Remogliflozin etabonate, a selective inhibitor of the sodium-dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients.

AIMS: Remogliflozin etabonate (RE) is the pro-drug of remogliflozin (R), a selective inhibitor of renal sodium-dependent glucose transporter 2 (SGLT2) that improves glucose control via enhanced urinary glucose excretion (UGE). This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of RE in subjects with type 2 diabetes mellitus (T2DM). METHODS: In a double-blinded, randomized, placebo-controlled trial, subjects who were drug-naïve or had metformin discontinued received RE [100 mg BID (n = 9), 1000 mg QD (n = 9), 1000 mg BID (n = 9)], or placebo (n = 8) for 12 days. Safety parameters were assessed, including urine studies to evaluate renal function. Plasma concentrations of RE and metabolites were measured with the first dose and at steady state. RE effects on glucose levels were assessed with fasting glucose concentrations, frequently sampled 24-h glucose profiles and oral glucose tolerance tests. RESULTS: No significant laboratory abnormalities or safety events were reported; the most frequent adverse events were headache and flatulence. Plasma exposure to RE and R were proportional to administered dose with negligible accumulation. Mean 24-h UGE increased in RE treatment groups. Compared with the placebo group, 24-h mean (95% CI) changes in plasma glucose were -1.2 (-2.2 to -0.3) (100 mg BID), -0.8 (-1.7 to 0.2) (1000 mg QD) and -1.7 (-2.7 to -0.8) mmol/l (1000 mg BID). CONCLUSIONS: Administration of RE for 12 days is well-tolerated and results in clinically meaningful improvements in plasma glucose, accompanied by changes in body weight and blood pressure in subjects with T2DM.

Lack of effect of ondansetron on the pharmacokinetics and analgesic effects of morphine and metabolites after single-dose morphine administration in healthy volunteers.

AIMS: The purpose of this investigation was to study the influence of ondansetron on the single-dose pharmacokinetics and the analgesic effects elicited by morphine and the 3- and 6-glucuronide metabolites of morphine in healthy volunteers. METHODS: This was a randomized, double-blind, placebo-controlled, two-way crossover study in which six male and six female subjects were administered a single 10 mg intravenous dose of morphine sulphate, followed 30 min later by a single 16 mg intravenous dose of ondansetron hydrochloride or placebo. Serum and urine concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) samples were quantified over 48 h using high performance liquid chromatography with detection by mass spectrometry. Analgesia was assessed in the volunteers with a contact thermode device to provide a thermal pain stimulus. Four analgesic response variables were measured including thermal pain threshold, thermal pain tolerance, temporal summation of pain and mood state. RESULTS: The two treatments appeared to be equivalent based on the 90% confidence intervals (0.6, 1.67) of the least squares means ratio. All least squares means ratio confidence intervals for each parameter, for each analyte fell within the specified range, demonstrating a lack of an interaction. CONCLUSIONS: The results of this study suggest that administration of ondansetron (16 mg i.v.) does not alter the pharmacokinetics of morphine and its 3- or 6-glucuronide metabolites to a clinically significant extent, nor does it affect the overall analgesic response to morphine as measured by the contact thermode system.

A population pharmacokinetic analysis of zanamivir in subjects with experimental and naturally occurring influenza: effects of formulation and route of administration.

The pharmacokinetics of zanamivir were evaluated in subjects from three phase I single-center and two phase II multicenter, randomized, double-blind, multidose, placebo-controlled trials. A total of 96 phase I subjects received zanamivir (3.6 to 16 mg) intranasally two or six times daily for 4 to 5 days beginning 4 hours before or 1 to 2 days after inoculation with influenza virus. A total of 75 phase II subjects with influenza or a history of exposure to naturally occurring influenza virus were administered zanamivir as an intranasal spray (3.4 mg/nostril), inhaled powder (10 mg), or combination of intranasal and inhaled formulations twice daily for 5 days. Population parameters (including demographic factors, zanamivir formulation, infection-related variables, and concurrent medication use) were estimated by a nonlinear mixed-effect modeling software program (NONMEM) using a one-compartment model with first-order absorption and conditional estimation algorithm. Formulation and route of administration were the most significant factors affecting the pharmacokinetics of zanamivir. Relative bioavailability of the inhaled powder to the intranasal drops and spray was 2.3 and 1.6, respectively. No significant differences in pharmacokinetic parameters were observed when demographic variables, indices of infection, or concurrent medication use were considered in either phase I or phase II population analyses.

