The clinical pharmacokinetics of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate.

BACKGROUND: A new oral pharmacokinetically enhanced formulation of the broad-spectrum antibiotic amoxicillin/clavulanate has been developed to provide more effective therapy against resistant pathogens than is provided by currently available formulations by maintaining therapeutically useful plasma amoxicillin concentrations for a longer period after dosing. OBJECTIVE: This study explored the pharmacokinetics of the new oral formulation of amoxicillin/clavulanate in healthy male and female subjects. METHODS: A single oral dose of pharmacokinetically enhanced amoxicillin/clavulanate (2000/125 mg; 16:1 ratio) was administered to subjects at the start of a meal. After dosing, blood samples were collected at frequent intervals up to 12 hours, and plasma was assayed for amoxicillin and clavulanate concentrations using validated procedures. The new formulation consisted of 1 layer of immediate-release amoxicillin and clavulanate and another of sustained-release amoxicillin in a proportion such that for an amoxicillin minimum inhibitory concentration (MIC) of 4 microg/mL, the time above the MIC (T >MIC) would be approximately > or = 40% over a 12-hour dosing interval. RESULTS: The study enrolled 24 and 31 healthy male and female subjects, respectively. Their mean age was 35 years (range, 18-58 years) and mean body weight was 69 kg (range, 51-86 kg). After the expected sharp peak in plasma amoxicillin concentration, there appeared to be a slower decline with the pharmacokinetically enhanced formulation than is usually seen with conventional formulations, and there was evidence of a second amoxicillin absorption phase. The mean T >MIC for an amoxicillin MIC of 4 microg/mL was 49.4% of a 12-hour dosing interval, a value that cannot be achieved with existing approved doses and formulations of amoxicillin/clavulanate. By 12 hours, plasma amoxicillin concentrations were very low (approximately 0.05 microg/mL), suggesting no expectation of notable dose-to-dose accumulation on repeat dosing with a BID regimen. The terminal half-lives of amoxicillin (1.27 hours) and clavulanate (1.03 hours) with the new formulation were similar to those of existing formulations of amoxicillin/clavulanate. No deaths or serious adverse events were reported. CONCLUSIONS: The enhanced pharmacokinetic profile of amoxicillin/clavulanate seen in this study suggests that this formulation is likely to be highly effective for the oral treatment of infections caused by bacteria--including beta-lactamase-producing organisms--and strains with amoxicillin MICs < or = 4 microg/mL.

Clinical pharmacokinetics of ropinirole.

Ropinirole is a selective non-ergoline dopamine D2 receptor agonist indicated for use in treating Parkinson's disease. When taken as oral tablets, ropinirole is rapidly and almost completely absorbed, and it is extensively distributed from the vascular compartment. The bioavailability is approximately 50%. Ropinirole shows low plasma protein binding. The drug is inactivated by metabolism in the liver, and none of the major circulating metabolites have pharmacological activity. The principal metabolic enzyme is the cytochrome P450 (CYP) isoenzyme CYP1A2. Ropinirole shows approximately linear pharmacokinetics when given as single or repeated doses, and is eliminated with a half-life of approximately 6 hours. Population pharmacokinetics have demonstrated that gender, mild or moderate renal impairment, Parkinson's disease stage and concomitant illnesses or the use of several common concomitant medications have no effect on the pharmacokinetics of ropinirole. Clearance is slower for patients older than 65 years compared with those who are younger, and in women taking hormone replacement therapy compared with those who are not. The CYP1A2 inhibitor ciprofloxacin produced increases in the plasma concentrations of ropinirole when these 2 drugs were coadministered, but no interaction was seen with theophylline which, like ropinirole, is also a substrate for CYP1A2. There is no obvious plasma concentration-effect relationship for ropinirole.

Timing of prophylactic antibiotics in abdominal surgery: trial of a pre-operative versus an intra-operative first dose.

