The cost-effectiveness of long-term antiviral therapy in the management of HBeAg-positive and HBeAg-negative chronic hepatitis B in Singapore.

The purpose of this study was the economic evaluation of short-duration treatments of chronic hepatitis B (CHB) and longer duration antiviral treatment for up to 5 years. Two 10-health state Markov models were developed for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB patients respectively. The perspective of this economic evaluation was the Singapore healthcare system and CHB patient. The models followed cohorts of HBeAg-positive and HBeAg-negative CHB patients, respectively, over a period of 40 years, by which time the majority of the cohorts would have died if left untreated. Costs and benefits were discounted at 5% per annum. Annual rates of disease progression and the magnitude of treatment effects were obtained from the literature, with a focus on data obtained in Asian patients and meeting the criteria for therapy as described in internationally recognized management guidelines. Short-course therapy with alpha-interferon, or 1-year treatment with pegylated interferon alpha-2a, lamivudine or adefovir had limited impact on disease progression. In contrast, treatment of CHB with antiviral therapy for 5 years substantially decreased the rate of disease progression. Treatment with lamivudine for 1-year is highly cost-effective compared with no treatment of CHB but has limited effect on reducing the rate of disease progression. Compared with 1-year treatment with lamivudine, sequential antiviral therapies for up to 5 years (i.e. lamivudine plus adefovir on emergence of lamivudine resistance or adefovir plus lamivudine on emergence of adefovir resistance) are highly cost-effective by international standards. These conclusions are robust to uncertainties in model inputs and are consistent with the findings of other recently published studies.

The effect of polyethylene glycol 400 on gastrointestinal transit: implications for the formulation of poorly-water soluble drugs.

PURPOSE: To assess the effect of polyethylene glycol 400 (PEG 400), a pharmaceutical excipient frequently employed to enhance the solubility and bioavailability of poorly water-soluble drugs, on the gastrointestinal transit of liquid and pellet preparations in human subjects using gamma scintigraphy. METHODS: Ten, healthy male volunteers each received, on separate occasions, a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). Non-disintegrating pellets of size 1.4-1.7 mm. encapsulated within a hard gelatin capsule, were simultaneously administered on both occasions to act as a marker for solid dosage form transit. The liquid and pellet preparations were radiolabelled with 111In and 99mTc respectively thus enabling their positions within the gastrointestinal tract to be followed using a gamma camera. RESULTS: Rapid liquid emptying from the stomach was observed, with no significant difference noted in the gastric residence times of the two preparations. Caecum arrival times for the liquid preparations were significantly different by virtue of their differential rates of transit through the small intestine. The mean small intestinal liquid transit time for the control preparation was 236 min whereas the corresponding value for the PEG 400-containing test preparation was 153 min. This 35% reduction in transit time was attributed to the presence of PEG 400. Pellet transit was largely unaffected by the presence of PEG 400. CONCLUSIONS: These findings clearly demonstrate that PEG 400 has a marked accelerating effect on small intestinal liquid transit, which in turn has implications for the formulation of poorly water-soluble drugs with PEG 400.

Colonic metabolism of ranitidine: implications for its delivery and absorption.

The aim of this study was to assess the in vitro stability of ranitidine to colonic bacteria by utilising a batch culture fermentation system to simulate the conditions of the colon. Three quantities of ranitidine, 100, 200 and 500 mg, in the form of the hydrochloride salt, were introduced into individual 100 ml fermenters consisting of buffer medium inoculated with freshly voided human faeces (10% w/v). Control experiments were also run in parallel using equivalent drug quantities in buffer medium without the presence of faeces. Samples were removed at pre-determined time intervals over a 24 h period and were subsequently analysed by high-performance liquid chromatography (HPLC) for drug concentration. A selection of the samples removed from the fermenters was also analysed by conventional UV spectroscopy and mass spectrometry. Subsequent to an initial dissolution phase in the fermentation system, a marked decline in ranitidine concentration was noted over time, thereby suggesting degradation and metabolism of the drug by colonic bacteria. No such decline in concentration was noted in the control buffer systems. The rate and extent of metabolism was rapid and complete within 12 and 24 h for the 100 mg and 200 mg samples, respectively, although the largest sample size, 500 mg, was only partly metabolised over the course of the experiment. UV and mass spectrometry analysis indicated that metabolism occurred via cleavage of an N-oxide bond within the molecule with the resultant loss of an oxygen atom, although further metabolic reactions are possible. Such metabolism may in part be responsible for the poor bioavailability of ranitidine from the colon.