Population pharmacokinetics of lamivudine in adult human immunodeficiency virus-infected patients enrolled in two phase III clinical trials.

Lamivudine population pharmacokinetics were investigated by using nonlinear mixed-effect modelling (NONMEM) analysis of data from 394 human immunodeficiency virus (HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two large, phase III clinical efficacy-safety trials, NUCA3001 and NUCA3002. Analyses of 1,477 serum lamivudine concentration determinations showed that population estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of distribution (V/F; 128 liters) were similar to values previously reported for HIV-infected patients in phase I pharmacokinetic studies. Lamivudine CL/F was significantly influenced by the covariates creatinine clearance and weight and not affected by age, Centers for Disease Control and Prevention (CDC) classification, CD4(+) cell count, HIV type 1 (HIV-1) RNA PCR, or gender and race when CL/F was corrected for differences in patient weight. The population estimate for lamivudine V/F was not significantly influenced by the covariates gender, race, age, weight, renal function, HIV-1 RNA PCR, or CDC classification and CD4(+) cell count when creatinine clearance was included with CL/F in the model. Lamivudine disposition was significantly influenced by renal function. However, as only three patients had an estimated creatinine clearance of <60 ml/min, dosage adjustments for patients with impaired renal function should not be determined based on the population parameters derived in this analysis.

Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection.

Zanamivir, a potent inhibitor of influenza A and B virus neuraminidases, is protective against experimental human influenza when given intranasally twice daily. We conducted two studies to assess the pharmacokinetics and protective efficacy of a reduced frequency dosing regimen of topical zanamivir. In the first study, 36 uninfected volunteers received a single dose of zanamivir by intranasal spray (6.4 mg), intranasal drops (16 mg) or dry powder oral inhalation (10 mg). At 4 h, median nasal wash concentrations were 50-fold higher after intranasal dosing than after inhalation. Substantial levels (spray group, median 4,596 ng/ml; drop group, 1,239 ng/ml) were detected in nasal wash 48 h after intranasal dosing. In the double-blinded efficacy study, 47 sero-susceptible volunteers were randomized to receive either placebo or zanamivir intranasal spray (6.4 mg). Among the 43 subjects evaluated, decreases in viral shedding occurred in the group receiving one dose of zanamivir 4 h prior to inoculation, whereas no significant benefit was observed in those receiving a single dose 48 h prior to challenge. In the group given three daily doses, reductions were seen in viral shedding and infection. In the two regimens providing zanamivir 4 h prior to inoculation, significant reductions in nasal mucus weight were observed. Decreases in total symptom scores and the incidence of upper respiratory illness also occurred, but they did not reach statistical significance. The efficacy of a single dose of zanamivir given 4 h prior to inoculation supports the hypothesis that influenza virus neuraminidase is essential for initial virus spread through respiratory secretions. These findings indicate that once daily dosing of zanamivir is protective against experimental influenza A infection.

Effects of the neuraminidase inhibitor zanamavir on otologic manifestations of experimental human influenza.

