Comparative pharmacokinetics of midazolam and loprazolam in healthy subjects after oral administration

The pharmacokinetics of oral midazolam (Dormicum, 15 mg) and loprazolam (Dormonoct, 1 mg) were studied in eight healthy young volunteers in a cross-over design. Plasma concentrations of midazolam were measured with a gas chromatographic method and loprazolam concentrations were determined by a radio-receptor technique. Absorption of midazolam proceeded very rapidly (median tmax = 0.4 h) and a rapid onset of sedative action was observed. Loprazolam absorption was relatively slow (median tmax = 3 h) and its absorption profile was often irregular. Most subjects fell asleep before peak concentrations were reached. Median peak concentrations were 94 ng ml-1 and 3.1 ng ml-1 for midazolam and loprozolam, respectively. The median elimination half-life of midazolam was 1.8 h and that of loprazolam 15 h. It is possible that the elimination half-life of loprazolam as determined by radioreceptor assay is determined by active metabolites rather than by loprazolam itself. Midazolam elimination half-life was the same when determined by radioreceptor assay or by GLC. There was no significant correlation between the half-lives of the two drugs.     

The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics

Metformin is the most widely used drug among type 2 diabetes mellitus patients. However, drug interaction on metformin will influence its glucose-lowering effect or increase its side effect of lactic acidosis. In this study, a randomized, two-stage, crossover study was conducted to unveil the potential drug interaction between metformin and the anti-hypertension drug, telmisartan. Totally, 16 healthy Chinese male volunteers were enrolled. Blood samples from various time-points after drug adminstration were analyzed for metformin quantification. Oral glucose tolerance test (OGTT) was conducted 2 h after metformin administration. The AUC_0-12 and Cmax of metformin in subjects co-administrated with telmisartan were significantly lower than with placebo. The geometric mean ratios (value of metformin plus telmisartan phase/value of metformin plus placebo phase) for Cmax and AUC_0-12 is 0.7972 (90%CI: 0.7202–0.8824) and 0.8336 (90%CI: 0.7696–0.9028), respectively. Moreover, telmisartan co-administration significantly increased the plasma concentrations of both glucose and insulin at 0.5 h since OGTT (7.64 ± 1.86 mmol/l·min vs 6.77 ± 0.83 mmol/l·min, P = 0.040; 72.91 ± 31.98 μIU/ml·min vs 60.20 ± 24.20 μIU/ml·min, P = 0.037), though the AUC of glucose and insulin after OGTT showed no significant difference. These findings suggested that telmisartan had a significant influence on the Pharmacokinetics of metformin in healthy groups, though the influence on glucose-lowering effect was moderate.     

Evaluation of a pharmacokinetic interaction between valsartan and simvastatin in healthy subjects

ABSTRACT

Objective: The potential for a pharmacokinetic drug interaction between valsartan, an antihypertensive drug, and simvastatin, a lipid-lowering agent, was investigated in this study. This was an open-label, multiple-dose, randomized, three-period, cross over study in 18 healthy subjects. Each subject received one 160?mg valsartan tablet or one 40?mg simvastatin tablet or co-administration of valsartan (160?mg) and simvastatin (40?mg) tablets for 7 days, with a 7?day inter-dose washout period. The steady-state pharmacokinetics of valsartan, simvastatin β?hydroxy acid (active metabolite of simvastatin) and simvastatin (pro-drug) were determined on day 7 of each dosing period.

Results: The results were interpreted based on the point estimates and the 90% confidence intervals.italic> These results indicated that the area under the curve of plasma concentration from 0 to 24 hours (AUC_(0–24)) of valsartan, simvastatin β?hydroxy acid and simvastatin was increased by 14%, 19%, and 23%, respectively, with the combination treatment. In addition, the maximum concentration (C_max) of valsartan and simvastatin β?hydroxy acid was increased by 10% and 22%, respectively, and the C_max of simvastatin was decreased by 26% with the combination treatment. All treatments were safe and well tolerated.

