Etintidine-propranolol interaction study in humans

Etintidine HCl is a potent H2-blocker. The effect of clinical doses of etintidine on the disposition of a single oral dose of propranolol was investigated in 12 normal subjects. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of Inderal (40 mg propranolol hydrochloride) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 hr following the administration of propranolol. The plasma samples were analyzed for propranolol and 4-hydroxypropranolol by HPLC. Comparison of the pharmacokinetic parameters of propranolol between etintidine and the placebo groups indicates that etintidine significantly increased the AUC0-infinity values (573.5 vs. 146.4 ng.hr/ml, p = 0.0001) and prolonged the elimination half-life (4.61 vs. 2.33 hr) of propranolol. Statistical evaluation of the pharmacokinetic parameters of 4-hydroxypropranolol indicates that etintidine also increased the AUC0-24 values (43.8 vs. 16.4 ng.hr/ml, p = 0.0028) and prolonged the elimination half-life (4.87 vs. 1.97 hr) of 4-hydroxypropranolol. The data suggest that etintidine, like cimetidine, impaired the elimination of propranolol. Etintidine also protracted the elimination of 4-hydroxypropranolol, an active metabolite of propranolol.     

Effect of food on pharmacokinetics of chlorambucil and its main metabolite,phenylacetic acid mustard

Summary The influence of food intake on the pharmacokinetics of chlorambucil (C) and its cytotoxic metabolite, phenylacetic acid mustard (PAM), has been studied in man after oral doses of chlorambucil. The administration of chlorambucil with food resulted in slower absorption than when fasting. However, the area under the plasma concentration-time curve (AUC) was unaffected. The mean ratio AUC_PAM/AUC_C was 2.8 (range 1.4–7.1) under fasting and 3.3 (range 1.3–7.4) under nonfasting conditions. The metabolite very probably plays an important role in the cytotoxic effects observed after administration of C, since calculations show that a major fraction of the metabolite is eliminated by alkylation reactions.     

Interaction of diazepam with famotidine and cimetidine, two H2-receptor antagonists

Famotidine is currently under investigation as an H2-receptor antagonist. Eleven healthy male volunteers received a single 10 mg intravenous dose of diazepam on three occasions: once during coadministration of famotidine 40 mg bid, once during coadministration of cimetidine 300 mg qid, and once without other drug treatment (control). Multiple blood samples were drawn during the seven days after each diazepam dose. Diazepam and desmethyldiazepam plasma concentrations were measured by electron capture gas chromatography. There were no significant differences among the three treatment conditions in diazepam central compartment volume or total volume of distribution. During the cimetidine as compared with the control treatment, diazepam elimination half-life was significantly increased (72 vs 55 hr, P less than .05), total area under the curve (AUC) increased (11.8 vs 9.8 hr-micrograms/mL, P less than .05), and total clearance reduced (0.20 vs 0.28 mL/min/kg, P less than .05). Seven-day AUC for desmethyldiazepam also increased (4.6 vs 3.8 hr-micrograms/mL, P less than .05). However, there were no significant differences between famotidine and control treatment conditions in diazepam elimination half-life (53 vs 55 hr), total AUC (9.5 vs 9.8 hr-micrograms/mL), or total clearance (0.28 vs 0.28 mL/min/kg) or in seven-day AUC for desmethyldiazepam (3.9 vs 3.8 hr-micrograms/mL). Thus, therapeutic doses of cimetidine significantly impair the clearance of diazepam and desmethyldiazepam. Therapeutic doses of famotidine do not impair diazepam and desmethyldiazepam kinetics, suggesting that there is no significant kinetic interaction when diazepam and famotidine are administered concurrently in clinical practice.     