Middle ear pressure (MEP) abnormalities are frequently observed during influenza virus infection and may serve as surrogate markers for the risk of otitis media. MEP abnormalities were evaluated in adult volunteers who were inoculated with influenza A/Texas/36/91(H1N1) or B/Yamagata/88 virus and given the antiviral zanamivir (GG167) intranasally as prophylaxis or early treatment in randomized, double-blind, placebo-controlled trials. In the influenza A prophylaxis studies, 15% of 61 zanamivir recipients versus 61% of 33 placebo recipients showed significant MEP abnormalities (P < .01). In the influenza A early treatment trial, 32% of 31 infected zanamivir recipients versus 73% of 26 infected placebo recipients developed MEP abnormalities (P < .01). In the influenza B prophylaxis trial, 16% of 25 zanamivir versus 44% of 9 placebo recipients showed abnormalities (P = .09). These findings indicate that the neuraminidase inhibitor zanamivir, which is effective in reducing experimental influenza illness, provides protection against the development of MEP abnormalities.

Safety, tolerability, and pharmacokinetics of sumatriptan suppositories following single and multiple doses in healthy volunteers.

A suppository formulation of the 5HT1 agonist sumatriptan could prove an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administration is unsuitable because of severe migraine-related vomiting. Two independent double-blind, randomized clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of sumatriptan suppositories following ascending single doses (four different dose levels) and multiple doses. In the four-period, crossover, single-dose study, 24 healthy male subjects were randomized to receive a suppository containing 12.5, 25, 50, or 100 mg on separate occasions 3-14 days apart. The suppositories were generally well tolerated; transient asthenia, drowsiness, and headache were the most frequently reported adverse events, and these were not dose-related. Peak plasma concentrations (Cmax) of sumatriptan were proportional to dose from 25 to 100 mg; area under the plasma concentration-time curve (AUC infinity) values were proportional to dose except at the highest doses, when they were greater than those predicted from lower doses. For all doses, the tmax of sumatriptan occurred within 2.5 h, and the t1/2 was approximately 2 h. In the two-period, placebo-controlled, crossover, repeat-dose study, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rectally twice a day, for 11 doses (5 1/2 days). Adverse events were no more frequent with sumatriptan than with placebo, and stool guaiac, rectal examinations, and physical examinations remained normal. No significant differences were noted between Day 1 and Day 6 values in the AUC, Cmax, time of peak serum concentration (tmax), elimination half-life (t 1/2), fraction of the dose excreted in the urine (fe), or renal clearance (Clr) of sumatriptan or its pharmacologically inactive indole acetic acid metabolite. Serum metabolite concentrations were two to three-fold higher than corresponding sumatriptan concentrations. No clinically significant accumulation of sumatriptan or its metabolite occurred. Overall, these studies show that sumatriptan administration via a suppository formulation is well tolerated, allows rapid absorption of sumatriptan, results in sumatriptan Cmax values that are proportional to dose from 25 to 100 mg, and is not associated with accumulation of sumatriptan or its metabolite.

Safety, tolerability, and pharmacokinetics of sumatriptan in healthy subjects following ascending single intranasal doses and multiple intranasal doses.