Conclusions: Based on the wide therapeutic dosage ranges of valsartan and simvastatin, and the highly variable pharmacokinetics of three analytes, the observed differences in the exposure and C_max of valsartan, simvastatin β?hydroxy acid and simvastatin in the combination treatment are unlikely to be of clinical relevance.     

Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects

ABSTRACT

Objective: Linagliptin (BI 1356) is a novel, orally available inhibitor of dipeptidyl peptidase-4 (DPP-4). Linagliptin improves glycaemic control in type 2 diabetic patients by increasing the half-life of the incretin hormone glucagon-like peptide-1 (GLP-1). Linagliptin is expected to be used as monotherapy or in combination with other antihyperglycaemic agents. This study was conducted to investigate potential pharmacokinetic or pharmacodynamic interactions between linagliptin and metformin.

Methods: This randomised, monocentric, open-label, two-way crossover design study was conducted in 16 healthy male subjects. Linagliptin (10?mg/day)?and metformin (850?mg three times daily) were each administered alone and concomitantly. The steady-state pharmacokinetics of linagliptin and metformin and the inhibition of DPP-4 activity were determined at the end of each dosing period.

Results: Co-administration of linagliptin had no apparent effect on metformin exposure (metformin AUC_τ,ss; geometric mean ratio [GMR] co-administration:individual administration was 1.01; 90% confidence interval [CI] was 0.89–1.14). Effects on maximum concentration (C_max,ss) were small (GMR: 0.89; 90% CI: 0.78–1.00). Co-administration of metformin did not significantly affect C_max,ss of linagliptin (GMR: 1.03; 90% CI: 0.86–1.24), but increased AUC_τ,ss by 20% (GMR: 1.20; 90% CI: 1.07–1.34). Metformin alone had no effect on DPP-4 activity, and the inhibition of DPP-4 caused by linagliptin was not affected by concomitant administration of metformin. Tolerability was good whether linagliptin and metformin were administered alone or concomitantly. No serious adverse events occurred and the frequency of adverse events was low; 7 events in 6 subjects. The most frequent events were related to the gastrointestinal tract, as expected with metformin. Importantly, no subjects experienced signs or symptoms relating to episodes of hypoglycaemia.

Conclusion: In this small, multiple dose study carried out in healthy subjects, co-administration of linagliptin with metformin did not have a clinically relevant effect on the pharmacokinetics or pharmacodynamics of either agent. This study suggests linagliptin and metformin can safely be administered concomitantly in type 2 diabetes patients without dose adjustment; larger, longer-term clinical trials in diabetic patients are underway.     

Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

Objective  Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, nebicapone has showed an inhibitory effect upon CYP2C9, which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of nebicapone on warfarin pharmacokinetics and pharmacodynamics in healthy subjects. Methods  Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the nebicapone morning dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment periods were separated by a washout of 14 days. Results  For R-warfarin, mean ± SD C_max was 1,619 ± 284 ng/mL for test and 1,649 ± 357 ng/mL for reference, while AUC_0-t was 92,796 ± 18,976 ng·h/mL (test) and 73,597 ± 11,363 ng·h/mL (reference). The R-warfarin test-to-reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878–1.077) for C_max and 1.247 (1.170–1.327) for AUC_0-t . For S-warfarin, mean ± SD C_max was 1,644 ± 331 ng/mL for test and 1,739 ± 392 ng/mL for reference, while AUC_0-t was 66,627 ± 41,199 ng·h/mL (test) and 70,178 ± 42,560 ng·h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI were 0.932 (0.845–1.028) for C_max and 0.914 (0.875–0.954) for AUC_0-t . No differences were found for the pharmacodynamic parameter (INR). Conclusion  Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found but is unlikely to be of clinical relevance.     