When prophylactic antibiotics are used in abdominal surgery it is customary to give the first dose before the operation. Whilst intra-operative antibiotics may be effective in elective surgery, there may be an advantage to starting pre-operatively when there is already an infective focus such as appendicitis. Antibiotics started pre-operatively (group P) have been compared with antibiotics started after initial abdominal exploration (group T). Three intravenous doses of 500 mg metronidazole plus 1 g cephazolin were given in a randomized, double-blind study of 700 emergency and elective high-risk abdominal operations. Antibiotic plasma concentrations at the end of the operation were significantly lower in group P but lay well within the therapeutic range. Wound infection rates, which included minor and delayed infections, were similar in both groups (group P, 57 of 342, 16.7 per cent; group T, 55 of 358, 15.4 per cent; 95 per cent confidence intervals for the difference being -4.1 to +6.7 per cent. In appendicitis, wound infection rates were 12.1 and 13.9 per cent for groups P and T respectively. However, non-fatal deep sepsis was more common in group P (nine cases) than in group T (two cases) (chi 2 = 4.9, P less than 0.05). Postoperative infection was twice as common in obese patients whose body mass index (BMI) was greater than or equal to 26 (39 of 132, 30 per cent) than in thin patients whose BMI was less than 24 (41 of 288, 14 per cent; chi 2 = 13.8, P less than 0.001). This study failed to show any advantage to starting antibiotics pre-operatively, even in appendicitis.

A review of the metabolism and pharmacokinetics of paroxetine in man.

Paroxetine is well absorbed from the gastrointestinal tract, and appears to undergo first-pass metabolism which is partially saturable. Consistent with its lipophilic amine character, paroxetine is extensively distributed into tissues. Its plasma protein binding at therapeutically relevant concentrations is about 95%. Paroxetine is eliminated by metabolism involving oxidation, methylation, and conjugation. All of these factors lead to wide interindividual variation in the pharmacokinetics of paroxetine. Renal clearance of the compound is negligible. The major metabolites of paroxetine are conjugates which do not compromise its selectivity nor contribute to the clinical response. Ascending single-dose studies reveal that the pharmacokinetics of paroxetine are non-linear to a limited extent in most subjects and to a marked degree in only a few. Also, steady-state pharmacokinetic parameters are not predictable from single-dose data. In many subjects, daily administration of 20-50 mg of paroxetine leads to little or no disproportionality in plasma levels with dose, although in a few subjects this phenomenon is evident. Steady-state plasma concentrations are generally achieved within 7 to 14 days. The terminal half-life is about one day, although there is a wide intersubject variability (e.g. with 30 mg, a range of 7-65 hours was observed in a group of 28 healthy young subjects). In elderly subjects there is wide interindividual variation in steady-state pharmacokinetic parameters, with statistically significantly higher plasma concentrations and slower elimination than in younger subjects, although there is a large degree of overlap in the ranges of corresponding parameters. In severe renal impairment higher plasma levels of paroxetine are achieved than in healthy individuals after single dose. In moderate hepatic impairment the pharmacokinetics after single doses are similar to those of normal subjects. Paroxetine is not a general inducer or inhibitor of hepatic oxidation processes, and has little or no effect on the pharmacokinetics of other drugs examined. Its metabolism and pharmacokinetics are to some degree affected by the induction or inhibition of drug metabolizing enzyme(s). From a pharmacokinetic standpoint, drug interactions involving paroxetine are considered unlikely to be a frequent occurrence. Data available have failed to reveal any correlation between plasma concentrations of paroxetine and its clinical effects (either efficacy or adverse events).

Effect of meal size and composition on the bioavailability of ketoprofen (Oruvail).

Seven young male volunteers received a single oral dose of Oruvail (ketoprofen 200 mg capsule) on two occasions, immediately after either a light/lean or a heavy/fatty meal at breakfast time. Administration of ketoprofen immediately following the heavy meal slightly, but significantly, delayed the absorption of the drug, as evidenced by mean (+/- S.D.)Tmax values of 6.7 (+/- 1.0) and 9.0 (+/- 1.4) hours respectively. Changing the type of meal had no statistically significant effect on the maximum plasma level, apparent plasma elimination half-life (t 1/2 h), area under the plasma level versus time curve, total plasma clearance, and urinary recovery of total ketoprofen, indicating that the bioavailability (and the systemic level) of ketoprofen was not affected by meal composition.

Metronidazole metabolism following oral benzoylmetronidazole suspension in children with giardiasis.