The delivery of sumatriptan doses intranasally could add greater flexibility in the treatment of migraine than is possible with the currently available subcutaneous and oral sumatriptan preparations. Two independent double-blind, randomized, placebo-controlled clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of intranasally administered sumatriptan following ascending single doses (three different dose levels) and multiple doses. In the four-way, crossover, ascending-dose study, 20 healthy female subjects were randomized to receive on separate occasions single intranasal spray doses of 5, 10, or 20 mg sumatriptan (as the hemisulphate salt) or placebo into one nostril. Adverse events were mild and consisted mainly of bitter taste at the back of the throat and events typical of sumatriptan administered by other routes (headache, lightheadedness and tingling). Area under the plasma sumatriptan concentration versus time curve (AUC infinity) and peak plasma concentration (Cmax) increased with the dose. Dose proportionality was demonstrated between 5 and 10 mg but not across the dose range 5-20 mg. Time to maximum plasma concentration (tmax) was variable due to multiple peaking. The elimination half-life (t1/2), approximately 2 h, was unaffected by the magnitude of dose. In the two-period, multiple-dose, crossover study, 12 healthy adult male and female subjects were randomized to receive either sumatriptan hemisulphate 20 mg or placebo, administered intranasally as a spray three times a day for 4 days. The two dosing periods were separated by 3 to 14 days. Multiple doses of sumatriptan were well tolerated, with no serious adverse events occurring or withdrawals due to adverse events. All patients reported a mild to moderate drug-related disturbance of taste. Nasal examinations remained normal, and olfactory function was unaffected. The AUC over the first 8 h following dosing (AUC8) and fraction of the dose excreted in the urine (fe; 6.2% vs 3.6%) were similar on Days 1 and 4. Day 4 values were significantly higher (p < or = 0.05) for Cmax (16.9 ng/ml vs 13.1 ng/ml), renal clearance (Clr; 19.0 l/h vs 14.2 l/h), and t1/2 (2.18 h vs 1.93 h), and shorter for tmax (0.88 h vs 1.75 h). Some accumulation (22%) occurred over the 4 days of dosing. Serum concentrations of the pharmacologically inactive indole acetic acid metabolite of sumatriptan were fourfold to fivefold higher than corresponding sumatriptan concentrations. Overall, these studies show that the sumatriptan intranasal spray formulation is well tolerated, allows rapid absorption of sumatriptan, and results in only a clinically insignificant degree of sumatriptan accumulation upon repeated dosing.

Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole.

OBJECTIVE: To determine the effect of multiple dosing of combined sulfamethoxazole and trimethoprim on the single-dose pharmacokinetics of lamivudine. METHODS: Fourteen subjects with human immunodeficiency virus who had CD4+ cells > or = 200/mm3 received two single doses of 300 mg lamivudine, separated by 7 to 14 days, in a randomized two-day crossover study. Treatment consisted of lamivudine alone versus trimethoprim-sulfamethoxazole (160/180 mg) daily on days 1 through 4 followed by lamivudine plus trimethoprim-sulfamethoxazole on day 5. Blood and urine were collected over 24 to 32 hours to determine lamivudine, trimethoprim, sulfamethoxazole, and N-4-acetylsulfamethoxazole concentrations. RESULTS: Coadministration of a single dose of lamivudine and trimethoprim-sulfamethoxazole after daily dosing for 5 days altered the pharmacokinetics of lamivudine. A 43% increase in area under the concentration-time curve (AUC infinity) and a 35% decrease in renal clearance (CLR) were observed when lamivudine was coadministered with trimethoprim-sulfamethoxazole compared with lamivudine alone. The geometric least-squares trimethoprim-sulfamethoxazole were as follows: AUC infinity, 10,124 (9,432-10,866) and 14,448 (13,461-15,508) ng . hr/ml, respectively; CLR, 16.6 (14.1-19.4) and 10.8 (9.5-12.6) L/hr, respectively. Coadministration did not significantly alter the pharmacokinetics of trimethoprim or sulfamethoxazole. CONCLUSIONS: Coadministration of lamivudine with trimethoprim-sulfamethoxazole resulted in an increased AUC infinity and a decreased CLR of lamivudine. However, given the favorable safety profile of lamivudine, it is unlikely that this interaction will result in a significant increase in concentration-related toxicity at the doses studied.

Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza.