The effect of paroxetine on the pharmacokinetics,safety, and tolerability of ramosetron in healthy subjects

Objective The aim of our study was to investigate the effects of multiple doses of paroxetine on the pharmacokinetics, safety, and tolerability of a single oral 10-μg dose of ramosetron. Methods This was an open, one-sequence crossover design study. On day 1, healthy male and female subjects were administered a single dose of 10 μg ramosetron. On the morning of day 3, the subjects were administered paroxetine to reach steady state, which consisted of morning doses of 20 mg on days 3–12. The dose on day 11 was administered in combination with a single dose of 10 μg ramosetron. Results In subjects genotyped as extensive CYP2D6 metabolizers, coadministration of paroxetine with ramosetron resulted in an increase in area under the curve from 0 to infinity (AUC_0-inf) and the peak concentration (C_max) of ramosetron by 1.14-fold (90% confidence interval (CI): 1.07–1.22) and by 1.06-fold (90% CI: 1.00–1.11), respectively. Conclusions It can be concluded that the single-dose pharmacokinetic profile of ramosetron 10 μg is not affected to a clinically relevant degree by paroxetine 20 mg once daily administered for 10 days.     

The effect of fluvoxamine on the pharmacokinetics, safety, and tolerability of ramosetron in healthy subjects

Objective  To investigate the effects of multiple doses of fluvoxamine on the pharmacokinetics, safety, and tolerability of a single oral 10-μg dose of ramosetron. Methods  This was a single-center, open, one-sequence cross-over study. On Day 1, healthy male and female subjects were administered a single dose of 10 μg ramosetron. Dosing of fluvoxamine started with an initial morning dose of 50 mg on Day 3, followed by a twice daily (12-h interval) dosing of 50 mg on Days 4–12. The morning dose on Day 11 was administered in combination with a single dose of 10 μg ramosetron. Results  Co-administration of fluvoxamine with ramosetron resulted in an increase in the C_max and AUC_0-inf of ramosetron by 1.42-fold (90% CI 1.35–1.49) and 2.78-fold (90% CI 2.53–3.05), respectively. Conclusion  Co-administration of the CYP1A2 inhibitor fluvoxamine with ramosetron resulted in an interaction. However, the safety data collected during the study do not indicate that this interaction will cause any major safety concerns.     

A study of the effects of zimeldine on the pharmacokinetics and pharmacodynamics of temazepam in healthy volunteers

In this double-blind two-period crossover study, ten healthy volunteers received either 200 mg zimeldine each morning for 5 days, or placebo on the same schedule. On day 5 they received 20 mg temazepam 2 h after zimeldine or placebo. A battery of psychometric tests and subjective measurements was carried out on days 4 and 5. Blood samples were collected on day 5 for pharmacokinetic analysis of temazepam.All the measures of psychomotor performance showed the effects of temazepam, as did two of the subjective measures, the alert/drowsy and steady/dizzy visual analogue scales. No effect of zimeldine alone on performance or subjective state was seen. Zimeldine showed no discernible interaction with the effects of temazepam as assessed by subjective reports, by psychomotor tests, or by pharmacokinetic analysis.     

Dopamine and human information processing: a reaction-time analysis of the effect of levodopa in healthy subjects

RATIONALE: Dopamine is involved in a variety of motor and non-motor information-processing operations. One way to determine its contribution to human information processing is to study reaction time (RT) performance after oral absorption of its precursor, levodopa, which increases its concentration in the nervous system. OBJECTIVE: The purpose of the present study was to investigate the effect of a single dose of levodopa on information processing in healthy human subjects using the additive-factor method. After oral absorption of a single dose of levodopa (200 mg) or a placebo (randomized, double-blind, cross-over design), eight adults (aged 21-28 years, mean 25 years) performed a two-choice visual RT task. Signal intensity, stimulus-response mapping and foreperiod duration were manipulated. RESULTS: The effects of these three variables were found additive on RT, indicating that that three independent stages - namely, stimulus preprocessing, response selection and motor adjustment - were manipulated. Levodopa improved RT performance in a specific way: it interacted with signal intensity but its effect was additive with those of stimulus-response mapping and foreperiod duration. CONCLUSION: These results show that levodopa specifically affects the stimulus preprocessing stage, which suggests that the dopaminergic system plays a role in sensory processing, possibly by acting on the level of arousal.     

