Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Objectives

To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC).

Methods

Open-label, randomized, two-period, active-controlled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson’s disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included C_min, C_max, C_max???C_min, AUC, t_1/2, and t_max.

Results

In healthy volunteers and PD patients, mean trough levels (C_min), C_max, and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to C_min, C_max, and AUC, differences between the treatments in variability of levodopa concentrations (C_max???C_min) were less consistent.

Conclusions

The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson’s disease using similar dosing regimens.     

中国青年男性左旋多巴药动学研究

目的探讨左旋多巴在中国青年人药动学。方法征集14名健康男性志愿者,口服200／50mg左旋多巴／苄丝肼片,给药后10,20,30,45．60,90．120,180,240．360,480,600min采血,高效液相色谱-电化学法测定左旋多巴血药浓度．3P87药动学软件计算药动学参数。结果左旋多巴t1／2β AUC0-∞CL／F、Cmax、tmax和V／F分别为54．97±12．4min、351．10±64．12ug·min／mL、589．12±118．54mL·min^-1、2．41±0．98μg·mL^-1、55．60±16．55min和45．82±20．02L。结论积累了左旋多巴在青年人药动学资料．可为临床合理用药提供参考。     

Effect of age on the pharmacokinetics of oral levodopa in patients with Parkinson's disease

Summary The influence of age on the kinetics of a standard oral dose of levodopa administered with an inhibitor of peripheral dopa decarboxylase enzymes (benserazide) has been evaluated in 40 patients with Parkinson's disease (age 34–78 y) on chronic therapy. They were divided into 2 groups, on the basis of age below (21 patients, Group A) or above (19 patients, Group B) 65 y.The area under the plasma concentration-time curve (AUC) of levodopa was significantly greater in the older group (547 versus 428 mol·1^–1·min in Group B), coupled with a reduced apparent oral clearance (8.1 versus 10.7 ml·min^–1 ·kg^–1) and a longer plasma elimination half-life (67.6 versus 54.6 min). The age of the patients was positively correlated with the AUC of levodopa (r=0.474) and its plasma elimination half-life (r=0.391), and was negatively correlated with clearance (r=–0.489).The findings confirm previous data on volunteers that showed a reduction in the systemic clearance of levodopa due to age, which would probably account for the finding of a greater AUC of levodopa in older patients. The observed, age-mediated differences in levodopa pharmacokinetics, albeit statistically significant, were moderate and were likely to be of only minor importance for the dosing schedule.This work was part of the Progetto finalizzato Invecchiamento of the National Research Council of Italy, Grant No. 912012     

Pharmacokinetics of azithromycin after single oral dosing of experimental animals.

Azithromycin, a macrolide antibiotic with an enhanced antimicrobial spectrum, was found to have a longer half-life than erythromycin, with marked tissue penetration. The pharmacokinetics of azithromycin after oral administration were compared with those of erythromycin in rats (200 mg kg-1) and rabbits (80 mg kg-1). Concentrations of azithromycin in liver, lung, kidney, ileum, and brain were higher than serum concentrations. The slow decline in tissue concentrations was evident from the biphasic elimination profile. Thus, advantageous pharmacokinetic properties and the broader antimicrobial spectrum of azithromycin relative to erythromycin appear to further support its therapeutic potential.     

Pharmacokinetics and effects of levodopa in advanced Parkinson's disease

Summary Five patients with severe Parkinson's disease were characterized with respect to their pharmacokinetic and pharmacodynamic responses to levodopa given: orally, intravenously (three different infusion rates) and intraduodenally. The best therapeutic infusion rate in the intravenous study was used for the intraduodenal infusion of levodopa. A lag time between plasma concentration and effect following oral administration was seen in three of the five patients and this disequilibrium was estimated as the rate constant k_e0 using model-independent analysis.The plasma concentration-effect relationship was similar for the three modes of administration and in all patients the therapeutic plasma concentration for full mobility was >4–5 g·ml^–1. The disequilibrium half-life for development of effect after oral administration was calculated to be about 30 min.The patients remained clinically stable during the period of the intraduodenal infusion.     