OBJECTIVE: The current study evaluated whether intranasal administration of the sialic acid analog 4-guanidino-Neu5Ac2en (GG167), an inhibitor of influenza virus neuraminidase, was effective and safe in either preventing or treating experimental human influenza. METHODS: Four randomized, double-blind, placebo-controlled trials involving three prophylaxis limbs, two early treatment limbs, and one delayed treatment limb were conducted. SETTING: Isolation in individual rooms. PARTICIPANTS: Susceptible (serum hemagglutination-inhibition antibody titer < or = 1:8) adult volunteers (n = 166) were inoculated intranasally with 10(5) TCID50 influenza A/Texas/91 (H1N1) virus. INTERVENTION: GG167, 3.6 to 16 mg, was administered intranasally two or six times daily beginning 4 hours before inoculation (prophylaxis) or 1 or 2 days afterward (early or delayed treatment). MAIN OUTCOMES: Virological measures were frequency of infection based on viral shedding and/or seroconversion (prophylaxis) or quantitative viral shedding based on titers and duration of virus recovery (treatment). Clinical measures were the frequency of febrile illness and symptom severity scores. RESULTS: Intranasal GG167 was well tolerated for both prophylaxis and therapy. For all dose groups combined, GG167 prophylaxis was 82% effective in preventing laboratory evidence of infection and 95% effective in preventing febrile illness (P < .01 vs placebo). Early treatment with GG167 reduced peak viral titers by 2.0 log10, the median duration of viral shedding by 3 days, and the frequency of febrile illness by 85% (P < .05 for each comparison). Other measures of illness were reduced by approximately 50% to 70% in the GG167 dosing groups. Twice daily dosing was as effective as six times daily. CONCLUSIONS: Direct respiratory administration of the selective neuraminidase inhibitor GG167 appears safe and effective for both prevention and early treatment of experimental influenza. Influenza virus neuraminidase is important for viral replication in humans.

Pharmacokinetics, absolute bioavailability, and absorption characteristics of lamivudine.

Lamivudine is a novel cytosine nucleoside analog, reverse transcriptase inhibitor that has shown activity against human immunodeficiency virus (HIV) types 1 and 2 and hepatitis B virus in vitro. This study was conducted to compare the absolute bioavailability, pharmacokinetics, and absorption characteristics of oral solution, 100-mg capsule, and 100-mg tablet formulations of lamivudine with those of intravenous lamivudine. Twelve patients with HIV were enrolled in a single-center, randomized, open-label, four-way cross-over study. Treatment arms consisted of 100 mg intravenous lamivudine (administered over 1 hour), 100 mg oral lamivudine (1 mg/mL), a 100-mg capsule, and a 100-mg tablet, each followed by a 3- to 14-day washout period. Serial blood samples over 24 hours were obtained after each dose administration. Serum concentration data were analyzed to determine pharmacokinetic parameter estimates including area under the curve (AUC), terminal half-life (t1/2), mean residence time (MRT) for each formulation, systemic clearance, oral clearance, and apparent volume of distribution (Vd). Absolute bioavailability and in vivo mean absorption time (MAT) and mean dissolution time (MDT) were calculated for the oral formulations. Deconvolution techniques were used to calculate the input rate for the oral solution, capsule, and tablet. The two one-sided t test was used to determine bioequivalency among oral formulations with respect to logarithmic transformed estimates of AUC and maximum peak concentration (Cmax). Mean (CV) systemic clearance and Vdss after intravenous administration of lamivudine were 22.6 L/h (15%) and 99 L (28%), respectively; mean t1/2 ranged from 8.41 to 9.11 hours for all formulations; and MRT ranged from 4.42 to 5.77 hours for all formulations. Mean absolute bioavailability ranged from 86% to 88% for the oral solution, capsule, and tablet. All oral formulations were considered bioequivalent for AUC and Cmax. The MAT was 1.32 hour for the oral solution, and MDT was 0.03 and -0.11 hours for the capsule and the oral solution, respectively. The oral formulations of lamivudine examined in this study demonstrated acceptable bioavailability for oral administration. The solid oral formulations (capsule and tablet) show rapid dissolution properties with an absorption rate similar to or exceeding those observed with the oral solution. This suggests that dissolution is not an important factor for the rate of absorption of lamivudine. The use of deconvolution techniques using PCDCON provides valuable insight into the absorption characteristics of lamivudine.

Sumatriptan absorption from different regions of the human gastrointestinal tract.

Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.

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.

Interspecies scaling and pharmacokinetic parameters of 3TC in humans.