Economic evaluation of lamivudine compared with interferon-alpha in the treatment of chronic hepatitis B in the United States.

OBJECTIVE: To determine whether lamivudine or interferon-alpha (IFN-alpha) is the more successful treatment for chronic hepatitis B given a fixed drug budget. STUDY DESIGN: A decision-tree model of 1 year. PATIENTS AND METHODS: Average wholesale prices were used to estimate drug costs. A fixed drug budget of $558,910, sufficient to treat 100 patients with IFN-alpha, was assumed. Clinical data were taken from randomized controlled trials. The outcome measures used were hepatitis B "e" antigen (HBeAg) seroconversion rates and rates of progression to cirrhosis. RESULTS: The analysis showed that given the fixed drug budget, 353 patients could be treated with lamivudine, resulting in an expected 62 HBeAg seroconversions, with 6 patients progressing to cirrhosis. Given the same drug budget, 100 patients could be treated with IFN-alpha, leaving 253 patients untreated. This treatment scenario would result in an expected 32 HBeAg seroconversions, with 28 patients progressing to cirrhosis. Compared with no treatment, the costs per additional HBeAg seroconversion obtained were $12,703 for lamivudine and $39,922 for IFN-alpha. In addition, each case of cirrhosis avoided through lamivudine treatment resulted in significant annual cost savings. Lamivudine therapy also provided additional clinical benefits (e.g., normalization of alanine transaminase levels, reduction in hepatitis B virus DNA levels, improvement in liver histology) to patients who do not seroconvert. CONCLUSION: From the perspective of a third-party payer with a fixed drug budget, lamivudine is more cost-effective therapy than IFN-alpha for the treatment of chronic hepatitis B.

Formulation of ranitidine pellets by extrusion-spheronization with little or no microcrystalline cellulose.

The present study was concerned with the feasibility of formulating ranitidine into pellets with a range of alternative excipients in place of microcrystalline cellulose (MCC). Eight ranitidine formulations employing two or more of the excipients lactose, barium sulfate, glyceryl monostearate, and MCC were processed by extrusion-spheronization, and characterized according to a series of physico-mechanical and dissolution criteria. Formulations containing lactose produced unsatisfactory pellets of wide size distribution and irregular shape, whereas formulations incorporating barium sulfate and glyceryl monostearate with or without MCC resulted in relatively spherical pellets of narrow size distribution and good mechanical properties. Ranitidine release was found to be rapid and virtually complete within 15 min, regardless of the pellet formulation. A direct relationship was observed between the concentration of MCC in the formulation and the properties of the pellets. In general, the higher the concentration of MCC, the rounder, stronger, and less friable the pellets. However, even pellets without MCC were also successfully prepared with a superior size distribution and shape over those with MCC. Overall, these results confirm that ranitidine can be formulated into pellet dosage forms with little or no MCC by the extrusion-spheronization process.

Evaluation of different partial AUCs as indirect measures of rate of drug absorption in comparative pharmacokinetic studies.

The performance of different partial AUCs, including partial AUC from zero to t(max) of the reference formulation (AUC(r)) and partial AUC from zero to tmax of test or reference formulation, whichever occurs earliest (AUC(e), as indirect measures of rate of absorption have been evaluated using simulated experiments. The performance of these metrics relative to C(max), t(max) and C(max)/AUC(infinity) was further assessed using the results of actual studies involving a Glaxo drug. The normalised metrics AUC(r)/AUC(infinity) and AUC(e)/AUC(infinity) have also been evaluated. Our provisional conclusions were: (1) AUC(r)/AUC(infinity) and AUC(e)/AUC(infinity) had greater statistical power than C(max) and the non-normalised partial AUCs at detecting true differences in rate of absorption. Using real data, the performance of AUC(e)/AUC(infinity) was poor, however, the performance of AUC(r)/AUC(infinity) was good; (2) C(max)/AUC(infinity) was more precisely estimated than AUC(r)/AUC(infinity) or AUC(e)/AUC(infinity) and may be a superior metric for assessing absorption rates of highly variable drugs.

Common noncompartmental pharmacokinetic variables: are they normally or log-normally distributed?