Pharmacokinetics of deramciclane in dogs after single oral and intravenous dosing and multiple oral dosing

The pharmacokinetics of a new serotonin 5-HT₂ antagonist, deramciclane, was studied. Single oral doses of 1, 3, 6 and 10 mg kg⁻¹ and intravenous doses of 1, 3 and 6 mg kg⁻¹ were administered in beagle dogs. Moreover, the steady state pharmacokinetics of 1, 3 and 6 mg kg⁻¹ doses were studied. Deramciclane was rapidly and completely absorbed from the gastrointestinal tract. Due to a moderate first-pass metabolism the absolute bioavailability was only 45–61%. Deramciclane had a large volume of distribution (32–37 L kg⁻¹) because of its lipophilic nature. Deramciclane was extensively metabolized after intravenous injection and only trace amounts of intact drug is excreted in the urine. The total body clearance decreased (from 32 to 17 L h⁻¹) as the dose increased. It is suggested that the metabolic capacity was not sufficient to eliminate deramciclane in a linear manner with increasing dose. Therefore, deramciclane exhibited nonlinear pharmacokinetics as the AUC_0–∞ increased disproportionally to the dose after both intravenous and oral dosing. Formation of the active metabolite, N-desmethyl deramciclane, was also nonlinear (p =0.0002). At steady state deramciclane accumulated less than 2-fold during repeated administration. Copyright © 1998 John Wiley & Sons, Ltd.     

Naturalistic evaluation of entacapone in patients with signs and symptoms of L-dopa wearing-off

ABSTRACT

Objective: To evaluate the effectiveness of entacapone in the management of levodopa wearing-off in Parkinson's disease (PD) in a naturalistic, real-life setting.

Research design and methods: This prospective, open-label, observational study included patients with idiopathic PD. Patients were eligible for inclusion if they had been taking 3–5 doses of levodopa per day for ≥2 months and had shown signs of levodopa wearing-off for ≥1 month. Subjects received entacapone (recommended dose: 1 × 200 mg tablet with each levodopa dose) for 28 days. Patients were asked to complete a wearing-off questionnaire and the eight-question Parkinson's Disease Questionnaire Quality of Life assessment (PDQ-8). Activities of daily living (both in the on and off states) were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part II. Clinical Global Impression (CGI) of severity of PD-related symptoms was assessed using a modified CGI tool. Patient global assessment of severity of PD symptoms was also obtained.

Results: A total of 341 patients were enrolled by 68 physicians across Canada. At Day 28, 56.9% of the subjects indicated improvement compared to baseline on the modified CGI of change (CGI-C); 21.4% reported no change. Improvements were also observed on the UPDRS II and the PDQ-8. Benefit from entacapone appeared to be relatively uniform across subgroups (e.g., number of daily levodopa doses, use of other anti-PD medications).

Study limitations: The results of this study may be biased due to factors inherent in open-label, community-based trials (e.g., compliance). This is, however, reflective of everyday clinical practice.

Conclusions: In this naturalistic, real-life study, the addition of entacapone to levodopa therapy provided benefits in quality of life and activities of daily living for a substantial proportion of PD patients experiencing wearing-off.     

Levodopa therapy with entacapone in daily clinical practice: results of a post-marketing surveillance study

The catechol-O-methyl transferase inhibitor entacapone is given in combination with levodopa/dopa decarboxylase inhibitor for Parkinson's disease (PD) patients experiencing end-of-dose wearing-off. This 4-week post-marketing surveillance study was undertaken to assess patients' responses to levodopa combined with entacapone in a real clinical practice setting. Overall, 466 patients with idiopathic PD treated with levodopa and experiencing symptoms of wearing-off were recruited. Both physicians and patients recorded the response to therapy, including improvements and side-effects. Following initiation of entacapone treatment, the average daily levodopa dose was reduced from 510 to 453mg. Physician assessment of entacapone efficacy was judged to be 'very good' or 'good' in 77.6% of the patients, and tolerability was considered to be 'very good' or 'good' in 92.4% of patients, with only 12 patients (2.6%) withdrawing from the study. Compared with

