Effect of dietary fat content in meals on pharmacokinetics of quazepam

Dietary fat content in meals has been reported to increase the absorption of several drugs proportionately. However, there is no information about the effects of dietary fat in meals on the sedative hypnotic agent quazepam, although limited data suggest that food intake alters quazepam absorption. Therefore, the authors measured and compared pharmacokinetic parameters of quazepam taken in a fasted state and taken 30 minutes after consuming meals containing different amounts of dietary fat. A three-arm randomized crossover study was conducted. Nine healthy male volunteers took a single oral 20-mg dose of quazepam under the following conditions: (1) after fasting overnight for at least 12 hours, (2) 30 minutes after consuming a low-fat meal (two slices of bread and 200 ml of apple juice), or (3) 30 minutes after consuming high-fat meal (two slices of bread with 30 gm of butter and 200 ml of apple juice). Plasma concentrations of quazepam and its metabolite, 2-oxoquazepam, were monitored up to 48 hours after the dosing. In comparison with corresponding plasma values for quazepam taken in a fasting state, the peak concentrations (Cmax) of quazepam taken 30 minutes after consuming a low-fat meal and high-fat meal were 243% (90% confidence interval [CI] = 161%-325%) and 272% (90% CI = 190%-355%), respectively. Area under the plasma concentration-time curve from 0 to 8 hours (AUC(0-8)) and 0 to 48 hours (AUC(0-48)) of quazepam was increased with the low-fat meal by 2-fold (90% CI = 1.5- to 2.7-fold) and 1.4-fold (90% CI = 1.0- to 1.7-fold), respectively, and with the high-fat meal by 2.2-fold (90% CI = 1.3- to 3-fold) and 1.5-fold (90% CI = 0.7- to 2.4-fold), respectively. The pharmacokinetic change in 2-oxoquazepam to the parent compound was similar. Quazepam was well tolerated, with no significant difference in the Stanford Sleepiness Scale between fasted and fed conditions. These findings show that food intake has an evident effect on quazepam absorption, but further studies are needed to clarify a determinant factor of this alteration (2.5-fold for Cmax and 2.1-fold for AUC(0-8), on average). It might not be necessary to do dose adjustment with meal content because quazepam is well tolerated.     

Drug interaction between St John's Wort and quazepam

AIM: St John's Wort (SJW) enhances CYP3A4 activity and decreases blood concentrations of CYP3A4 substrates. In this study, the effects of SJW on a benzodiazepine hypnotic, quazepam, which is metabolized by CYP3A4, were examined. METHODS: Thirteen healthy subjects took a single dose of quazepam 15 mg after treatment with SJW (900 mg day(-1)) or placebo for 14 days. The study was performed in a randomized, placebo-controlled, cross-over design with an interval of 4 weeks between the two treatments. Blood samples were obtained during a 48 h period and urine was collected for 24 h after each dose of quazepam. Pharmacodynamic effects were determined using visual analogue scales (VAS) and the digit symbol substitution test (DSST) on days 13 and 14. RESULTS: SJW decreased the plasma quazepam concentration. The Cmax and AUC(0-48) of quazepam after SJW were significantly lower than those after placebo [Cmax; -8.7 ng ml(-1) (95% confidence interval (CI) -17.1 to -0.2), AUC0-48; -55 ng h ml(-1) (95% CI -96 to -15)]. The urinary ratio of 6beta-hydroxycortisol to cortisol, which reflects CYP3A4 activity, also increased after dosing with SJW (ratio; 2.1 (95%CI 0.85-3.4)). Quazepam, but not SJW, produced sedative-like effects in the VAS test (drowsiness; P < 0.01, mental slowness; P < 0.01, calmness; P < 0.05, discontentment; P < 0.01). On the other hand, SJW, but not quazepam impaired psychomotor performance in the DSST test. SJW did not influence the pharmacodynamic profile of quazepam. CONCLUSIONS: These results suggest that SJW decreases plasma quazepam concentrations, probably by enhancing CYP3A4 activity, but does not influence the pharmacodynamic effects of the drug.     

Influence of food intake on the bioavailability and efficacy of oral calcitonin

AIMS

To investigate the influence of food intake on the bioavailability and pharmacodynamic effects of salmon calcitonin (sCT).

METHODS

A single-blind, randomized, partly placebo-controlled study was conducted in 36 healthy postmenopausal female volunteers aged 62–74 years. The influence of food intake on oral dosing with 0.8 mg of sCT at 22.00 h was evaluated for a (i) predose meal at 18.00 h, (ii) predose meal at 20.00 h, (iii) predose meal at 21.00 h, (iv) postdose meal at 22.10 h, (v) no meal, and (vi) meal at 20.00 h and placebo at 22.00 h. Study biomarkers were plasma sCT levels and changes in the bone resorption marker CTX-I (C-terminal telopeptide of collagen type I).

