Separate Tablets Research Articles

Adherence with levodopa/carbidopa/entacapone versus levodopa/carbidopa and entacapone as separate tablets in patients with Parkinson’s disease

Background:Observational studies suggest that single-tablet formulations are associated with improved adherence versus the same components taken as separate tablets. The objective of this study was to compare adherence in patients with Parkinson’s disease (PD) receiving levodopa therapy as levodopa/carbidopa/entacapone tablets (LCE) versus levodopa/carbidopa (LC) tablets and entacapone (E) as separate tablets (LC and E).Methods:This was a retrospective, observational cohort study using a large health insurance claims database. Subjects included persons with a PD diagnosis who were receiving LC without E and then received either an add-on therapy with E as a separate tablet (LC and E) or LCE as one tablet (LCE). The primary study outcome was treatment adherence, estimated from pharmacy refills based on the ‘percent of days covered’ (PDC) with LCE or LC and E during follow-up and compared for patients receiving LCE and LC and E using multivariate regression analyses.Results:In multivariate analyses controlling for differences between groups in baseline characteristics, including pre-index dosage of and adherence with LC, receipt of LCE (n = 388) was associated with 79% lower mean non-adherence during follow-up (95% CI: 73–83%; p < 0.001) versus LC and E (n = 823), 86% lower odds of unsatisfactory adherence (95% CI: 80–91%; p < 0.001), and a 26% lower risk of discontinuation (95% CI: 6–42%; p < 0.013).Limitations:This was an observational study with the inherent potential for selection bias. Pharmacy claims may not provide an accurate estimate of adherence. Requiring subjects to have a certain number of prescriptions before and after the index date may yield a sample that is not representative of all patients initiating levodopa therapy in typical clinical practice.Conclusions:Better adherence with LCE may have important implications for maintaining function in patients receiving chronic oral levodopa therapy. Further research is needed to confirm these results and examine the association between improved adherence and clinical and economic outcomes.

Amlodipine/Atorvastatin

Amlodipine/atorvastatin (Caduet) is a single-tablet, fixed-dose combination of the dihydropyridine calcium channel antagonist amlodipine and the HMG-CoA reductase inhibitor atorvastatin. The bioavailability of amlodipine and atorvastatin with a single-tablet, fixed-dose amlodipine/atorvastatin combination was not significantly different to that with coadministered separate amlodipine and atorvastatin tablets. In well controlled clinical trials in patients with hypertension and dyslipidaemia, once-daily amlodipine and atorvastatin (administered as the single-tablet, fixed-dose combination or coadministered as two separate tablets) effectively reduced systolic BP (SBP) and low-density lipoprotein cholesterol (LDL-C) levels, and enabled more patients to achieve BP and LDL-C goals than single-agent or placebo therapy. There was no modification of the effect of amlodipine on SBP when administered in combination with atorvastatin and there was no modification of the effect of atorvastatin on LDL-C when administered in combination with amlodipine. In noncomparative, titration-to-goal, open-label 'real-world' trials, the single-tablet, fixed-dose combination of amlodipine/atorvastatin enabled patients with hypertension and dyslipidaemia to achieve both BP and LDL-C goals. Administration of a single tablet of amlodipine/atorvastatin, compared with coadministration of these agents as two separate tablets, improved patient adherence, according to a retrospective study that utilized prescription refill rates from a large US insurance database. Data from the large, randomized, double-blind, placebo-controlled ASCOT-LLA trial also demonstrated that the combination of amlodipine-based therapy and atorvastatin was effective in preventing cardiovascular (CV) endpoints in hypertensive patients at risk of CV disease (CVD). In summary, amlodipine/atorvastatin offers a convenient and effective approach to improving adherence and managing CV risk in hypertensive patients with dyslipidaemia or at risk of CVD.

Population pharmacokinetics of artesunate and amodiaquine in African children.