We investigated the hypothesis that distributions of continuous pharmacokinetic variables are positively skewed in nature and that logarithmic transformation of these variables restores normality. The distributions of common continuous noncompartmental pharmacokinetic variables were investigated for four different Glaxo Wellcome compounds, administered by three different routes of administration: ranitidine (po), sumatriptan (sc), ondansetron (iv), and bismuth, from ranitidine bismuth citrate (po). The distributions of all the investigated noncompartmental pharmacokinetic variables were adequately described by a log-normal distribution, whereas statistically significant departures from normality occurred in the majority of cases. Thus, unless there is strong and consistent evidence for a departure from log-normality, the parametric statistical analysis of common noncompartmental pharmacokinetic variables should be carried out after a priori log transformation.

Modeling of trough plasma bismuth concentrations.

Disposition pharmacokinetics of bismuth following oral dosing of ranitidine bismuth citrate are complicated and variable. An analysis of data from healthy volunteers suggests a model with three disposition compartments and first-order absorption. Patient data are pooled from 10 separate studies and consist of 1140 trough concentrations measured in 802 patients following dosing of 2 to 12 weeks duration. There are therefore insufficient data to obtain reliable parameter estimates for the full model and we use instead a much reduced model and an informative prior based on the volunteer data. Individual parameter estimates from this model can then be used to establish covariate relationships. Trough concentrations were influenced by the coadministration of clarithromycin and by creatinine clearance. A simulation study was carried out to check the validity of the estimates obtained from the reduced model. We carry out analysis via Bayesian sampling-based techniques. Throughout, we use predictive distributions for both diagnostic and inference purposes. In particular, we determine predicted distributions for the Cmax, Cmin and AUC characteristics of new individuals.

Effect of ranitidine hydrochloride (150 mg twice daily) on the pharmacokinetics of increasing doses of ethanol (0.15, 0.3, 0.6 g kg-1).

1. The interaction of ranitidine hydrochloride (150 mg twice daily for 15 doses) with single doses (0.15, 0.3 and 0.6 g kg-1) of ethanol was investigated in a placebo controlled study in 24 male subjects. Ethanol was given 1 h after a standard breakfast to maximise a drug ethanol effect if there is one. A balanced incomplete block design was used in that each subject received two of the three ethanol doses in the presence or absence of ranitidine. Blood samples (n = 18) were taken for 8 h after dosing and blood ethanol concentrations (BAC) were determined by head space analysis using a validated gas liquid chromatographic method. 2. At the lowest dose of ethanol studied the pharmacokinetic profile was largely first order but at the higher doses the usual zero order kinetics were seen. Using the technique of simultaneous fitting across all doses the Km and Vmax constants were similar and close to literature value of 100 mg l-1 and 200-300 mg h l-1 respectively. 3. Ranitidine, in common with other H2-receptor antagonists tested under the same experimental conditions, caused a small rise in BAC. However this was only evident at the smallest dose of ethanol studied and in common with many other publications, no effects were seen at the higher doses. The mean rise in blood ethanol following the 0.15 g kg-1 dose was 2.6 mg dl-1 (13.3 mg dl-1 for placebo and 15.9 mg dl-1 for ranitidine) and this change is of no clinical relevance.

GR122311X (ranitidine bismuth citrate), a new drug for the treatment of duodenal ulcer.

BACKGROUND: Ranitidine bismuth citrate (GR122311X) is a new drug which offers potential benefits in healing duodenal ulcers and prevention of relapse. METHODS: This randomized, multi-centre double-blind study of 1620 patients compared the effect of 4 weeks of treatment with GR122311X 200 mg b.d. (n = 401), 400 mg b.d. (n = 404) or 800 mg b.d. (n = 404) or ranitidine hydrochloride 150 mg b.d. (n = 411) on the rates of duodenal ulcer healing and of overall success (ulcers healed and remaining ulcer free in the 24-week follow-up phase). RESULTS: All four treatments were equally effective at ulcer healing (79%, 85%, 84% and 81% of patients, respectively). GR122311X 400 mg b.d. (38%) and 800 mg b.d. (37%) were significantly more effective than ranitidine hydrochloride 150 mg b.d. (32%) with respect to overall success (P = 0.050 and P = 0.030, respectively) but there was no difference with GR122311X 200 mg b.d. (31%). GR122311X caused effective, dose-related suppression of H. pylori (47%, 61% and 74%); H. pylori eradication rates were 18%, 21% and 22%. GR122311X was safe and well tolerated, with an adverse event profile similar to that of ranitidine hydrochloride 150 mg b.d. Median week 4 trough plasma bismuth levels were 1.3 ng/mL, 2.3 ng/mL and 3.3 ng/mL with GR122311X 200 mg b.d., 400 mg b.d. and 800 mg b.d. respectively. No individual plasma bismuth concentrations were of clinical concern. CONCLUSIONS: GR122311X is a safe and effective ulcer healing drug, and provides a platform on which anti-H. pylori therapy can be based.