An application of population kinetics analysis to estimate pharmacokinetic parameters of sodium tungstate after multiple-dose during preclinical studies in rats

The purpose of this study was to use a population approach in the preclinical development program of sodium tungstate in the rat in order i) to compute individual pharmacokinetic parameters of this compound after repeated oral administrations, until the 4-week toxicology study, using an empirical Bayes methodology; and ii) to study the influence of the administered dose, of the gender and of the duration of treatment on the pharmacokinetic parameters. Four studies were used representing a mixture of single intravenous administration and multiple oral administrations. The treatment duration ranged from 7 to 28 days. Intravenous dose was 9 mg/kg; three different oral doses were tested, 50, 100 and 200 mg/kg/day. Plasma concentration profiles versus time were compatible with a two-compartment model. A significant gender effect was found on bioavailability. The duration of treatment and the administered dose did not significantly explain part of the interindividual variability of pharmacokinetic parameters. The absorption of tungsten was rapid (1-3 hr). Total plasma clearance and elimination half-life averaged 2.8 ml/min/kg and 3.04 hr in males, and 3 ml/min/kg and 2.74 hr in females. The bioavailability was on an average 70%; being significantly higher in females than in males (0.78 versus 0.61). This compartmental approach should be considered as complementary to the usual non-compartmental approach used for analysis of preclinical data and should be a valuable tool to characterise the pharacokinetic/pharmacodynamic behaviour of a drug.     

Pharmacokinetics of the ketolide telithromycin after single and repeated doses in patients with hepatic impairment

The pharmacokinetic profiles of single and repeated oral doses of telithromycin 800 mg/day were compared in patients with hepatic impairment and healthy subjects in two open-label, non-randomized, parallel-group, multicentre studies. The maximal plasma concentrations (Cmax) and the area under the plasma concentration-time (AUC) curves for telithromycin were similar in hepatically impaired patients and healthy subjects in the single- and repeated-dose studies. The extent of formation of RU 76363, the major circulating metabolite of telithromycin, was decreased following single and repeated doses in patients with hepatic impairment compared with healthy subjects. In the single-dose study, the Cmax of RU 76363 was 2-fold lower (P<0.01) and the initial elimination half-life (t(1/2lambda1)) was 44% higher (P<0.01). The Cmax and AUC from 0 to 24 h post-dose were approximately 50% lower on Day 1 (P< or =0.01) and Day 7 (P< or =0.001) in the repeated-dose study. The terminal elimination half-life (t(1/2lambdaz)) of telithromycin was 1.4-fold higher (P<0.001) in the hepatically impaired patients compared with the healthy subjects in the single-dose study. However, t(1/2lambda1) and t(1/2lambdaz) were similar after repeated doses in both populations, suggesting that the decrease in formation of RU 76363 is compensated by an increase in clearance via other pathways. Telithromycin 800 mg was well tolerated in both populations. In conclusion, a once-daily dose of telithromycin is well tolerated in patients with hepatic impairment. Exposure to telithromycin was comparable in patients with hepatic impairment and healthy subjects and thus, no dosage adjustment is required in this patient group providing renal function is not severely impaired.     

Relative bioavailability and bioequivalence of metforphin hydrochloride extended-released and immediate-released tablets in healthy Chinese volunteers.

The aim of the present study was to investigate the relative bioavailability and bioequivalence of a new tablet formulation of metformin hydrochloride with reference to a standard product in healthy Chinese adult male volunteers. Two randomized, comparative, two-way crossover studies were therefore conducted. In study 1, which was a single-dose study, 20 subjects received 1000 mg metformin hydrochloride test product extended-release (MXR) tablets followed by the same amount of metformin hydrochloride reference product immediate-release (MIR) tablets with a 7-day washout period between the two doses. In study 2, which was a multiple-dose study, 22 subjects received MXR 1000 mg/d for 9 consecutive days followed by MIR 1000 mg/d with a 14-day washout period between the doses of the test and reference product. The serum metformin concentrations were monitored using a selective and sensitive high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection. The pharmacokinetic parameters were calculated using a 3P97 program. Analysis of variance (ANOVA) of the half-life of the absorption phase (t(1/2ka)), the half-life of the elimination phase (t(1/2ke)) and the mean retention time (MRT) and the Wilcoxon Signed Rank test of T(max) for the two preparations were significantly different. A significant difference was found in the ANOVA for C(max) in the single-dose study, while this was not the case in the multiple-dose study. Two one-sided t-tests showed that there were no significant differences in the area under the concentration-time curve (AUC) values between the two formulations. The present study indicates that the test preparation was bioequivalent to the reference preparation when both MXR and MIR were investigated in healthy Chinese adult male volunteers. And on the basis of the mean AUC(0-t), AUC(0-infinity) and AUC(ss), the relative bioavailability of the MXR was found to be 107.80%, 111.89% and 110.61% respectively compared with MIR.     