baseline, there was a decrease in the mean duration of daily 'off' time from 3.0 to 1.3h per day during the treatment period. Adverse events were in line with those previously reported, with diarrhoea being the most frequent event. The percentage of patients suffering from dyskinesia decreased from 46 to 34%, and of those patients still suffering from dyskinesia, the average daily duration of dyskinesia was reduced from 2.2 to 7h.The use of adjunct dopamine agonists decreased from 67 to 59%. At study end, the percentage of patients who rated their quality of life (QoL) as 'very good' or 'good' increased from 12.1 to 51.7% and the percentage of patients who rated their QoL as 'bad' or 'very bad' decreased from 40 to 10.7%. In summary, the results of this survey conducted in real clinical practice support the findings of previous clinical trials demonstrating the efficacy and tolerability of entacapone, as well as the benefits of improved QoL, for patients achieved with entacapone.     

Pharmacokinetics of nitroglycerin and metabolites in humans following oral dosing

Single dose oral nitroglycerin (GTN) was administered to six healthy subjects as 6.5, 9.0, and 13.0 mg aqueous solutions in sequential study phases to characterize the oral pharmacokinetics of GTN and the dinitrate metabolites. Blood samples were collected periodically up to 10 h. Plasma concentrations of GTN were measurable in some subjects up to 1/2 and 1 h, respectively, after the 9.0 and 13.0 mg dose. The mean GTN Cmax values of the three solution doses were 0.28, 0.78, and 0.42 ng ml-1 in ascending dosage. The erratic nature of GTN plasma profiles prevented meaningful pharmacokinetic analysis, although tmax was consistently 5 min. In all three treatments, both GTN metabolites (1,2- and 1,3-glyceryldinitrates, GDNs) peaked at about 20 min, followed by a distributive phase and a log-linear decline in concentrations. Terminal half-lives for both GDNs were approximately 50 min in all three doses. The plasma concentrations of the metabolites were higher than nitroglycerin with 1,2-GDN exhibiting the highest overall profile.     

Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing

AIMS: The pharmacokinetics of dihydrocodeine (DHC) and its active metabolite dihydromorphine (DHM) were assessed after a single oral dose of DHC and after increasing doses of DHC at steady-state. Methods Twelve healthy male volunteers (18-45 years, CYP2D6 extensive metabolizers (EMs), MR<1 took a single oral dose (s.d.) of DHC 60 mg after breakfast. After 60 h DHC 60 mg was administered twice daily for 3 days, the dose was increased to 90 mg twice daily for 3 days, the final dose of 120 mg was administered twice daily for 3 days (multiple dose: m.d.). Blood sampling and urine collection: during 60 h after s.d. and during 12 h after m.d. Results No significant differences in the area under the curve (AUC) of both, DHC and DHM could be detected after a single oral dose of 60 mg DHC (AUC (0,infinity)) and during steady-state doses of 60 mg DHC (AUC(0,12 h)). During increasing steady-state doses of DHC, the data showed a dose linearity of AUC, maximal serum concentration (Cmax ) and minimal steady-state serum levels (Cssmin) of both, DHC and DHM (P<0.0001), point estimates of DHC dose corrected AUCs were well within the bioequivalence range (60 mg: 0.989; 90%CI 0.951-1. 028, 90 mg: 0.997; 90%CI 0.959-1.036, 120 mg: 0.977; 90%CI 0.940-1. 016). O-demethylation from DHC to DHM remained constant within the increasing steady-state doses of DHC in the 12 extensive metabolizers of CYP2D6. CONCLUSIONS: In the studied dose range (60-120 mg) the pharmacokinetics of DHC and its active metabolite DHM are linear in EMs of CYP2D6.     