Sibutramine pharmacokinetics in young and elderly healthy subjects

Objective: To investigate the pharmacokinetics of the pharmacologically active metabolites of sibutramine (metabolites 1 and 2) in healthy young and elderly volunteers following a single oral dose of sibutramine. Methods: This was an open, parallel-group study completed by 12 young (six male, six female; mean age 24.0 years) and 12 elderly (six male, six female; mean age 70.3 years) healthy volunteers. Blood samples were taken at intervals up to 48 h post-dose. Plasma concentrations of metabolites were determined using HPLC-MS. Model-independent pharmacokinetic parameters of the two metabolites were compared for the two age groups. Results: The similarity of the plasma profiles of the two desmethyl metabolites showed that despite the possibility of reduced hepatic function due to age, the rate and extent of formation of these was the same in both young and elderly, i.e. sibutramine metabolism was not impaired in elderly subjects. There were also no significant differences in elimination of metabolite 2 between groups, although the elderly group showed a slight trend for a reduction in k_el. Conclusions: The pharmacokinetics of the two pharmacologically active metabolites of sibutramine (metabolites 1 and 2) were not significantly different between the young and elderly groups in this study. Based on this information, a similar dosing regimen would be appropriate for both the young and elderly. Received: 8 June 1998 / Accepted in revised form: 18 September 1998     

The pharmacokinetics of lamivudine in healthy Chinese subjects

AIMS: The purpose of this study was to investigate the pharmacokinetics of daily oral doses of lamivudine administered to healthy Chinese subjects for 1 week. METHODS: Twenty-four subjects were enrolled, 12 males and 12 females, all between the ages of 18 and 40 years. After an overnight fast, all subjects received a single oral dose of 100 mg lamivudine. Blood was obtained before lamivudine administration and at regular intervals to 24 h post dose. Subsequent doses were given once daily for a total of 7 days. On the last day another full pharmacokinetic profile was obtained to 24 h postdose. Timed urine collections were performed for all subjects on day 1 only. Pharmacokinetic parameters were calculated by using standard non compartmental techniques. RESULTS: Lamivudine was well absorbed in all subjects (tmax 1 h). On day 1 and day 7 the overall geometric mean Cmax was 1304 and 1385 ng ml-1, and AUC(0,24h) was 4357 and 4353 ng ml-1 h, respectively. On average 78% of the lamivudine dose was recovered in urine as parent compound. Pharmacokinetic parameters were very similar between male and female subjects, between day 1 and day 7 and in comparison with data obtained in many other pharmacokinetic studies. CONCLUSIONS: This study demonstrated that the pharmacokinetics of lamivudine are essentially identical between Chinese and Caucasian subjects, and between males and females. It confirms 100 mg lamivudine is an appropriate dose for use in Chinese patients, providing adequate exposure for optimal antiviral effect.     

Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil

Aim It has been reported that verapamil and atorvastatin are inhibitors of both P-glycoprotein (P-gp) and microsomal cytochrome P450 (CYP) 3A4, and verapamil is a substrate of both P-gp and CYP3A4. Thus, it could be expected that atorvastatin would alter the absorption and metabolism of verapamil. Methods The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared after oral administration of verapamil (60 mg) in the presence or absence of oral atorvastatin (40 mg) in 12 healthy volunteers. Results Pharmacokinetics of verapamil were significantly altered by the coadministration of atorvastatin compared with those of without atorvastatin. For example, the total area under the plasma-concentration time curve to the last measured time, 24 h, in plasma (AUC_{0−24 h}) of verapamil increased significantly by 42.8%. Thus, the relative bioavailability increased by the same magnitude with atorvastatin. Although the AUC_{0−24 h} of norverapamil was not significantly different between two groups of humans, the AUC_{0−24 h, norverapamil}/ AUC_{0−24 h, verapamil} ratio was significantly reduced (27.5% decrease) with atorvastatin. Conclusion The above data suggest that atorvastatin could inhibit the absorption of verapamil via inhibition of P-gp and/or the metabolism of verapamil by CYP3A4 in humans.     