Pharmacokinetics and bioavailability of omeprazole after single and repeated oral administration in healthy subjects.

1. Ten healthy subjects were given 20 mg omeprazole EC (enteric coated) granules once daily for 8 days. An i.v. tracer dose of [14C]-omeprazole was given simultaneously with the first and last oral doses and blood sampling was performed thereafter. In order to study the extent of absorption at minimal acid exposure, a single dose of 20 mg omeprazole was also given as a buffered solution, before and after the treatment with EC granules. 2. Kinetic parameters of omeprazole after the i.v. tracer dose were unchanged on repeated dosing while AUC increased by approximately 40% for the solution and 60% for the EC granules. 3. The increased AUC is caused by an increased systemic availability, which may be explained by a decreased first-pass elimination during repeated treatment and/or by a reduced degradation of omeprazole in the stomach secondary to the profound decrease in intragastric acidity caused by the drug. 4. The implication of these findings is that the antisecretory effect of therapeutic doses of omeprazole must be studied during repeated administration and not judged from studies using single doses only.     

Pharmacokinetics and bioavailability of oral 5'-deoxy-5-fluorouridine in cancer patients

AIMS: Oral administration of 5-fluorouracil (FUra), an important cytotoxic agent, is limited by a wide variation in bioavailability. 5'-deoxy-5-fluorouridine (dFUrd), a masked form of FUra, has shown promise clinically when given intravenously or orally as a solution or tablet. This study investigates the efficacy of an oral capsule formulation of dFUrd in generating continuous systemic levels of this compound in cancer patients. METHODS: Six patients with advanced intestinal or ovarian malignancies were given three cycles of dFUrd, days 1-5, at intervals of 4 weeks. The doses of dFUrd were 600 mg m-2 three times daily, 800 mg m-2 three times daily, and 1000 mg m-2 three times daily, on cycles one, two and three, respectively (total dose 36 g m-2 ). The initial dose in each cycle was given as a slow intravenous injection over 10 min, and the remainder orally. Plasma and urine levels of dFUrd and two of its metabolites, FUra and 5,6-dihydro-5-fluorouracil (FUraH2 ), were monitored in six patients at each dose level. RESULTS: All six patients completed the study, receiving three different doses over a 3 month period, following which one had achieved a partial response, one had stable disease, and four had developed progressive disease. Side-effects were negligible, and only two instances of transient diarrhoea WHO grade 1 were seen. Total body clearance (CLtot) of intravenous dFUrd decreased with increasing dose; 2.7, 2.0 and 1.3 l min-1 m-2, following doses of 600, 800 and 1000 mg m-2, respectively. The mean elimination half-life of intravenous dFUrd increased with the dose from 15 to 22 min. Oral dFUrd was rapidly absorbed with a lag time of less than 20 min. The mean elimination half-life (t1/2, z ) of oral dFUrd was 32-45 min in the dose range 600-1000 mg m-2. The AUC of FUra and FUraH2 increased overproportionally with increasing intravenous doses of dFUrd. The mean systemic bioavailability of oral dFUrd was 34-47%. CONCLUSIONS: dFUrd, which selectively releases the antimetabolite FUra in tumour cells, can be given orally at doses of 600-1000 mg m-2 three times daily for 5 days. The systemic levels achieved are equivalent to those seen following continuous infusions of dFUrd or FUra. Toxicity is tolerable, and further clinical investigation of oral dFUrd is warranted.     