Pharmacokinetics and safety of deramciclane during multiple oral dosing

Deramciclane is a new putative non-benzodiazepine-type anxiolytic compound. It is a selective serotonin 5-HT(2A) and 5-HT(2C) receptor antagonist and has also inverse agonist properties. The aim of this study was to reveal the pharmacokinetics and tolerability of deramciclane during repeated oral dosing in healthy male volunteers. SUBJECTS, MATERIAL AND METHODS: A randomized double-blind, placebo-controlled design was used. The study had three consecutive groups that received first a single oral dose of 10, 30 and 60 mg of deramciclane followed by twice a day administration for seven days. The total number of subjects was 28. The pharmacokinetic parameters were calculated for a single dose and after repeated administration. Tolerability was assessed by monitoring safety laboratory variables, electrocardiogram, heart rate, blood pressure and adverse events. RESULTS: The steady-state was reached during the seven-day administration. The pharmacokinetics of deramciclane was dose-proportional at steady-state at each dose level. Deramciclane accumulated about three-fold during repeated administration. The relative bioavailability of deramciclane increased about 1.4-fold compared to that of a single dose at each dose level. The mean elimination half-life of deramciclane for 10, 30 and 60 mg doses prolonged from 24.3, 20.9 and 22.9 h after a single dose to 30.5, 25.6 and 28.7 h at steady-state, respectively. Only few adverse events were reported, all mild and transient in nature. The most frequently reported adverse drug reactions were tiredness and headache. There were no deramciclane-induced changes in the clinical chemistry or hematology variables, blood pressure, heart rate or in electrocardiogram. CONCLUSIONS: In conclusion, the pharmacokinetics of deramciclane is linear over the dose range of 10 - 60 mg at steady-state. The slight non-linearity within the dose levels during repeated administration of seven days was regarded as clinically irrelevant. Deramciclane was safe and well tolerated up to doses of 60 mg b.i.d. for seven days.     

The effect of different dosing regimens of levodopa/carbidopa/entacapone on plasma levodopa concentrations

Background  

Repeated dosing of levodopa/carbidopa/entacapone (LCE) has shown a favourable pharmacokinetic (PK) profile compared with levodopa/carbidopa (LC), but increases maximum plasma levodopa concentrations (C_max) during the day. High levodopa concentrations are associated with peak-dose dyskinesias.     

Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacokinetics after oral and intravenous administration of entacapone

The inhibition of soluble catechol-O-methyltransferase (S-COMT) in red blood cells (RBCs) by entacapone, and the pharmacokinetics of entacapone after single oral (5–800 mg) and IV (25 mg) doses have been examined in an open study in 12 healthy young male volunteers.Oral entacapone dose-dependently decreased the activity of S-COMT in RBCs with a maximum inhibition of 82% after the highest dose (800 mg). The inhibition of S-COMT in RBCs was reversible and the activity recovered within 4–8 h.Entacapone showed linear pharmacokinetics over the dose range studied: C_max and AUC were correlated with the dose of the drug. Oral absorption of entacapone was fast, with a t_max ranging from 0.4 to 0.9 h, depending on the dose. Systemic availability of entacapone varied between 30 and 46%. Entacapone was rapidly eliminated by metabolism with a half-life of 0.27–0.30 h after oral doses of 5 to 50 mg. After doses from 100 to 800 mg the disposition was best described by two phases with a t_1/2 of 0.27–0.37 h and t_1/2 of 1.59–3.44 h.Over the dose range studied, the single oral and IV doses of entacapone were well tolerated. No haematological, biochemical or haemodynamic adverse effects were seen.The results show that entacapone is an orally effective and reversible COMT inhibitor in man and has simple, linear pharmacokinetics.     