BackgroundPharmacokinetic (PK) data on amodiaquine (AQ) and artesunate (AS) are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC) of artesunate and amodiaquine.MethodsA prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm) to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA) and desethylamodiaquine (DeAq), the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI) between the areas under the plasma concentration-time curves (AUC).ResultsThe two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138) for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range) elimination half-life of 9 (7 to 12) days. Efficacy was similar in the two treatments groups, with cure rates of 0.946 (95% CI: 0.840–0.982) in the AS+AQ group and 0.892 (95% CI: 0.787 – 0.947) in the AS/AQ group. Four out of five patients with PCR confirmed recrudescences received AQ doses < 10 mg/kg. Both regimens were well tolerated. No child developed severe, post treatment neutropaenia (<1,000/μL). There was no evidence of AQ dose related hepatotoxicity, but one patient developed an asymptomatic rise in liver enzymes that was resolving by Day-28.ConclusionThe bioavailability of the co-formulated AS-AQ FDC was similar to that of the separate tablets for desethylamodiaquine, DHA and the total anti-malarial activity. These data support the use this new AS-AQ FDC in children with acute uncomplicated falciparum malaria.

Fixed combination of repaglinide and metformin in the management of type 2 diabetes

Fixed combination of repaglinide and metformin in the management of type 2 diabetes Robert MosesClinical Trials and Research Unit, South East Sydney and Illawarra Area Health Service, New South Wales, AustraliaAbstract: Treatment to target fasting blood glucose (FBG), postprandial glucose (PPG) and HbA1c are essential in the management of type 2 diabetes to reduce the risk of vascular complications. Early combination therapy with oral agents is increasingly being seen as important to achieve this. Repaglinide, a rapid-acting insulin secretagogue, targets PPG, and metformin, an insulin sensitizer, targets FBG. Because of their complementary modes of action these therapies are frequently given as combination therapy in separate tablets. To overcome the issues with adherence to multiple tablets, repaglinide and metformin are now available in a fixed-dose combination (FDC). Repaglinide/metformin FDC is bioequivalent to each tablet given separately, suggesting that the efficacy and safety profile is similar. There is no effect of food on repaglinide when in the FDC. Repaglinide/metformin FDC is as effective in reducing HbA1c and FBG whether given twice or three times daily, with a similar safety profile. Repaglinide/metformin FDC twice daily is as effective in reducing HbA1c and FBG as rosiglitazone/metformin FDC with a similar safety profile, but unlike the rosiglitazone/metformin FDC, repaglinide/metformin FDC improves the lipid profile. Repaglinide/metformin FDC represents a new option in the pursuit of achieving glucose targets and reducing vascular risk in type 2 diabetes, with the advantage of improving adherence.Keywords: type 2 diabetes, metformin, repaglinide, fixed-dose combination

Fixed combination of repaglinide and metformin in the management of type 2 diabetes

Treatment to target fasting blood glucose (FBG), postprandial glucose (PPG) and HbA(1c) are essential in the management of type 2 diabetes to reduce the risk of vascular complications. Early combination therapy with oral agents is increasingly being seen as important to achieve this. Repaglinide, a rapid-acting insulin secretagogue, targets PPG, and metformin, an insulin sensitizer, targets FBG. Because of their complementary modes of action these therapies are frequently given as combination therapy in separate tablets. To overcome the issues with adherence to multiple tablets, repaglinide and metformin are now available in a fixed-dose combination (FDC). Repaglinide/metformin FDC is bioequivalent to each tablet given separately, suggesting that the efficacy and safety profile is similar. There is no effect of food on repaglinide when in the FDC. Repaglinide/metformin FDC is as effective in reducing HbA(1c) and FBG whether given twice or three times daily, with a similar safety profile. Repaglinide/metformin FDC twice daily is as effective in reducing HbA(1c) and FBG as rosiglitazone/metformin FDC with a similar safety profile, but unlike the rosiglitazone/metformin FDC, repaglinide/metformin FDC improves the lipid profile. Repaglinide/metformin FDC represents a new option in the pursuit of achieving glucose targets and reducing vascular risk in type 2 diabetes, with the advantage of improving adherence.

Fixed‐dose single tablet antidiabetic combinations

Combinations of two or more oral agents with different mechanisms of action are often used for the management of hyperglycaemia in type 2 diabetes. While these combinations have customarily been taken as separate tablets, several fixed-dose single tablet combinations are now available. These are based on bioequivalence with the separate tablets, giving similar efficacy to the separate tablets and necessitating the same cautions and contraindications that apply to each active component. Fixed-dose combinations can offer convenience, reduce the pill burden and simplify administration regimens for the patient. They increase patient adherence compared with equivalent combinations of separate tablets, and this is associated with some improvements in glycaemic control. Presently available antidiabetic fixed-dose combinations include metformin combined with a sulphonylurea, thiazolidinedione, dipeptidylpeptidase-4 inhibitor or meglitinide as well as thiazolidinedione-sulphonylurea combinations, each at a range of dosage strengths to facilitate titration. Anticipated future expansion of multiple drug regimens for diabetes management is likely to increase the use of fixed-dose single tablet combinations.