Evaluation of different metrics as indirect measures of rate of drug absorption from extended release dosage forms at steady-state.

Bioequivalence assessment of extended release (ER) dosage forms is usually carried out at steady-state, using area under the curve (AUC) to evaluate extent of absorption and maximum concentration (Cmax) and % peak trough fluctuation ratio (%PTF) to evaluate rate of absorption. Other metrics such as Cmax/AUC and partial AUCs have recently been proposed as alternatives for assessing the absorption rate of drugs from immediate release (IR) dosage forms under single dose conditions. The performances of these metrics were assessed using the results of two sets of simulated experiments of ER dosage forms at steady-state and 2 actual pharmacokinetic studies involving ER dosage forms of a Glaxo drug. In the first set of simulations there was no difference in bioavailability between the two formulations; in the second set of simulations the test formulation had a 50% greater absorption rate-constant (ka) than the reference formulation. The following conclusions were reached: 1. For ER dosage forms at steady-state, all the metrics, with the exception of %PTF, resulted in much smaller increases than the underlying 50% increase in ka. Although, %PTF gave the largest effect it was also the most imprecisely estimated. 2. In our studies, none of the metrics tested provided reliable information about changes in the underlying rate of absorption from ER dosage forms under steady-state conditions. 3. The current practice of comparing rate of absorption from ER dosage forms using steady-state Cmax is inappropriate due to lack of sensitivity. The use of %PTF may require a widening in the currently accepted 80-125% permissible range set for Cmax and AUC.

Single dose pharmacokinetics of sumatriptan in healthy volunteers.

Sumatriptan is classified as a vascular 5HT1 receptor agonist and is effective in the acute treatment of migraine and cluster headache. Sumatriptan is available as an injection for subcutaneous administration and as a tablet for oral administration. The pharmacokinetics of sumatriptan differ depending on the route of administration. The mean subcutaneous bioavailability is 96% compared to 14% for the oral tablet. The lower bioavailability following oral administration is due mainly to presystemic metabolism. The inter-subject variability in plasma sumatriptan concentrations is greater following oral administration and a faster rate of absorption of drug into the systemic circulation is achieved following subcutaneous dosing. The pharmacokinetics of sumatriptan are linear up to a subcutaneous dose of 16 mg. Following oral dosing up to 400 mg, the pharmacokinetics are also linear, with the exception of rate of absorption, as indicated by a dose dependent increase in time to peak concentration. Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism to the pharmacologically inactive indoleacetic acid analogue. Both sumatriptan and its metabolite are excreted in the urine. Although the renal clearance of sumatriptan is only 20% of the total clearance, it exceeds the glomerular filtration rate, indicating that sumatriptan undergoes active renal tubular secretion. Sumatriptan has a large apparent volume of distribution (170 l) and an elimination half-life of 2 h. Oral doses of sumatriptan were administered as a solution of dispersible tablets and subcutaneous dosing was by injection into the arm. In clinical practice, sumatriptan is administered as a film coated tablet or by subcutaneous injection into the thigh.

Evaluation of different indirect measures of rate of drug absorption in comparative pharmacokinetic studies.

As indirect measures of rate of drug absorption (metrics), maximum plasma concentration (Cmax) is confounded by extent of drug absorption and the time to reach Cmax (tmax) is a discrete variable, dependent on blood sampling frequency. Building on the work of Endrenyi et al., we have compared different metrics, including Cmax/area under the curve of concentration versus time from time zero to infinity (AUC infinity), partial AUC from zero to tmax (AUCp), and Cmax.tmax with simulated experiments. Importantly, the performance of these metrics was assessed with the results of actual pharmacokinetic studies involving Glaxo drugs. The results of the simulated and real experiments were consistent and produced the following unambiguous findings: (1) Cmax/AUC infinity is a more powerful metric than Cmax in establishing bioequivalence when the formulations are truly bioequivalent; (2) Cmax/AUC infinity is more sensitive than Cmax at detecting differences in rate of absorption when they exist; and (3) the treatment ratios for AUCp, AUCp/AUC infinity, and Cmax.tmax are very imprecisely estimated and are of no practical value as measures of rate of absorption. Of the metrics examined, Cmax/AUC infinity is the most sensitive and powerful indirect measure of rate of drug absorption in comparative pharmacokinetic studies involving immediate-release dosage forms and should be used instead of Cmax in bioequivalence testing.