3TC is a dideoxy-nucleoside analogue that has demonstrated in-vitro activity against human immunodeficiency virus (HIV). 3TC concentrations in humans were predicted before the initiation of clinical trials by interspecies scaling of pharmacokinetic parameters observed in animal species. Clearance and volume of distribution were estimated for humans using linear regression on a log-log scale of each parameter versus body weight for rats and dogs. The concentration-time profile and the average serum concentration at steady state after various dosage regimens were estimated as a basis for initial dose selection for clinical trials. The predicted parameters (clearance of 16.3 L/hr and volume of distribution of 40 L for a 70-kg man) were compared with that observed (mean clearance of 24 L/hr and mean volume of distribution of 96 L, mean weight of 74 kg) in 20 asymptomatic, HIV positive, volunteers after single intravenous doses of 3TC. Interspecies scaling was applied prospectively as a rationale for dose selection of 3TC in clinical trials.

The safety and pharmacokinetics of a reverse transcriptase inhibitor, 3TC, in patients with HIV infection: a phase I study.

OBJECTIVE: To determine the safety and pharmacokinetics of the nucleoside analogue, 3TC. DESIGN: A Phase I, open-label, single-centre study. METHODS: Twenty asymptomatic, HIV-infected male patients with CD4 lymphocyte counts < 500 x 10(6)/l who had not received previous antiretroviral therapy completed the study. Each patient received a single intravenous dose followed by a single oral dose of 3TC. Four patients were dosed at each of five dose levels (0.25, 1.0, 2.0, 4.0 and 8.0 mg/kg). RESULTS: The most commonly reported adverse event was headache, which was generally reported to be mild. The mean bioavailability of 3TC was 82% following oral administration. The majority of the dose (approximately 70%) was excreted unchanged in the urine. CONCLUSIONS: Overall, 3TC was well tolerated following dosing, and there were no significant changes in the safety parameters measured. Phase I/II clinical trials with 3TC are ongoing to evaluate its safety, pharmacokinetics and preliminary activity.

Comparison of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine.

Twelve healthy male subjects completed this randomized, placebo controlled, four-period crossover trial to determine the effect of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine. Subjects received a 7-day course of one of four treatments; verapamil (120 mg every 8 hr), diltiazem (90 mg every 8 hr), labetalol (200 mg every 12 hr), or placebo (every 12 hr) during each study period. Imipramine (100 mg) was administered orally on the morning of day 4 of each study period. Plasma and urine samples were collected periodically over the ensuing 96 hours. Samples were assayed by HPLC for imipramine, desipramine, 2-hydroxyimipramine, and 2-hydroxydesipramine. Verapamil, diltiazem, and labetalol increased imipramine area under the plasma concentration time curve (relative bioavailability) as compared with placebo by 15%, 30%, and 53%, respectively. Verapamil and diltiazem did not demonstrate consistent changes in the formation of the measured metabolites. Labetalol caused a significant decrease in the amount of imipramine metabolized to 2-hydroxyimipramine (mean decrease: 22%) and from desipramine to 2-hydroxydesipramine (mean decrease: 8%). The molar ratios of plasma AUC of 2-hydroxyimipramine and 2-hydroxydesipramine to the parent compounds were significantly decreased. Since these metabolic processes are dependent on the cytochrome P450IID6 isozyme, these data suggest that labetalol decreases the oral clearance of imipramine by inhibiting this system. All three of these commonly used agents decreased the oral clearance of imipramine. These drug interactions could lead to elevated imipramine concentrations and have the potential for clinically important adverse events.

Albuterol extended-release products: effect of food on the pharmacokinetics of single oral doses of Volmax and Proventil Repetabs in healthy male volunteers.