Fixed-Dose Combination Tablet of Repaglinide and Metformin is Bioequivalent to Concomitantly Administered Individual Tablets of Repaglinide and Metformin

Repaglinide and metformin enhance insulin secretion and decrease hepatic gluconeogenesis, respectively, and are commonly coadministered as separate formulations to treat patients with type 2 diabetes mellitus. A single combination therapy tablet offers increased patient convenience and the subsequent potential for increased therapy compliance. The aim of this randomized, single-blind, three-period crossover study was to determine the bioequivalence of a fixed-dose combination (FDC) tablet of repaglinide/metformin 2 mg/500 mg versus repaglinide 2 mg and metformin 500 mg coadministered as separate formulations. Secondary objectives included a comparison of the dose proportionality of an FDC tablet of repaglinide/metformin 1 mg/500 mg and an FDC tablet of repaglinide/metformin 2 mg/500 mg, as well as the safety and tolerability of repaglinide and metformin in combination tablet therapy. Healthy subjects (n = 93, age 18-45 years) were randomized to one of six possible treatment sequences (Williams design) of an FDC tablet of repaglinide/metformin 2 mg/500 mg, repaglinide 2 mg and metformin 500 mg coadministered as separate tablets and an FDC of repaglinide/metformin 1 mg/500 mg. Fifty-five subjects completed the study. Four primary pharmacokinetic endpoints (area under the plasma concentration-time curve [AUC] from time 0 hours to infinity; AUC from time 0 to 24 hours; AUC from time 0 hours to time t [the last time of measurable concentration after dosing]; and the maximum plasma concentration) were used to assess bioequivalence and dose proportionality. The safety and tolerability of repaglinide and metformin in combination tablet therapy were also evaluated. Both repaglinide and metformin in the combination tablet were determined to be bioequivalent to the individual tablets of repaglinide 2 mg and metformin 500 mg, as the limits of the 90% confidence interval of the mean treatment ratio for all pharmacokinetic parameters were contained within the pre-specified interval required for bioequivalence (0.8, 1.25). Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was determined to be dose proportional to an FDC of repaglinide/metformin 1 mg/500 mg for all analysed endpoints. No withdrawals as a result of adverse events occurred during this study. In addition, no clinically relevant abnormalities were found during physical examinations, in vital signs, ECG parameters or clinical laboratory parameters. An FDC tablet of repaglinide/metformin 2 mg/500 mg was bioequivalent to individual tablets of repaglinide 2 mg and metformin 500 mg. Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was dose proportional to an FDC tablet of repaglinide/metformin 1 mg/500 mg. Finally, no unexpected safety concerns were noted with repaglinide/metformin combination tablet therapy. Our results suggest that FDC tablets of repaglinide and metformin would provide safety and efficacy comparable to that of repaglinide and metformin administered as separate formulations.

Adherence patterns among patients treated with fixed-dose combination versus separate antihypertensive agents

Adherence patterns of patients treated with a fixed-dose combination of amlodipine-benazepril versus an angiotensin-converting-enzyme (ACE) inhibitor plus a dihydropyridine calcium-channel blocker (CCB) prescribed as separate drugs were studied. In this retrospective analysis of pharmacy claims from a managed care organization in the northeastern United States, patients who received at least two prescriptions for fixed-dose amlodipine-benazepril (n = 2839) or at least two prescriptions for an ACE inhibitor plus a dihydropyridine CCB (n = 3367) were followed over one year. Adherence, defined as the medication possession ratio (MPR), was calculated based on daily possession of the prescribed drug or drugs over the study period. To estimate the impact of overall drug burden on adherence to antihypertensive therapy, concomitant medication use was calculated as the number of American Hospital Formulary Service (AHFS) drug classes prescribed. Adherence rates among patients receiving fixed-dose amlodipine-benazepril versus an ACE inhibitor plus a dihydropyridine CCB were 87.9% and 69.2%, respectively (p < 0.0001) over a mean follow-up of 259 and 247 days, respectively. Patients received a mean 4.0 major AHFS drug classes in the amlodipine-benazepril group and 5.2 in the ACE inhibitor plus dihydropyridine CCB group. As the number of concomitant drugs increased, the difference in the MPR between the two treatment groups increased in favor of fixed-dose amlodipine-benazepril. Fixed-dose amlodipine-benazepril was associated with higher adherence rates versus an ACE inhibitor plus a dihydropyridine CCB taken as two separate tablets, regardless of the number of concomitant medications prescribed.