The effect of renal function on the pharmacokinetics of ranitidine.

This open study evaluated the influence of renal function on the pharmacokinetics of ranitidine (50 mg i.v. infusion given over 6 min). Five groups, each of 8 subjects, 1 with normal renal function and 4 with different degrees of renal impairment were studied. Renal function was assessed in each patient by 51Cr-EDTA (glomerular filtration rate, GFR), creatinine clearance (GFR) and N-methylnicotinamide clearance (reflecting glomerular and tubular function). Sixteen blood samples (5 ml) taken up to 48 h post dose from each subject were analysed for plasma ranitidine concentrations by reversed phase HPLC. Patient groups with renal impairment had significantly increased AUC infinity and t1/2 with corresponding decreases in CLp and lambda z when compared with normal subjects. There was also a significant increase in tmax but not in Cmax. There was a high linear correlation between the degree of renal impairment and ranitidine clearance. In patients with GFR < or = 20 ml min-1, the AUC infinity mean ratio (compared with normal subjects) was up to 4.6 while for patients with GFR 20-50 ml min-1, the average AUC infinity ratio was 2.6. It is recommended that the dose of ranitidine is halved in patients with GFR < or = 20 ml min-1.

Comparative pharmacokinetics of bismuth from ranitidine bismuth citrate (GR122311X), a novel anti-ulcerant and tripotassium dicitrato bismuthate (TDB).

GR122311X (ranitidine bismuth citrate, Glaxo Group Research Ltd.) is a salt of ranitidine with a complex of bismuth and citric acid which is being developed for the treatment of peptic ulceration. In this study, 4 groups of 12 healthy male subjects were dosed for 10 days with either GR122311X 500 mg bid (301 mg bismuth per day), GR122311X 1.0 g bid (602 mg bismuth per day), tripotassium dicitrato bismuthate (TDB, DeNoltab, Gist Brocades Ltd., Weybridge, England) 240 mg bid (431 mg bismuth per day) or placebo. After the last dose the geometric mean for Cmax for 500 mg bid of GR122311X was 5 ng.g-1, for 1.0 g bid GR122311X it was 12 ng.g-1 and it was 21 ng.g-1 for 240 mg TDB bid. The corresponding trough plasma levels were 2 ng.g-1, 4 ng.g-1 and 4 ng.g-1, respectively. The AUC over a dosing interval after the last dose (AUC tau) were 34 ng.h.g-1, 71 ng.h.g-1 and 79 ng.h.g-1, respectively. The bismuth urinary recoveries over the last dosing interval (Ae tau) were 97 micrograms, 227 micrograms and 309 micrograms, respectively, which is less than 1% of the administered doses. The renal clearance of bismuth was less than the glomerular filtration rate. After adjustment for bismuth dose, the Cmax for GR122311X 500 mg was 35% that of TDB, while for GR122311X 1.0 g the Cmax was 42% that of TDB. Similar differences were observed for Ae tau. In conclusion bismuth pharmacokinetics after oral administration of GR1223311X exhibited lower Ae tau and Cmax, with a much narrower Cmax range than those observed for TDB.

Lack of effect of flunarizine on the pharmacokinetics and pharmacodynamics of sumatriptan in healthy volunteers.

Twenty-four healthy subjects completed a double-blind, placebo controlled, parallel group study to evaluate the effect of treatment with flunarizine on the pharmacokinetics and pharmacodynamics of sumatriptan, a 5HT1-like agonist. Subjects received a single oral 200 mg dose of sumatriptan on the eighth day of a once daily treatment with either flunarizine 10 mg or matching placebo. There were no significant differences between treatments in relation to Cmax (82.3 ng ml-1 in the absence and 81.4 ng ml-1 in the presence of flunarizine), AUC (368 ng ml-1 h in the absence and 360 ng ml-1 in the presence) and elimination half-life (2.2 h in the absence and 2.4 h in the presence of flunarizine) of sumatriptan. Similarly pretreatment with flunarizine was not found to have any clinically significant effect on the pharmacodynamics of sumatriptan as measured by pulse rate, blood pressure and ECG.

Lack of an interaction between propranolol and sumatriptan.

