios of C_max, AUC_0–t, and AUC_0–∞ were 92.14–110.95, 92.72–107.37 and 89.42–110.23 % respectively, meeting the criteria for BE (80–125 %). Administration of a single dose of test and reference formulations did not result in statistically significant differences between in vitro and in vivo BE parameters in healthy Iranian male volunteers. Thus in the case of rate and extent of absorption the test and reference formulations were considered bioequivalent.     

Pharmacokinetic–pharmacodynamic modelling of intravenous and oral topiramate and its effect on phonemic fluency in adult healthy volunteers

Aims

The aim was to develop a quantitative approach that characterizes the magnitude of and variability in phonemic generative fluency scores as measured by the Controlled Oral Word Association (COWA) test in healthy volunteers after administration of an oral and a novel intravenous (IV) formulation of topiramate (TPM).

Methods

Nonlinear mixed-effects modelling was used to describe the plasma TPM concentrations resulting from oral or IV administration. A pharmacokinetic–pharmacodynamic (PK-PD) model was developed sequentially to characterize the effect of TPM concentrations on COWA with different distributional assumptions.

Results

Topiramate was rapidly absorbed, with a median time to maximal concentration of 1 h and an oral bioavailability of ∼100%. Baseline COWA score increased by an average of 12% after the third administration on drug-free sessions. An exponential model described the decline of COWA scores, which decreased by 14.5% for each 1 mg l⁻¹ increase in TPM concentration. The COWA scores were described equally well by both continuous normal and Poisson distributions.

Conclusions

This analysis quantified the effect of TPM exposure on generative verbal fluency as measured by COWA. Repetitive administration of COWA resulted in a better performance, possibly due to a learning effect. The model predicts a 27% reduction in the COWA score at the average observed maximal plasma concentration after a 100 mg dose of TPM. The single-dose administration of relatively low TPM doses and narrow range of resultant concentrations in our study were limitations to investigating the PK-PD relationship at higher TPM exposures. Hence, the findings may not be readily generalized to the broader patient population.     

Pharmacokinetics and pharmacodynamics of cicaprost in healthy volunteers after oral administration of 5 to 20 μG

Summary In a Phase I study, the tolerability, pharmacodynamics and pharmacokinetics of cicaprost have been investigated in 6 male volunteers given 5, 10, 15 and 20 g as tablets of the -cyclodextrin clathrate.Individual inhibition of platelet aggregation and changes in facial colour (measured by chromametry) were dose-dependent and reached a maximum 30 to 60 min post-dose. The maximum inhibition of platelet aggregation was about 40%. After 3 to 4 h pre-treatment values had returned. Blood pressure remained within the normal range. The peak plasma level of cicaprost was reached within 15 to 90 min after drug intake. Both C_max-and AUC were individually dose-dependent. The terminal half-life in plasma of cicaprost was approx. 1 h, and its total clearance amounted to 4–7 ml·min^–1·kg^–1. The time courses of the plasma levels and of the pharmacodynamic actions were in agreement. Interindividual differences were observed in the occurrence of unwanted effects (e.g. headache).Thus, cicaprost is an orally available PGI₂-mimetic, for which effects on platelet aggregation and vascular perfusion have been demonstrated in healthy volunteers after doses of 5 to 15 g.The results will form part of the M.D. thesis of T.Staks. Some of the findings were presented at the CPT meeting, Mannheim/Heidelberg, 1989     

Ketamine impairs response inhibition and is positively reinforcing in healthy volunteers: a dose–response study