A suspension of benzoylmetronidazole (6.4% w/v) was given orally at a dose of 15-25 ml, equivalent to 0.6-1 g metronidazole, once a day for three days to 11 children with giardiasis. Blood samples were collected after the first and third doses for analysis of plasma metronidazole and its main oxidative metabolite by high performance liquid chromatography. Peak metronidazole concentrations were 22.60 +/- 8.52 mg/l (mean +/- S.D.) after the first dose, and 30.22 +/- 10.06 mg/l after the third dose, occurring at 3.6 +/- 1.4 and 4.4 +/- 2.9 hours post-dose, respectively. Peak concentrations of the metabolite were 4.26 +/- 1.94 mg/l after the first dose and 7.96 +/- 3.63 mg/l after the third dose, occurring 7.2 +/- 1.6 and 9.1 +/- 3.3 h post-dose, respectively. Calculation of plasma metronidazole half-life and clearance values was not possible. This study shows that oral administration of metronidazole as its benzoyl ester slows the rate of metronidazole absorption, followed by sustained plasma concentrations and a prolonged elimination phase. Giardiasis does not appear to prevent metronidazole absorption. Concurrent giardiasis is unlikely to influence metronidazole therapy for systemic anaerobic infections.

A comparison of plasma and synovial fluid profiles of standard and controlled-release formulations of ketoprofen in patients with rheumatoid arthritis.

The plasma and synovial fluid profiles of standard and controlled-release formulations of ketoprofen were compared in 8 patients with rheumatoid arthritis. During chronic dosing with both forms of ketoprofen, peak drug concentrations were lower and occurred later in the synovial fluid than in the plasma. These findings were more pronounced in the case of the controlled-release formulation. The apparent elimination half-life of standard ketoprofen in synovial fluid was prolonged compared to its half-life in plasma, a finding which has not been previously documented. This may explain the clinical observation that, despite a very short plasma elimination half-life, standard ketoprofen exerts a satisfactory therapeutic effect when given twice daily. There was no accumulation of ketoprofen from either formulation in synovial fluid after steady state had been achieved. It is suggested that future pharmacological studies with anti-inflammatory agents should include both synovial fluid and plasma concentration data.

Acebutolol: ten years of experience.

During 10 years of clinical use involving almost 3 million patient-years, acebutolol has become established as a remarkably safe and well-tolerated beta-blocking agent, effective in treating essential hypertension and cardiac arrhythmias. The existence of a long-lived active metabolite (diacetolol) confers a 24-hour duration of action, which permits effective use of a once-daily regimen, particularly for hypertension. Acebutolol has low lipid solubility and low protein binding; the former property reduces the risk of central side effects, and the latter means that displacement interactions with other drugs are unlikely. Because acebutolol and its metabolite normally have both renal and hepatic excretion pathways, an alternative pathway is available should either be compromised through disease. Acebutolol is cardioselective, and clinical use has borne out the low incidence of bronchospasm in patients with impaired lung function. The possession of intrinsic sympathomimetic activity (ISA) leads to only modest reductions in cardiac output, which in turn reduces the chance of excessive bradycardia and the likelihood of precipitating heart failure. A combination of selectivity and ISA may be responsible for the low incidence of tiredness and cold extremities observed with acebutolol compared with other beta blockers. The unique pharmacologic and pharmacokinetic profile of acebutolol confers several therapeutic advantages and may be responsible for the generally low level of side effects experienced in clinical use.

Preliminary study of the disposition in man of acebutolol and its metabolite, diacetolol, using a new stereoselective hplc method.

A new stereospecific hplc method that is capable of simultaneously quantitating the S-(-)- and R-(+)-enantiomers of acebutolol and its major metabolite, diacetolol, in plasma and urine, is described. When applied to the assay of biological fluids collected during single and chronic oral dosing with acebutolol (Sectral), this procedure failed to reveal any important stereoselectivity in the disposition of either acebutolol or diacetolol in man. This may occur because acebutolol is metabolized by hydrolysis and N-acetylation, whereas the other beta-blockers which exhibit some degree of stereoselective disposition (e.g. metoprolol and propranolol) are primarily metabolized by oxidation.

The penetration of trimethoprim and sulphamethoxazole into synovial fluid.

A group of six patients with non-infected synovial effusions requiring diagnostic or therapeutic aspiration, were given a short oral course of 'Septrin' (two tablets bd for two doses, each tablet containing 80 mg of trimethoprim plus 400 mg of sulphamethoxazole). Serum and synovial fluid (SF) were sampled frequently following antibiotic administration. It was found that concentrations of trimethoprim in SF approached serum levels after a short lag time (about 3 h) and thereafter approximated to the serum levels, whereas sulphamethoxazole did not as readily penetrate into SF. With the regimens used MIC levels for trimethoprim were achieved in SF, which suggests that this drug could be usefully prescribed in normal doses for the treatment of septic arthritis due to bacterial infection.