Ceftriaxone pharmacokinetics in elderly subjects and penetration into epididymis

In a prospective study, the epididymal penetration of ceftriaxone was evaluated in order to use it in the treatment of orchi-epididymitis in men. A bolus intravenous dose of 1 g of ceftriaxone was administered to 15 patients hospitalized for surgery as part of treatment for prostatic adenoma or prostatic cancer. Nine successive blood samples were collected in the interval from 0 to 24 h after administration, and epididymis samples were taken 0.75 h after administration. Concentrations of drug in all samples were assayed by a reverse-phase-ion pairing high-performance liquid chromatography method with UV detection. The results showed that the pharmacokinetics of ceftriaxone in serum did not differ from those determined previously in healthy volunteers. The terminal half-life was 6.9 ± 1.7 h, and the mean residence time 9.5 ±2.3 h. The volume of distribution was 0.144 ± 0.018 1 kg^?1 and the total body clearance 1.17 ± 0.29 1 h^?1. The concentrations in tissue reached 27.2 ± 6μg g^?1 in right epididymis, and 25.4 ± 6.2 μg g^?1 in left epididymis. The tissue-versus-serum concentration ratios ranged from 0.175 to 0.545 (mean value, 0.295 ± 0.099). The concentrations in serum and tissue observed in this study were in excess of the MICs for bacteria considered to be susceptible to ceftriaxone, particularly Neisseria gonorrhea and coliform bacteria.     

A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin,pioglitazone and fenofibrate in healthy subjects*

ABSTRACT

Objective: Hypertension and type 2 diabetes are common comorbidities, thus many patients receiving antihypertensive medication require concomitant therapy with hypoglycemic or lipid-lowering drugs. The aim of these three studies was to investigate the pharmacokinetics, safety and tolerability of aliskiren, a direct renin inhibitor for the treatment of hypertension, co-administered with the glucose-lowering agents metformin or pioglitazone or the lipid-lowering agent fenofibrate in healthy volunteers.

Methods: In three open-label, multiple-dose studies, healthy volunteers (ages 18 to 45 years) received once-daily treatment with either metformin 1000?mg (n?=?22), pioglitazone 45?mg (n?=?30) or fenofibrate 200?mg (n?=?21) and aliskiren 300?mg, administered alone or co-administered in a two-period study design. Blood samples were taken frequently on the last day of each treatment period to determine plasma drug concentrations.

Results: Co-administration of aliskiren with metformin decreased aliskiren area under the plasma concentration–time curve during the dose interval (AUC_τ) by 27% (geometric mean ratio [GMR] 0.73; 90% confidence interval [CI] 0.64, 0.84) and maximum observed plasma concentration (C_max) by 29% (GMR 0.71; 90% CI 0.56, 0.89) but these changes were not considered clinically relevant. Co-administration of aliskiren with fenofibrate had no effect on aliskiren AUC_τ (GMR 1.05; 90% CI 0.96, 1.16) or C_max (GMR 1.05; 90% CI 0.80, 1.38); similarly, co-administration of aliskiren with pioglitazone had no effect on aliskiren AUC_τ (GMR 1.05; 90% CI 0.98, 1.13) or C_max (GMR 1.01; 90% CI 0.84, 1.20). All other AUC_τ and C_max GMRs for aliskiren, metformin, pioglitazone, ketopioglitazone, hydroxypioglitazone and fenofibrate were close to unity and the 90% CI were contained within the bioequivalence range of 0.80 to 1.25.