Half-life of oxazaphosphorines in biological fluids

Plasma AUC and half-life values for cyclophosphamide were determined in rats manipulated to hydroxylate cyclophosphamide at different rates; plasma AUC and apparent half-life values for two pharmacologically important metabolites of cyclophosphamide, viz. 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard, were also determined in these animals. Apparent plasma half-life values for 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard increased with an increase in plasma half-life values for cyclophosphamide. AUC values for cyclophosphamide increased approximately linearly with an increase in its plasma half-life but AUC values for 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard remained approximately constant with an increase in their respective apparent plasma half-life values. Given that the cytotoxic effects of cyclophosphamide are directly proportional to AUC values for 4-hydroxycyclophosphamide/aldophosphamide and/or phosphoramide mustard, we conclude that changes in the rate of cyclophosphamide hydroxylation will not alter the systemic toxic and therapeutic responses to a given dose of cyclophosphamide. Actual half-life values for 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard after the iv infusion of these agents were also determined. A comparison of the actual plasma half-life values for cyclophosphamide (29 min), 4-hydroxycyclophosphamide/aldophosphamide (14 min), and phosphoramide mustard (14 min) with the apparent plasma half-life values obtained for 4-hydroxycyclophosphamide/aldophosphamide (34 min) and phosphoramide mustard (55 min) following cyclophosphamide administration suggests that the major determinant with regard to the apparent plasma half-life of 4-hydroxycyclophosphamide/aldophosphamide is its rate of formation whereas in the case of phosphoramide mustard, an additional determinant, perhaps efflux from the cell, is operative.(ABSTRACT TRUNCATED AT 250 WORDS)     

Etintidine-propranolol interaction study in humans

Etintidine HCl is a potent H₂ -blocker. The effect of clinical doses of etintidine on the disposition of a single oral dose of propranolol was investigated in 12 normal subjects. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of Inderal® (40 mg propranolol hydrochloride) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 hr following the administration of propranolol. The plasma samples were analyzed for propranolol and 4-hydroxypropranolol by HPLC. Comparison of the pharmacokinetic parameters of propranolol between etintidine and the placebo groups indicates that etintidine significantly increased the AUC_0–,values (573.5 vs. 146.4 ng·hr/ml, p=0.0001)and prolonged the elimination half-life (4.61 vs. 2.33 hr) of propranolol. Statistical evaluation of the pharmacokinetic parameters of 4-hydroxypropanolol indicates that etintidine also increased the AUC_0–24 values (43.8 vs. 16.4 ng·hr/ml, p=0.0028) and prolonged the elimination half-life (4.87 vs. 1.97 hr) of 4-hydroxypropranolol. The data suggest that etintidine, like cimetidine, impaired the elimination of propranolol. Etintidine also protracted the elimination of 4-hydroxypropranolol, an active metabolite of propranolol.     

The metabolism of chlorambucil

After injection of chlorambucil into rats, metabolites have been isolated from blood and identified by g.l.c.-mass spectrometry as (E)-4-[4N,N-bis(2-chloroethyl)aminophenyl] 3-butenoic acid (3,4-dehydrochlorambucil) and 2-[4-N,N-bis(2-chloroethyl)aminophenyl] acetic acid (phenyl acetic acid mustard). Analysis of urine 24 hr after administration indicates the absence of chlorambucil, 3,4-dehydrochlorambucil and phenyl acetic acid mustard but the presence of 2-[4-N(2-chloroethyl) ami-nophenyl] acetic acid as the major metabolite. All metabolites isolated have been independently synthesized, allowing confirmation of structures proposed by g.l.c.-mass spectrometry. It has been shown that 3,4-dehydrochlorambucil is an intermediate in the β-oxidation of chlorambucil by injecting an authentic sample into rats and observing the production of phenyl acetic acid mustard in the blood. The contribution that metabolism makes to the anti-tumor activity of chlorambucil is discussed.     

Absolute bioavailability of cefixime in man

In a four-way cross-over study, the absolute bioavailability of cefixime was determined in 16 healthy volunteers. Each subject received a single 200-mg dose as an intravenous (IV) and oral solution, and 200-mg and 400-mg capsule doses of the drug. Blood and urine samples were collected for 24 hours after each dose. Cefixime was well tolerated after IV and oral doses of the drug and no serious drug-related adverse effects were observed. The maximal serum concentration (Cmax) of cefixime following the 200-mg oral solution and 200-mg and 400-mg capsule doses were 3.22, 2.92, and 4.84 micrograms/mL, respectively. Mean area under the serum concentration time curves (AUC) following the IV, 200-mg oral solution, and 200-mg and 400-mg capsule doses were 47.0, 26.0, 23.6, and 39.4 micrograms.hr/mL, respectively. Mean elimination half-life values of the drug were comparable after oral and IV doses, ranging from 3.2 to 3.5 hours. Based on serum AUC values, the absolute bioavailability of cefixime was 52.3%, 47.9%, and 40.2% after the 200-mg oral solution, 200-mg capsule and 400-mg capsule doses, respectively. Respective ratios based on 24-hour urinary recovery data were 44.7%, 41.7%, and 40.5%. Therefore, the results show that the percent of cefixime adsorbed after 200-mg and 400-mg oral doses was similar.     