1. The effect of twice-daily dosing with propranolol on the pharmacokinetics and pharmacodynamics of a single oral dose of sumatriptan was investigated in 10 healthy male subjects. 2. Each subject received 7 days dosing with propranolol (80 mg twice daily) plus a single dose of sumatriptan (300 mg orally) on day 7; on another separate occasion, placebo was administered for 7 days plus a single dose of sumatriptan on day 7. There was at least a 7 day washout interval between the two periods of dosing. Pulse and blood pressure were measured up to 10 h after dosing with sumatriptan and blood samples were taken up to 26 h post-dose. 3. Propranolol had no significant effect on any of the derived pharmacokinetic parameters of sumatriptan. The appropriate average parameter values in the presence of propranolol were, respectively: Cmax (120 ng ml-1 vs 126 ng ml-1), tmax (4.5 h vs 3.0 h), AUC (580 ng ml-1 h vs 566 ng ml-1 h), t 1/2,z (1.9 h vs 1.8 h). 4. Propranolol had no significant effect on the pharmacodynamics of sumatriptan, as measured by pulse rate and blood pressure. 5. The results of this study would suggest that no alteration in the sumatriptan dosage will be necessary for migraine patients taking propranolol prophylactic therapy.

Pharmacokinetics of cefuroxime and ceftazidime in patients with acute renal failure treated by continuous arteriovenous haemodialysis.

To determine appropriate doses of cefuroxime and ceftazidime for septic patients with acute renal failure (ARF) treated by continuous arteriovenous haemodialysis (CAVHD), we performed pharmacokinetic studies in patients receiving these antibiotics. All patients were treated by CAVHD using Hospal AN69S 0.43 m2 filters and Fresenius 1.5% peritoneal dialysis fluid at dialysate flow rates (Qd) of 1 and 2 l/h. Patients received cefuroxime 500 mg (n = 11) or 750 mg (n = 1), or ceftazidime 500 mg (n = 9) i.v. 12-hourly and all studies were done at steady-state. For cefuroxime, volume of distribution (Vdarea) was 22.8 +/- 3.5 l, terminal elimination half-life (t1/2) 12.6 +/- 2.2 h and total body clearance (TBC) 22.3 +/- 3.0 ml/min (mean +/- SEM). Mean sieving coefficient (SC) was 0.90 +/- 0.12 and filter clearances at Qd 1 and 2 l/h were 14.0 +/- 2.3 and 16.2 +/- 3.4 ml/min respectively. For ceftazidime, Vdarea was 31.1 +/- 6.5 l, t1/2 14.7 +/- 3.3 h, and TBC 24.8 +/- 0.8 ml/min. Mean SC was 0.86 +/- 0.03, and filter clearances at Qd 1 and 2 l/h 13.1 +/- 1.2 and 15.2 +/- 1.5 ml/min. Satisfactory plasma concentrations of both antibiotics were maintained in all patients during treatment. These data suggest that cefuroxime 500-750 mg and ceftazidime 500 mg 12-hourly are suitable doses for patients with ARF treated by CAVHD.

The clinical pharmacology, pharmacokinetics and metabolism of sumatriptan.

Clinical pharmacology studies were undertaken in young healthy volunteers, in a small number of elderly subjects and in migraine subjects during and between attacks. Absorption after subcutaneous and oral administration was rapid. Bioavailability was nearly 100% after subcutaneous administration and averaged 14% after oral administration. Elimination was predominantly by metabolism to a non-active indoleacetic acid analogue. The plasma half-lives of sumatriptan and the metabolite were about 2 h. Pharmacokinetic and pharmacodynamic variables were similar in all groups studied and were not altered by the presence of food, alcohol, dihydroergotamine or prophylactic migraine treatments. Sumatriptan produced a number of minor adverse events, but had no clinically significant effect on routine haematological or biochemical investigations using the intravenous, subcutaneous or oral routes. Transient rises in blood pressure were observed which were no greater than those that would be anticipated during moderate exercise. The physician-administered subcutaneous injection resulted in transient stinging at the site of injection in many subjects; administration using the auto-injector was better tolerated.

A lack of pharmacokinetic interaction between ranitidine and piroxicam.

The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects. In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (Cmax) was 467 ng.ml-1 for ranitidine alone and 466 ng.ml-1 in the presence of piroxicam: mean area under the plasma concentration vs time curve (AUC) was 2460 h.ng ml-1 and 2551 h.ng ml-1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively. In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean Cmax was 2.1 micrograms.ml-1 in the presence of placebo and 2.0 micrograms.ml-1 in the presence of ranitidine respectively; mean AUC was 133 h.microgram ml-1 and 137 h.microgram ml-1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.