Conclusion: Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment.     

Sensorimotor effects of pergolide, a dopamine agonist, in healthy subjects: a lateralized readiness potential study

Objective The major purpose of the present study was to further elucidate dopaminergic modulation of sensorimotor processing in healthy human subjects. Materials and Methods To more specifically analyze dopaminergic effects on premotor and motor stages of sensorimotor processing, lateralized readiness potentials (LRPs) were obtained. In a randomized double-blind crossover design, either 0.075 mg of the D1/D2 dopamine (DA) agonist pergolide or placebo were administered to 12 healthy male volunteers ranging from 19 to 25 years in age. The subjects performed a two-choice visual reaction time task. In addition to behavioral measures, such as response speed and error rate, stimulus-locked LRP (S-LRP) and response-locked LRP (LRP-R) latencies were determined. To better dissociate potential central and peripheral motor effects, measures of response dynamics and response-locked electromyogram (EMG-R) recordings were also obtained.Observations Pergolide reliably enhanced speed of stimulus-related information processing as indicated by shorter S-LRP latencies while LRP-R latencies, reaction time, and indicators of response dynamics were not influenced by DA agonistic treatment. Furthermore, lower EMG-R amplitudes and an increased number of wrong-hand responses were observed under pergolide compared to placebo.Conclusion The results indicate that dopaminergic neurotransmission effectively modulates early perceptual and cognitive stages of information processing as suggested by neural network models of the functional role of prefrontal DA. The lack of an effect on aspects of motor processing may be due to a higher capacity of the nigrostriatal compared to the mesocortical DA system to compensate pharmacologically induced changes in dopaminergic activity.     

Multiple-dose pharmacokinetics of the new H1-receptor antagonist tazifylline in healthy volunteers

The multiple-dose pharmacokinetics of the new H1-receptor antagonist, tazifylline, were investigated in healthy volunteers. From single-dose data, tazifylline appeared to be rapidly absorbed (median tmax of 0.6 h) and eliminated (t1/2 = 1.0 +/- 0.2 h). However, plasma levels measured on days 3 and 8 of the multiple-dose regimen (10 mg b.i.d. for 8 days) indicated moderate accumulation. A two-compartment model best described multiple-dose data with a terminal half-life of 15.6 +/- 7.6 h consistent with twice-daily dosing of tazifylline.     

An electromyographic analysis of the effect of levodopa on the response time of healthy subjects

Abstract Rationale. Recently, we have shown that oral absorption of levodopa shortens reaction time (RT), measured as the interval between the response signal and the onset of voluntary electromyographic (EMG) activity. The motor time (MT) interval that elapses from the EMG activity to the mechanical response was not analysed. Objective. The purpose of the present study was to analyse the effect of the dose of levodopa administrated in our previous study on the MT. Eight healthy adults (aged 21–28, mean=25), performed a two-choice visual RT task after oral absorption of a single dose of levodopa (200 mg) or a placebo (randomized, double-blind, cross-over design). Results. Like RT, MT was shorter under levodopa than under placebo. Statistical analyses demonstrated that this effect was present for all deciles of the RT and MT distributions. Conclusion. Levodopa shortens not only RT but also MT, which points at the implication of the dopaminergic system in both premotor and motor processes. Electronic Publication     

HPLC-UV determination of metformin in human plasma for application in pharmacokinetics and bioequivalence studies

In this study, a simple, rapid and sensitive HPLC method with UV detection is described for determination of metformin in plasma samples from bioequivalence assays. Sample preparation was accomplished through protein precipitation with acetonitrile and chromatographic separation was performed on a reversed-phase phenyl column at 40 degrees C. Mobile phase consisted of a mixture of phosphate buffer and acetonitrile at flow rate of 1.0 ml/min. Wavelength was set at 236 nm. The method was applied to a bioequivalence study of two drug products containing metformin, and allowed determination of metformin at low concentrations with a higher throughput than previously described methods.