Pharmacokinetics of xamoterol after intravenous and oral administration to volunteers

Summary The pharmacokinetics of xamoterol, a -adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design.After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml·min^–1 and the volume of distribution at steady-state (V_ss) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose.Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation.     

Bioavailability and cardiovascular safety of Dexatrim (phenylpropanolamine hydrochloride) from a controlled-release caplet

The bioavailability and pharmacokinetics of phenylpropanolamine hydrochloride (PPA HCl) from a Dexatrim controlled-release (CR) caplet and solution was studied. Each subject (n = 12) received either a 75 mg PPA HCl CR caplet once daily or a 25 mg PPA HCl solution given three times a day. All subjects received the medication for 4 consecutive days. On Day 1, the mean +/- SEM, AUC, tmax, and Cmax values were 1651 +/- 127 ng x h ml-1, 4.5 +/- 0.26 h and 143 +/- 13.5 ng ml-1, respectively, for the CR caplet and 1716 +/- 90.3 ng x h ml-1, 1.25 +/- 0.08 h and 126 +/- 5.8 ng ml-1 for the solution, respectively. At steady state (Day 4), the mean +/- SEM, AUC, tmax, and Cmax values were 1832 +/- 101 ng x h ml-1, 4.17 +/- 0.17 h and 151 +/- 6.5 ng ml-1, respectively, for the CR caplet and 2014 +/- 116 ng x h ml-1, 1.33 +/- 0.09 h and 143 +/- 8.7 ng ml-1, respectively, for the solution. The data from Day 1 were fitted to an oral one compartment model with a first order absorption rate constant, kA, first order elimination rate constant, k and lag time. The mean +/- SEM, kA, elimination half-life and lag time for PPA HCl from the CR caplet were 0.488 +/- 0.182 ng h ml-1, 5.84 +/- 1.66 h and 0.394 +/- 0.224 h, respectively. The mean +/- SEM, kA, elimination half-life and lag time for PPA HCl from the solution were 2.87 +/- 1.51 ng x h ml-1, 3.73 +/- 1.21 h, and 0.325 +/- 0.101 h, respectively. The smaller apparent kA and longer elimination half-life for PPA HCl from the CR caplet is due to the slow release of PPA HCl, thereby slowing its absorption producing sustained plasma drug concentrations. Blood pressures (supine and sitting) and heart rates measured at the time of blood sampling after the administration of the PPA HCl dosage forms demonstrated no clinically significant relationship between cardiovascular response and PPA HCl plasma concentration. These data demonstrate the bioavailability and pharmacokinetics of PPA HCl from a CR caplet and an immediate release solution.     

Comparative single dose and steady-state pharmacokinetics of bevantolol in young and elderly subjects

Summary The pharmacokinetics of bevantolol were examined following single and repeated oral doses to young and elderly volunteers. Following administration of a single 200-mg bevantolol tablet mean maximum plasma bevantolol concentrations in young and elderly subjects were 1690 ng/ml and 1810 ng/ml, respectively. Maximum bevantolol concentrations occurred approximately 1.1 h postdose in both young and elderly subjects. There were no significant differences in mean steady state bevantolol concentrations on Day 14 between young and elderly subjects. However, disproportionate increases in C_max, and in AUC, but not in t_max values were observed between Days 1 and 14.On Days 1 and 14, most young and elderly subjects exhibited monoexponential decline in bevantolol plasma concentrations after absorption phase. In those subjects Day 14 elimination half-lives in young and elderly were 1.9 and 2.2 h, respectively. In subjects who exhibited biexponential decline in bevantolol, an age effect in elimination became apparent, on Day 14 elimination half-lives were 5.7 and 11.2 h in young and elderly subjects, respectively. Bevantolol Metabolite III concentrations were observed in plasma of some subjects during the first 6 h after dosing. At steady-state AUC (0-ldc) values for the metabolite were less than 2% those of bevantolol.Bevantolol plasma levels accumulate to a small extent with repeated 200 mg daily doses. This is probably due to the contribution of a late and more persistent terminal elimination phase that was discernable in only certain individuals.     

Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers

OBJECTIVE: To investigate the pharmacokinetics and tolerability of ZD1839 (Iressa), an orally active selective epidermal growth factor receptor-tyrosine kinase inhibitor, in healthy volunteers. DESIGN: Two randomised, double-blind, placebo-controlled, parallel-group studies of pharmacokinetics and tolerability, followed by a nonblind, randomised, 2-period crossover study to assess the effect of food on bioavailability. SETTING: Two centres in the UK. STUDY PARTICIPANTS: Healthy male volunteers aged between 18 and 62 years. INTERVENTIONS: The first study investigated the pharmacokinetics and tolerability of ascending single oral doses of ZD1839 (1 to 75mg). The second study investigated the pharmacokinetics and tolerability of multiple doses of ZD1839 (100mg once daily for 3 days). The third study investigated the effect of food on the bioavailability of a single 50mg dose of ZD1839. OUTCOME MEASURES AND RESULTS: Peak plasma drug concentrations (Cmax) of ZD 1839 occurred between 3 and 7 hours after administration. Cmax and area under the concentration-time curve (AUC) were dose-proportional from 10 to 100mg. The terminal elimination half-life (t1/2beta) was 28 hours (range 12 to 51 hours). Cmax was reduced by 34% and AUC by 14% by ingestion of food; t1/2beta was not affected. Urinary recovery of ZD1839 was <0.5%, indicating that this was not a major route of elimination. The pharmacokinetics of ZD1839 during administration of multiple doses could be predicted from day 1 values. There were no serious adverse events or withdrawals, and the frequency of adverse events was similar that with placebo. CONCLUSIONS: These data support the further clinical investigation of ZD 1839. The elimination half-life suggests that once daily oral administration is appropriate.     

On the pharmacokinetics of fenflumizole, a novel antiinflammatory agent, after single oral administration to healthy subjects

The disposition of fenflumizole, a recently developed imidazole derivative which inhibits prostanoid formation, was studied after single oral administration to eight healthy subjects. Fenflumizole was given in the doses 0.1, 1 and 2 mg/kg as an aqueous suspension. Plasma concentrations within the first 24 hrs were amenable to a two-compartment open model and showed a rapid absorption with a half-life of about 0.5 hr and peak concentrations in plasma after about 1 hr. The elimination phase became dominating after about 10 hrs with a half-life of 14-15 hrs. Peak plasma levels and areas under the concentration-time curves prior to onset of the elimination phase indicated a small reduction of the bioavailability with dose on comparison of the highest and the lowest dose (P less than 0.05) but for the whole observation period of 24 hrs no dose-dependent bioavailability was revealed. The mean transit time in plasma ranged from 21 to 22 hrs. Two metabolites (demethylation products) were detected in both plasma and urine. Their plasma concentrations amounted to only about 5% of those of the parent compound, and they were rapidly eliminated. The total urinary recovery of the intact fenflumizole and the two metabolites was less than 0.1% of the given doses. The renal clearance of fenflumizole was estimated to about 0.02 ml/hr.     

Multiple-dose pharmacokinetics, pharmacodynamics and tolerability of the oral ET(A) endothelin-receptor antagonist SPP301 in man