The absorption of albuterol from a single 4-mg oral dose of Volmax and Proventil Repetabs was investigated under both fasting and fed conditions in an open-label, randomized, four-period, crossover study in 24 healthy male volunteers. Blood was collected for determination of albuterol plasma concentrations by HPLC over 30 hours postdose. Twenty subjects were evaluable for data analysis. The mean Cmax for Volmax; administered after a meal was 19% lower than that of the drug administered in a fasting state (3.9 ng/mL vs. 4.8 ng/mL; P less than .01). An almost equivalent lowering of the mean Cmax (by 21%) was observed for Proventil Repetabs after administration with a meal versus fasting (4.2 ng/mL vs. 5.3 ng/mL; P less than .01). There were no significant differences between the two formulations in the degree of Cmax reduction due to the presence of food. The tmax occurred significantly later during the fed treatment for Volmax only (4.9 hours fasted vs. 6.4 hours fed; P less than .01). The lag time was significantly greater during the fed treatments for Volmax. No differences were observed in the area under the plasma concentration-time curve (AUC) for either formulation under fasting versus fed conditions, suggesting that the extent of absortion was not altered by food. Overall, food caused a more sustained release of albuterol from both Volmax and Proventil Repetabs.

Albuterol extended-release products: a comparison of steady-state pharmacokinetics.

A new extended-release formulation of albuterol, Volmax, was developed based on the oral osmotic drug delivery system. Proventil Repetabs, another extended-release formulation of albuterol, is a repeat-action tablet. The steady-state pharmacokinetic profile of Volmax 8 mg orally every 12 hours for 3 days was compared with that of Proventil Repetabs 8 mg orally every 12 hours for 3 days in a randomized, two-way, crossover study in 23 healthy men. Results were determined for both daytime and nighttime dosing intervals. Volmax demonstrated significantly less peak-trough fluctuation during both dosing intervals than Proventil Repetabs (p less than 0.05). Peak plasma concentrations were higher and occurred earlier with Proventil Repetabs. There were no significant differences between the two formulations with respect to reported adverse experiences. Volmax exhibited a more controlled release of albuterol during both daytime and nighttime dosing intervals than Proventil Repetabs.

Evaluation of the pharmacokinetic interaction between diazepam and ACC-9653 (a phenytoin prodrug) in healthy male volunteers.

The protein binding and pharmacokinetics of diazepam, ACC-9653 (a phenytoin prodrug), and phenytoin were evaluated in nine healthy male volunteers following administration of diazepam and ACC-9653, alone or concomitantly, in a randomized crossover design. No significant differences were observed in the fraction unbound or pharmacokinetic parameters of ACC-9653, phenytoin, or diazepam when ACC-9653 was administered alone compared to concomitant administration with diazepam. The phenytoin fraction unbound increased significantly with increased concentrations of ACC-9653, indicating displacement of phenytoin from its binding sites by ACC-9653. ACC-9653 also demonstrated concentration dependent binding. The lack of a significant pharmacokinetic drug interaction between ACC-9653 and diazepam suggests that these drugs may be safely administered together, although this conclusion should be confirmed in the intended patient population.

Correlation of delayed peak concentration with infusion-site irritation following diazepam administration.

Diazepam 10 mg/2 mL iv was administered undiluted over five minutes to nine healthy men on two separate occasions. The infusion site was evaluated before and after each infusion by subject assessment of pain on a severity scale of zero (none) to ten (most). Blood samples were collected at 0, 5, 20, 30, 45, and 60 minutes, and periodically for 72 hours postinfusion. Diazepam plasma concentrations were determined by HPLC. Concentrations at five minutes (end of infusion) ranged from 0 to 889 ng/mL. Maximum plasma concentration (Cmax) was observed at 5 minutes for 10 treatments, at 20 minutes for 7 treatments, and at 30 minutes for 1 treatment. The observed Cmax ranged from 221 to 889 ng/mL. When time to reach peak plasma concentration (tmax) was 5 minutes, the Cmax was significantly greater than when tmax was 20 minutes (670 +/- 87 vs. 267 +/- 40 ng/mL, p less than 0.005). The area under the curve did not differ significantly between these two groups. The pain score at the end of infusion ranged from zero to five and was inversely related to the concentration at five minutes (r2 = 0.45, p = 0.002). The association between venous irritation, a low plasma concentration at the end of the infusion, and a delayed Cmax suggests that diazepam precipitated in the vein.