Pharmacokinetics of two lorazepam formulations, oral and sublingual, after multiple doses

The pharmacokinetic profiles of a sublingual and a conventional oral lorazepam tablet formulation were established following chronic administration to twelve healthy male volunteers. Fitting a multi-dose equation based on a one-compartment model to the observed data, the average elimination half-lives for the sublingual and oral doses are estimated to be 11 and 8 h, respectively, while the corresponding absorption half-lives are 15 and 55 min; this confirms earlier reports that the sublingual formulation is more rapidly absorbed. The observed time to steady-state for both formulations was approximately 3 days, which agrees well with that predicted from previous single dosing studies. Although the sublingual formulation yields a higher average steady-state minimum plasma concentration than the oral formulation (41.6 versus 38.1 ng ml-1), the maximum lorazepam concentration achieved during steady state was approximately 83 ng ml-1 for both formulations. The average steady-state plasma concentration is estimated to be 63 ng ml-1, independent of the formulation used.     

The effect of carbidopa on the pharmacokinetics and metabolism of intravenously administered levodopa in blood plasma and skeletal muscle

Summary The effect of carbidopa on the pharmacokinetics and metabolism of levodopa (l-dopa) in blood plasma and skeletal muscle extracellular fluid (ECF) has been studied by repeated measurements in one beagle dog.The administration of a single dose of l-dopa (25 mg/kg i.v) without carbidopa pretreatment (controls) resulted in an increase in the concentrations of l-dopa and 3-O-methyldopa (3-OMD) in blood plasma and skeletal muscle ECF dialysates. This effect was clearly potentiated for l-dopa in blood plasma (186% increase in AUC) and 3-OMD in skeletal muscle dialysates (108% increase in AUC) after pretreatment with carbidopa (100 mg/day). In addition, carbidopa prolonged the halflife of the elimination of l-dopa in blood plasma by 48% and in skeletal muscle ECF by 66% but did not influence its blood plasma distribution half-life (t_1/2 = 0.17 h). The elimination half-life of l-dopa in the controls was higher in muscle (t_1/2 = 1.76 h) than in blood plasma (t_1/2 = 0.50 h). Carbidopa pretreatment resulted in a relatively small increase (29%) in the l-dopa content of skeletal muscle ECF as indicated by the AUC.The accumulation of 3-OMD in muscle dialysates, in contrast to that in plasma, was significantly enhanced after the administration of l-dopa following treatment with carbidopa. In the control experiments, dopamine (DA) was detectable only in the dialysates from muscle ECF 3,4-Dihydroxyphenylacetic acid (DOPAC) concentrations in dialysates from blood plasma and muscle showed similar changes in their pharmacokinetic profiles following carbidopa treatment suggesting that their concentrations reflected the formation of these metabolites at other peripheral organs.Our data support the hypothesis that carbidopa, at least in this experimental setting, exerts a l-dopa sparing effect in skeletal muscle ECF and therefore might play a role in maintaining blood plasma levels of this amino acid.Correspondence to: D. Deleu at the above address     

Effect of entacapone,a COMT inhibitor,on the pharmacokinetics of levodopa and on cardiovascular responses in patients with Parkinson's disease

Summary In an open, randomised, cross-over study we investigated the effect of a single 200 mg oral dose of entacapone, a novel catechol-O-methyltransferase (COMT) inhibitor, on the pharmacokinetics and metabolism of levodopa/carbidopa, and on the cardiovascular responses (blood pressure and pulse rate variation to standard stimuli) in eight parkinsonian patients.Entacapone significantly increased the mean area under the plasma concentration curve (AUC) of levodopa by 46%, from 3620 to 5280 h·ng·ml^–1 and prolonged its elimination half-life (t_1/2el) from 1.5 h to 2.0 h. The mean AUC of 3,4-dihydroxyphenylacetic acid (DOPAC), the monoamine oxidase-dependent metabolite of levodopa, was significantly increased from 122 to 343 h·g·ml^–1 by entacapone. A small decrease in the AUC of homovanillic acid (HVA), the COMT dependent metabolite of levodopa, was observed (from 455 to 303 h·ng·ml^–1). Entacapone also decreased the excretion of HVA but not that of 3-methoxytyramine in the urine.Cardiovascular autonomic responses to sympathetic and parasympathetic stimuli were not changed by entacapone.We conclude that a single dose of entacapone moderately increases the AUC and prolongs the t_1/2el of levodopa in man and that that does not affect cardiovascular autonomic regulation.     