BACKGROUND: SPP301 is a competitive antagonist of ET-1 with a high selectivity for the ET(A) receptor. The multiple-dose pharmacokinetics, pharmacodynamics, safety and tolerability of SPP301 were investigated in healthy male subjects. METHODS: In an ascending-dose, double-blind, placebo-controlled trial doses of 5, 20, 40 and 60 mg SPP301 were given orally on Day 1 and, after a wash-out period of 48 hours, once daily for seven days. At regular intervals, blood pressure and pulse rate, plasma levels of ET-1, and of SPP301 and its hydroxymethyl metabolite as well as urinary excretion of the parent drug and its metabolite were determined. RESULTS: SPP301 was generally well-tolerated. With the higher doses asymptomatic and transient increases in liver transaminases were observed. No other clinically relevant effects of SPP301 on hematology, biochemistry or urinalysis parameters were observed. Vital signs, ECG parameters and physical examinations showed no time or treatment effect. The pharmacokinetics of SPP301 and its hydroxymethyl metabolite (Ro 68-5925) were linear up to 40 mg SPP301. Steady state was reached after 3-4 days. The apparent terminal half-life of SPP301 and the metabolite was in the range of 7-10 hours after single and repeated doses. At the 60 mg dose level plasma concentrations of SPP301 decreased from the first to the last day of oral treatment. The average decreases in Cmax and AUC were 33% and 37%, respectively. Cmax and AUC of the metabolite amounted to about 4-6% of the values for SPP301 under single and repeated-dose conditions. Urinary excretion of SPP301 and of its metabolite were below 0.1% and 5%, respectively. CONCLUSION: SPP301 is quite well-tolerated, pharmacokinetics are linear and time-independent up to 40 mg multiple doses. Steady state is reached after 3-4 days. Urinary excretion of the unchanged drug plays a minor role in the elimination process of SPP301. ET-1 plasma concentrations increased about 1.5-fold at 20 mg and all further doses.     

Pharmacokinetics of treprostinil sodium administered by 28-day chronic continuous subcutaneous infusion

The objective of this study was to assess the pharmacokinetics and safety of treprostinil sodium administered as a 28-day continuous subcutaneous infusion at escalating infusion rates of 2.5 to 15 ng/kg/min in normal subjects. Fourteen healthy adult volunteers received a 28-day continuous sub-cutaneous infusion of treprostinil at escalating infusion rates of 2.5, 5, 10, and 15 ng/kg/min. Doses were escalated every 7 days with no washouts between escalations. Serial plasma samples were collected predosing, during dosing, and postdosing. Samples were also collected every 3 hours on Day 7 of each dosing period to evaluate diurnal variation over a 24-hour steady-state interval. Plasma treprostinil concentration was measured by a validated liquid chromatography atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 25 pg/mL. Distinct steady states were achieved for each of the four treprostinil doses. Linear regression analysis of mean steady-state treprostinil concentration versus targeted dose yielded a fitted line with an r(2) of 0.92. Variation in apparent plasma clearance for the four doses was small (i.e., 9.77-10.4 mL/kg/min). Consistent diurnal cycles of two peak and two trough treprostinil concentrations were observed over a 24-hour steady-state interval for each dose with peak levels 20% to 30% higher than trough levels. The terminal half-life of treprostinil was 2.93 hours. Intersubject variability for mean pharmacokinetic parameters was small (coefficients of variation ranging from 13.6%-25.5%). At clinically relevant doses, the pharmacokinetics of treprostinil were linear and dose independent with modest, consistent diurnal cycles consisting of two daily peaks and two daily troughs observed for all four doses. In addition, the elimination half-life was about 3 hours.     

Diltiazem pharmacokinetics in elderly volunteers after single and multiple doses

In young healthy volunteers diltiazem does not have linear kinetics between single and multiple doses. Elimination half-life increases and gives AUC's and Cmax higher than those predicted from single dose data. Kinetics of diltiazem were assessed in 16 healthy elderly after a single 60 mg dose and in 24 healthy elderly after 60 mg every 8 h for 7 days. Thirteen participants completed both studies. Elimination half-life, AUC0-24, AUC0-infinity, and Cmax were (mean +/- SE) 7.4 (1.2) h, 349 (34) ng/ml.h, 392 (44) ng/ml.h, and 43 (5) ng/ml respectively after a single dose. After multiple doses elimination half-life, AUC0-48, AUC0-infinity, Cmax and Cmin were respectively 5.7 (0.3) h, 974 (107) ng/ml.h, 1022 (108) ng/ml.h, 102 (7) ng/ml and 43 (5) ng/ml. Exploratory statistics on the 13 volunteers common to both studies showed that the ratio of AUC desacetyl-diltiazem (DAD)/AUC diltiazem rose between single and multiple doses while elimination half-life of both diltiazem and N-desmethyl-diltiazem (MA), tmax, and AUC MA/AUC diltiazem were not affected. The conclusion of this study is that elimination half-life of diltiazem does not increase in elderly between single and multiple doses, possibly due to an increased biotransformation into DAD.