Intravenous metronidazole in the newborn.

Twenty four neonates at high risk of anaerobic sepsis were treated with intravenous metronidazole, 7.5 mg/kg, 8 hourly, for a mean period of 5 days. The highest observed concentration after the first dose (mean +/- SD) 9.6 +/- 4.0 mg/l (56.1 +/- 23.4 mumol/l) was significantly lower (P less than 0.001) than the highest observed concentration after the final dose (mean +/- SD) 19.3 +/- 8.6 mg/l (112.7 +/- 50.2 mumol/l). The overall metronidazole half life was (mean +/- SD) 23.4 +/- 13.1 hours. The half life after the first dose (mean +/- SD) 21.9 +/- 10.1 hours was not appreciably different from the half life after the final dose (mean +/- SD) 21.6 +/- 12.4 hours. The concentrations of the major metabolite of metronidazole (20396RP) also rose appreciably during treatment. No side effects of metronidazole were noted and its extended half life in neonates suggests that less frequent dosage would be appropriate.

Acebutolol and coronary artery surgery. Plasma levels following oral pre-operative treatment.

Plasma levels of acebutolol and its major human metabolite, diacetolol, were determined before, during and after aortocoronary bypass grafting in 10 patients who had received a chronic oral regimen of acebutolol 200 mg t.d.s. for at least 6 days before surgery, a 200 mg dose with the premedication and 5-10 mg intravenously immediately before intubation. It was found that this regimen produced beta-adrenoceptor antagonist levels which were within the range in which attenuation of hypertension and tachydysrhythmia occurs. These effective plasma levels were sustained throughout surgery and persisted into the early recovery period.

Disposition of oral metronidazole in hepatic cirrhosis and in hepatosplenic schistosomiasis.

The pharmacokinetics of metronidazole 500 mg orally were determined in patients with hepatosplenic schistosomiasis and normal controls in the Sudan, and in cirrhotics and normal controls in Bristol. Plasma metronidazole levels were above the minimum inhibitory concentration of most susceptible anaerobic bacteria for four to six hours post-dose in all groups. Liver disease did not markedly influence the disposition of single oral doses of metronidazole. Cirrhotics showed some prolongation of metronidazole half-life, and somewhat greater metronidazole concentrations 24 hours after the dose. Concentrations of the oxidative metabolite of metronidazole were lower in Sudanese patients and normal controls than in normal British subjects. In chronic liver disease adjustment of metronidazole dosage is probably not required provided renal function is unimpaired.

Pharmacokinetics of metronidazole and its principal metabolites and their activity against Gardnerella vaginalis.

The hydroxy metabolite of metronidazole was found to be more active against 21 strains of Gardnerella vaginalis than the parent compound and less affected by culture in carbon dioxide. After 400 mg oral metronidazole (Flagyl) plasma concentrations of the two agents were below the minimum inhibitory concentrations (MICs) for most G vaginalis strains tested. With 2 g metronidazole the plasma concentrations exceeded the MICs of the more sensitive strains. Even with the lower dose of metronidazole clinically useful concentration of metronidazole and its hydroxy metabolite were present in the urine. Urinary excretion of these compounds may contribute to the efficacy of metronidazole in the treatment of vaginitis associated with G vaginalis.

The penetration of metronidazole into synovial fluid.

Six patients with non-infected synovial effusions, associated either with inflammatory or degenerative arthropathy and requiring diagnostic or therapeutic aspiration, were given a short course of 400 mg metronidazole (Flagyl) 8-hourly for 3 doses. Serum and synovial fluid (SF) were sampled frequently during this time, and assayed for metronidazole by a specific high pressure liquid-chromatographic method. It was found that concentrations of metronidazole in SF reached those in serum after a short time-lag, and thereafter approximated to the serum concentration. With this regimen, metronidazole concentrations were readily achieved in synovial fluid, above the minimum inhibitory concentrations for most susceptible anaerobes. These results indicate that the drug freely enters the synovial fluid and suggests that metronidazole would prove effective in the treatment of septic arthritis due to anaerobic bacteria.