Rationale Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that has medical indications but is also used as a recreational drug. Previous research has found persisting cognitive and psychotogenic effects of ketamine in chronic abusers of this drug 3 days after an acute dose.Objective The present study aimed to investigate the effects of ketamine on two processes related to drug abuse, response inhibition and reinforcement, and to examine whether an acute dose of ketamine produced residual cognitive effects in healthy volunteers.Methods Fifty-four healthy volunteers were given an 80-min infusion of one of two doses (0.4, 0.8 mg kg^–1) of ketamine or placebo. Subjects completed a battery of tests at three time points: pre-infusion, during the infusion and 3 days later at follow-up. The battery consisted of tests of episodic and semantic memory, schizophrenic-like and dissociative symptoms, response inhibition and measures of subjective effects, including mood, bodily symptoms and enjoyment of and desire for the drug.Results Ketamine acutely impaired response inhibition and had related biphasic effects on the subjective reinforcing effects of the drug. Ketamine also acutely impaired episodic but not semantic memory and increased schizophrenic-like and dissociative symptoms. No residual cognitive effects were observed 3 days following an acute dose.Conclusions The lack of residual effects in healthy volunteers on day 3 indicates that impairments found on day 3 in ketamine abusers are chronic effects. The abuse of ketamine may be related to its capacity both to reinforce and to decrease response inhibition.     

Assessment of absolute oral bioavailability of linezolid tablets in Chinese healthy male volunteers

AIM： Linezolid is a member of oxazolidinones, which is a novel class of antibiotics. The study is to determine the absolute bioavailability of linezolid tablets in Chinese healthy male volunteers. METHODS： A randomized, open cross-over study was conducted in 22 healthy male volunteers, a single oral dose of 600 mg linezolid tablets or Ⅳ infusion of 600 mg linezolid were given to subjects, respectively. Blood sampies were obtained at different time points and sent to American AvTech laboratories. Plasma concentrations of linezolid were determined by high-performance liquid chromatography （HPLC）, pharmacokinetic parameters and absolute bioavailability were calculated. RESULTS： After oral and IV infusion administration of 600 mg linezolid, the elimination half-life （ t1/2 ） was （4.3 ± 1.0） h and （4.4±0.9） h, respectively. The area under plasma concentration-time curve （AUC0-∞ ） of linezolid were （87 ± 20） μg·mL^-1·h and （96 ± 21） μg·mL^-1·h, respectively. The absolute oral bioavailability was 93 % ± 23 % following single oral dose of 600 mg linezolid tablets. Analyses of two one-sided t tests and 90% confidence interval showed that linezolid tablet and Ⅳ formulation are equivalent with respect to AUC.[第一段]     

Determination of talinolol tablets plasma concentration in healthy volunteers by LC-MS/MS

AIM： To establish an LC-MS/MS method for determination of talinolol in human plasma. METHODS： Propranolol was added as internal standard before extraction. The analysis involved a Cosmosil C18 （2.0 mm × 150 mm, 5 μm） column and the column temperature was set at 40℃. The mobile phase included in acetonitrile： 10 mmol ammonium formate water solution （with 0.05% formic acid） （60： 40, v/v）,the flow rate was 0.2 mL/min. ESI ＋ was performed in the MRM mode using target ions at m/z 364- 308 （talinolol） and m/z 260 - 184 （propranolol）.[第一段]     

Bioequivalence study of 2 orodispersible formulations of ondansetron 8 mg in healthy volunteers

This study was designed to compare the rate and extent of absorption of 2 oral formulations of ondansetron (CAS 99614-02-5) 8?mg orodispersible tablets in healthy volunteers. 22 subjects were administered ondansetron orodispersible tablets of test and reference formulation in a single-dose, 2-period, 2-sequence, fasting, open-label, crossover and randomised study. Plasma concentrations were determined by LC/MS/MS. Log-transformed AUCs and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). Tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80-125%. According to the European Guideline [1] it may be therefore concluded that test formulation of ondansetron 8?mg orodispersible tablet is bioequivalent to the reference formulation.     