2.212 Improved adherence to levodopa/carbidopa/entacapone (Stalevo®) or levodopa/carbidopa and entacapone as separate tablets reduces medical care utilization and costs among Parkinson's disease patients

2.212 Improved adherence to levodopa/carbidopa/entacapone (Stalevo®) or levodopa/carbidopa and entacapone as separate tablets reduces medical care utilization and costs among Parkinson's disease patients

An open label randomized comparison of mefloquine–artesunate as separate tablets vs. a new co‐formulated combination for the treatment of uncomplicated multidrug‐resistant falciparum malaria in Thailand

Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria. On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2-95.6) in the fixed combination group and 89.2% (85.0-93.4) in the loose tablets group (P=0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.

Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects

To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA). In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25). The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated. The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.

Treatment of End-of-Dose Wearing-Off in Parkinson’s Disease: Stalevo® (Levodopa/Carbidopa/Entacapone) and Levodopa/DDCI Given in Combination with Comtess®/Comtan® (Entacapone) Provide Equivalent Improvements in Symptom Control Superior to That of Traditional Levodopa/DDCI Treatment

The aim of this study was to evaluate the efficacy of the new optimised levodopa, Stalevo^® (levodopa, carbidopa and entacapone) in patients with Parkinson’s disease experiencing end-of-dose wearing-off. Treatment with Stalevo was compared to treatment with traditional immediate-release levodopa and dopa-decarboxylase inhibitor (DDCI) formulations along with adjunct entacapone (Comtess^®/Comtan^®). A European, open, parallel-group, active treatment-controlled phase IIIb study evaluating 176 patients randomised to switch from their current regimen of levodopa/DDCI to either an equivalent dose of Stalevo or levodopa/DDCI plus entacapone. After 6 weeks, treatments were assessed using the Clinical Global Impression of Change, the Unified Parkinson’s Disease Rating Scale and a Motor Fluctuations Questionnaire. Over 70% of patients in both the Stalevo and adjunct entacapone arms felt that they were clinically improved and over 80% experienced a reduction in fluctuations. Although there was no significant difference between Stalevo and levodopa/DDCI plus entacapone with regard to motor improvement and side effects, 81% of patients stated that they preferred treatment with Stalevo compared with taking two separate tablets (i.e. levodopa/DDCI and entacapone). Stalevo was well tolerated and safe when substituted for levodopa DDCI preparations.

A Combined‐Formulation Tablet of Lamivudine/Nevirapine/Stavudine: Bioequivalence Compared With Concurrent Administration of Lamivudine, Nevirapine, and Stavudine in Healthy Indian Subjects

Generic fixed-dose combinations of antiretrovirals are frequently prescribed for the treatment of human immunodeficiency virus infection. A randomized, 2-way study was conducted in 24 fasting, healthy, Indian male subjects to assess bioequivalence between a single combination tablet containing lamivudine, stavudine, and nevirapine (treatment A) with respect to separate marketed tablets administered simultaneously (treatment B). Each subject received treatments A and B separated by 19 days of a drug-free washout period. Plasma concentrations of antiretrovirals, determined by a validated liquid chromatography/tandem mass spectrometry assay, were used to assess pharmacokinetic parameters such as maximum observed plasma concentration and area under the plasma concentration curve. Pharmacokinetic parameters were comparable for either treatment. As geometric mean ratios (% treatment A/treatment B) of log-transformed parameters of area under the plasma concentration curve and plasma concentration, as well as their resultant 90% confidence intervals, were within 80% to 125% and 75% to 133%, respectively, 2 treatments were considered bioequivalent in the extent and rate of absorption. Both treatments exhibited similar tolerability under fasting conditions.