Pharmacokinetics of baclofen in spastic patients receiving multiple oral doses

The pharmacokinetics of racemic baclofen as determined from plasma and urine data in six spastic patients treated with individualized oral doses, 30–80 mg daily, are presented. Peak plasma concentrations were achieved 1.9 h (±0.7) after a dose. The fluctuation in the plasma concentration was great, ranging from 188 to 439%. The total body clearance averaged 175 ml·min^–1 (±44), plasma protein binding 35% (±6). Baclofen was for the greater part excreted unchanged by the kidney, 65% (±16). Its apparent renal clearance equalled the creatinine clearance. The contribution of the renal clearance to the total body clearance can explain the previously described toxicity when renal impairment is present. The results agree with earlier reports on single doses in healthy subjects.     

Effects of entacapone and tolcapone on mitochondrial membrane potential

Catechol-O-methyl transferase (COMT) inhibitors, entacapone and tolcapone, are used as an adjunctive treatment to L-dopa in Parkinson's disease. Based on their catechol structure, both inhibitors are potential uncoupling agents, but only tolcapone shows this effect in vitro at clinically relevant concentrations. This study was designed to evaluate the direct uncoupling effects of the two COMT inhibitors in vitro and in vivo. In isolated rat liver mitochondria, entacapone had no effect on the membrane potential at therapeutical concentrations, but both tolcapone and the reference compound 2,4-dinitrophenol disrupted the potential at low microM concentrations. Since protein binding is speculated to decrease the uncoupling effects in vivo, the COMT inhibitory effect of entacapone and tolcapone as a surrogate for the overall activity of these inhibitors was evaluated in vitro with or without serum. The COMT inhibitory activity of entacapone was reduced to half, while tolcapone had only about 1/10 of its activity left in the presence of serum. Further, uncoupling is known to induce an increase in the body temperature in vivo, and these effects were evaluated in the rat by a possible hyperthermic response to the treatment with entacapone or tolcapone in combination with L-dopa (10 mg/kg) and carbidopa (20 mg/kg). This combination with entacapone (400 mg/kg) had no effect on the rectal body temperature. In contrast, tolcapone (50 mg/kg) caused an elevation in the body temperature together with L-dopa and carbidopa (P < 0.01). Both in vitro and in vivo results indicate that entacapone does not impair energy metabolism related to uncoupling of oxidative phosphorylation.     

Pharmacokinetics of furosemide after three different single oral doses

Furosemide solution was orally administered to 21 healthy adult males to determine dose proportionality over the dose range used and the reproducibility of disposition following a repeated dose. Furosemide solution was given in doses of 20, 40, and 80 mg, with the 40 mg dose repeated once. Blood was collected for 12 hours post-dose and urine for 24 hours. The maximum plasma concentrations resulting from 20, 40, and 80 mg doses were significantly different (p less than 0.05). Dose normalized maximum concentrations for the 20 and 80 mg doses were significantly different (p less than 0.05). Mean time to Cpmax was 50 minutes, with no differences observed among doses. Plasma AUCs were significantly different (p less than 0.05) for 20, 40, and 80 mg. Dose normalized AUCs were not significantly different. Mean amounts of furosemide in urine (Xu) were 9.62, 16.7, and 32.0 mg for the 20, 40, and 80 mg doses, respectively. These amounts were significantly different (p less than 0.05); dose normalized amounts were not significantly different. Renal clearances of furosemide following the three doses were not significantly different. Regressions of Cpmax, AUC and Xu on dose were significant. There were no significant differences in Cpmax, tmax, AUC or Xu for 40 mg given on two separate days. Renal clearance of furosemide was statistically different for 40 mg given on two separate days, but the difference was not clinically significant. The pharmacokinetics of furosemide are linear over the dosage range studied. Furosemide 40 mg given on two separate days results in similar disposition parameters.