Cognitive, psychomotor and actual driving performance in healthy volunteers after immediate and extended release formulations of alprazolam 1 mg

Rationale Alprazolam extended-release (XR) is approved for the treatment of panic disorder. This sustained formulation is absorbed in a delayed manner and is therefore expected to produce fewer and less severe side effects than its immediate release equivalent (alprazolam IR). The effect of alprazolam XR on potentially dangerous daily activities, such as driving a car, is expected to be less as compared to alprazolam IR. Objectives The present study was designed to compare the effects of alprazolam XR (1 mg) and alprazolam IR (1 mg) on actual driving ability and cognitive function. Method Eighteen healthy volunteers (aged 20–45 years) participated in a double-blind, placebo-controlled, three-way crossover study. At 4 h post-dose, subjects performed a standardized driving test on a primary highway in normal traffic. Cognitive and psychomotor tests were assessed 1, 2.5, and 5.5 h post-dose. Memory functioning was measured only 1 h after administration. Results Both formulations severely impaired driving performance between 4 and 5 h after administration. The magnitude of impairment in the driving test observed with alprazolam XR was about half that observed with alprazolam IR. Laboratory test results were in line with the driving data. Conclusions The acute impairing effects of alprazolam XR 1 mg on driving and psychomotor functions were generally less, as compared to its immediate-release equivalent, but still of sufficient magnitude to increase the risk of becoming involved in traffic accidents.     

Pharmacokinetic and bioequivalence study of endogenous compound tretinoin 10 mg capsules in healthy volunteers by base line correction approach

Tretinoin belongs to the class of retinoids indicated in induction of remission in acute promyelocytic leukemia (APL-FAB classification AML-M3). It is an endogenous metabolite of Vitamin A and is normally present in human plasma. The objective of the present study was to evaluate the bioequivalence between the Tretinoin 10?mg capsules of Ranbaxy Laboratories Limited and VESANOID^® 10?mg capsules of Roche Pharmaceuticals Inc. It was a 2-way cross-over single dose study in 60 adult Indian male volunteers under fasting conditions. Since tretinoin is endogenously present in the human body, for baseline adjustment four pre-dose samples were collected. Plasma samples were analyzed for tretinoin by using validated liquid chromatographic mass spectrometry (LC-MS/MS) method. This method has separated both isomeric metabolites (i.e. isotretinoin and 9-oxo retinoic acid) from tretinoin to accurately measure the tretinoin concentrations in plasma for this study. The Mean ± SD of pharmacokinetic parameters T_max, C_max, and AUC_0?t for tretinoin were 2.55?±?0.84 and 2.40?±?0.86?h, 34.29?±?10.45 and 32.77?±?9.16?ng/ml, 87.28?±?30.99 and 80.81?±?24.68?ng.h/ml, respectively, for test and reference. The ratios of least square means and its 90% confidence interval for C_max, AUC_0?t and AUC_0–∞ on both baseline corrected and uncorrected data were found to be within 80–125%.     

Do cardiac glycosides affect platelet function? A flow cytometric study in healthy volunteers

OBJECTIVE: Cardiac glycosides exert their inotropic effect by increasing intracellular calcium. Increased intracellular calcium is a key event in platelet aggregation. In aggregometer studies, digitalis has been found to augment platelet agonist responses. A prothrombotic effect of digitalis might be concealed since heart failure and atrial fibrillation per se predispose to thromboembolism. The present study investigates the effects of digitoxin on platelet function in healthy volunteers. METHODS: Twenty healthy, non-smoking volunteers were randomised to receive digitoxin ( n = 10, 0.6 mg day 1, 0.4 mg day 2, then 0.1 mg daily) or placebo ( n = 10) for 10 days. Platelet function was then analysed ex vivo using three-colour whole-blood-flow cytometry, both in non-stimulated mode and after agonist stimulation with 0.1 micromol/l adenosine diphosphate (ADP), 10 micromol/l ADP and 5.0 micromol/l epinephrine (final concentrations). Expression of activated fibrinogen receptor, von Willebrand's factor receptor and P-selectin, formation of platelet-platelet and platelet-leukocyte aggregates and particle size were examined. RESULTS: No significant difference between the placebo and the digitoxin group (digitoxin levels 17-42 nmol/l) was found, neither on a global level nor for any isolated parameter. CONCLUSIONS: Theory and in vitro data suggest that digitoxin treatment could activate platelets. No evidence for this was found in healthy volunteers. This observation is strengthened by the unequivocal results for all parameters measured. However, thrombosis-prone patients with heart failure and/or atrial fibrillation may respond differently to digitalis therapy.