Avandamet: combined metformin-rosiglitazone treatment for insulin resistance in type 2 diabetes

Insulin resistance is a major endocrinopathy underlying the development of hyperglycaemia and cardiovascular disease in type 2 diabetes. Metformin (a biguanide) and rosiglitazone (a thiazolidinedione) counter insulin resistance, acting by different cellular mechanisms. The two agents can be used in combination to achieve additive glucose-lowering efficacy in the treatment of type 2 diabetes, without stimulating insulin secretion and without causing hypoglycaemia. Both agents also reduce a range of atherothrombotic factors and markers, indicating a lower cardiovascular risk. Early intervention with metformin is already known to reduce myocardial infarction and increase survival in overweight type 2 patients. Recently, a single-tablet combination of metformin and rosiglitazone, Avandamet, has become available. Avandamet is suitable for type 2 diabetic patients who are inadequately controlled by monotherapy with metformin or rosiglitazone. Patients already receiving separate tablets of metformin and rosiglitazone may switch to the single-tablet combination for convenience. Also, early introduction of the combination before maximal titration of one agent can reduce side effects. Use of Avandamet requires attention to the precautions for both metformin and rosiglitazone, especially renal, cardiac and hepatic competence. In summary, Avandamet is a single-tablet metformin-rosiglitazone combination that doubly targets insulin resistance as therapy for hyperglycaemia and vascular risk in type 2 diabetes.

Pharmacokinetics and bioequivalence of a combined oral formulation of eniluracil, an inactivator of dihydropyrimidine dehydrogenase, and 5-fluorouracil in patients with advanced solid malignancies

This study was performed to evaluate the pharmacokinetics, bioequivalence, and feasibility of a combined oral formulation of 5-flurouracil (5-FU) and eniluracil (Glaxo Wellcome Inc., Research Triangle Park, North Carolina), an inactivator of dihydropyrimidine dehydrogenase (DPD). The rationale for developing a combined eniluracil/5-FU formulation oral dosing form is to simplify treatment with these agents, which has been performed using separate dosing forms, and decrease the probability of severe toxicity and/or suboptimal therapeutic results caused by inadvertently high or conversely insufficient 5-FU dosing. The trial was a randomized, three-way crossover bioequivalence study of three oral dosing forms of eniluracil/5-FU tablets in adults with solid malignancies. Each period consisted of two days of treatment and a five- to seven-day washout phase. Eniluracil at a dose of 20 mg, which results in maximal DPD inactivation, was administered twice daily on the first day and in the evening on the second day of each of the three treatments. On the morning of the second day, all patients received a total eniluracil dose of 20 mg orally and a total 5-FU dose of 2 mg orally as either separate tablets (treatment A) or combined eniluracil/5-FU tablets in two different strengths (2 tablets of eniluracil/5-FU at a strength (mg/mg) of 10/1 (treatment B) or 8 tablets at a strength of 2.5/0.25 (treatment C)). The pharmacokinetics of plasma 5-FU, eniluracil, and uracil, and the urinary excretion of eniluracil, 5-FU, uracil, and alpha-fluoro-beta-alanine (FBAL), were studied. To determine the bioequivalence of the combined eniluracil/5-FU dosing forms compared to the separate tablets, an analysis of variance on pharmacokinetic parameters reflecting eniluracil and 5-FU exposure was performed. Thirty-nine patients with advanced solid malignancies had complete pharmacokinetic studies performed during treatments A, B, and C. The pharmacokinetics of eniluracil and 5-FU were similar among the three types of treatment. Both strengths of the combined eniluracil/5-FU dosing form and the separate dosing forms were bioequivalent. Mean values for terminal half-life, systemic clearance, and apparent volume of distribution for oral 5-FU during treatments A/B/C were 5.5/5.6/5.6 hours, 6.6/6.6/6.5 liters/hour, and 50.7/51.5/50.0 liters, respectively. The intersubject coefficient of variation for pharmacokinetic variables reflecting 5-FU exposure and clearance in treatments ranged from 23% to 33%. The urinary excretion of unchanged 5-FU over 24 hours following treatments A, B, and C averaged 52.2%, 56.1%, and 50.8'%, of the administered dose of 5-FU, respectively. Parameters reflecting DPD inhibition, including plasma uracil and urinary FBAL excretion following treatments A, B, and C were similar. Toxicity was generally mild and similar following all three types of treatments. The pharmacokinetics of 5-FU and eniluracil were similar and met bioequivalence criteria following treatment with the separate oral formulations of 5-FU and eniluracil and two strengths of the combined formulation. The availability of a combined eniluracil/5-FU oral dosing form will likely simplify dosing and decrease the probability of severe toxicity or suboptimal therapeutic results caused by an inadvertent 5-FU overdose or insufficient 5-FU dosing in the case of separate oral formulations, thereby enhancing the overall feasibility and 0therapeutic index of oral 5-FU therapy.

Pharmacokinetic comparison of a combination tablet of enalapril and hydrochlorothiazide with enalapril and hydrochlorothiazide tablets administered together and separately

Enalapril and hydrochlorothiazide (HCT) are established single agent treatments for mild hypertension and cardiac failure and are a potent combination in more severe or resistant cases. We have compared the pharmacokinetics of enalaprilat (the active metabolite of enalapril) and HCT in a four-way comparison of a combination tablet of enalapril (10 mg)/HCT (25 mg) with a single dose of an enalapril tablet (10 mg), a single dose of a HCT tablet (25 mg) and simultaneous administration of separate tablets of enalapril (10 mg) and HCT (25 mg) in normotensive volunteers (n = 12, 21-26 years). Each subject received all four treatments and the study was conducted as a randomized, latin square, open design with at least 1 week washout between studies. Overall, HCT was bioequivalent under all conditions and enalaprilat was bioequivalent when given in combination with HCT either as one tablet or as two separate tablets. However, when given with HCT, the mean AUC and Cmax of enalaprilat were reduced up to 20 per cent compared with enalapril administered alone. This is unlikely to be of clinical significance as the differences did not reach statistical significance and the total enalaprilat excreted in the urine over 96 h was similar after all treatments.

Patients compliance in hypertension‐the importance of number of tablets.

The importance of number of tablets for patient compliance was investigated in 160 patients with mild-moderate essential hypertension treated with a beta-adrenoceptor blocker and a thiazide diuretic. Mean BP at entry 146 +/- 16/92 +/- 8 mm Hg. All patients were given pindolol 10 mg and clopamide 5 mg in one combination tablet or in separate tablets for 4 months respectively. Approximately 90% of the patients took greater than 90% of the prescribed dose throughout the study. Mean BP decreased progressively and heart rate increased slightly. Side effects were more frequently reported during the first month of the study than previously, and 30 patients discontinued the treatment. No differences in this respect were seen between 1 and 2 tablets daily. Approximately 75% of the patients preferred 1 tablet daily, but combining two drugs in one tablet had no effect upon compliance.

Biopharmaceutical characteristics of a new propranolol/ hydrochlorothiazide tablet combination

Experiments have been carried out in dogs and man to determine the effect of hydrochlorothiazide (HCT) on the pharmacokinetics of propranolol and to evaluate the bioavailability of two dosage forms containing both propranolol and HCT (40/25 and 80/25 mg, respectively). In adult male beagles, 50 mg of HCT had no apparent effect on AUC, Cmax, Tmax, and T1/2 of propranolol administered concurrently. In man, INDERIDE (40/25 mg) and INDERIDE (80/25 mg) were shown to be similar in bioavailability to the reference formulations, i.e. the same amount of drugs administered as the separate tablets of INDERAL plus HYDRODIURIL.

The effect on plasma potassium of a combined preparation of frusemide and slow-release potassium chloride (Diumide-K Continus tablets).

An open trial was carried out on ten middle-aged and elderly patients in cardiac failure to assess the effect on plasma potassium levels of one or more tablets containing 40 mg frusemide and a controlled-release formulation containing 600 mg potassium chloride. Patients had previously been maintained on frusemide and potassium supplements given as separate tablets. No significant rise or fall was observed when treatment was changed to the combined tablet.

Aging of tablets made with dibasic calcium phosphate dihydrate as matrix.

The aging of direct compression tablets made using dibasic calcium phosphate dihydrate as the tablet matrix was investigated over 16 weeks. The formula included 6% amaranth as a dye tracer. Two sets of stress storage conditions were used: 25 degrees and 50% relative humidity and 45 degrees and 75% relative humidity. Tablets were evaluated periodically by visual inspection; determination of the weight of 10 separate tablets, the size of 10 tablets measured by a micrometer screw gauge, and the hardness of 10 tablets as indicated by a Strong-Cobb hardness tester; the USP disintegration time test; and the USP dissolution test. Tablets stored at 25 degrees and 50% relative humidity showed an approximately linear increase in disintegration and dissolution time over 16 weeks with no other significant changes. Storage at 45 degrees and 75% relative himidity resulted in significant changes in most measured parameters; tablets showed blotching, substantial weight loss, and complex changes in disintegration and dissolution. The changes at elevated temperatures are related to loss of water of hydration; changes at 25 degrees must be due to other causes.