RESULTS

The predose meal at 18.00 and 21.00 h significantly decreased relative oral bioavailability of sCT to 26% [95% confidence interval (CI) 0.09, 0.73 and 0.09, 0.75, P= 0.009 and P= 0.01]. The meal consumed 10 min after dosing decreased the oral bioavailability of sCT to 59% (95% CI 0.21, 1.68), although nonsignificant (P= 0.48). This decreased bioavailability led to lower relative suppression of serum CTX-I, with an AUC of the 4-h efficacy response of −91%–×–hours for those receiving a meal at 18.00 h, compared with −238%–×–hours for fasting subjects. The Dunnett-adjusted difference between these two treatment sequences was 147%–×–hours (95% CI 68, 225) (P= 0.0003). The AUC was comparable among fasting subjects and those consuming a meal 10 min after dosing.

CONCLUSIONS

Postprandial dosing may limit the bioavailability of orally administered sCT. Maximal benefit can be achieved by dosing at least 10 min prior to meal time.     

Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam

Objective: Grapefruit juice (GFJ) inhibits cytochrome P450 (CYP) 3A4 in the gut wall and increases blood concentrations of CYP3A4 substrates by the enhancement of oral bioavailability. The effects of GFJ on two benzodiazepine hypnotics, triazolam (metabolized by CYP3A4) and quazepam (metabolized by CYP3A4 and CYP2C9), were determined in this study. Methods: The study consisted of four separate trials in which nine healthy subjects were administered 0.25 mg triazolam or 15 mg quazepam, with or without GFJ. Each trial was performed using an open, randomized, cross-over design with an interval of more than 2 weeks between trials. Blood samples were obtained during the 24-h period immediately following the administration of each dose. Pharmacodynamic effects were determined by the digit symbol substitution test (DSST) and utilizing a visual analog scale. Results GFJ increased the plasma concentrations of both triazolam and quazepam and of the active metabolite of quazepam, 2-oxoquazepam. The area under the curve (AUC)(0–24) of triazolam significantly increased by 96% (p<0.05). The AUC(0–24) of quazepam (+38%) and 2-oxoquazepam (+28%) also increased; however, these increases were not significantly different from those of triazolam. GFJ deteriorated the performance of the subjects in the DSST after the triazolam dose (−11 digits at 2 h after the dose, p<0.05), but not after the quazepam dose. Triazolam and quazepam produced similar sedative-like effects, none of which were enhanced by GFJ. Conclusion These results suggest that the effects of GFJ on the pharmacodynamics of triazolam are greater than those on quazepam. These GFJ-related different effects are partly explained by the fact that triazolam is presystemically metabolized by CYP3A4, while quazepam is presystemically metabolized by CYP3A4 and CYP2C9.     

Chronotherapy of high-dose active vitamin D3 in haemodialysis patients with secondary hyperparathyroidsm: a repeated dosing study

AIMS: Renal osteodystrophy is the major complication in patients with end-stage renal failure. Oral or intravenous vitamin D3 (D3) is given to these patients, but severe hypercalcaemia sometimes interrupts this therapy. This study was undertaken to determine whether the effectiveness and safety of D3 also depend on its dosing time during a repeated treatment. METHODS: A higher dose (3 micro g) was given orally to 13 haemodialysis patients at 08.00 h or 20.00 h for 12 months by a randomized, cross-over design. RESULTS: Three patients were withdrawn due to severe hypercalcaemia after switching from 08.00 h to 20.00 h dosings. The elevation in serum calcium concentration was significantly (P < 0.001) greater during the 08.00 h dosing in the remaining ten patients. Mean serum Ca concentration after the trial was 10.92 (95% confidence interval (CI) 10.79, 11.06) and 9.55 mg dl-1 (95% CI 9.30, 9.71) by 08.00 h and 20.00 h dosing, respectively. On the other hand, the suppression of the elevated serum parathyroid hormone (PTH) and subsequent increment in bone density were significantly greater during the 08.00 h dosing. Mean PTH concentration after the trial was 414 (95% CI 360, 475) and 220 pg ml-1 (95% CI 202, 249) by 08.00 h and 20.00 h dosing, respectively (P = 0.02). Mean increment of bone density after the trial was 22 (95% CI 8, 32) and 57 g cm-3 (95% CI 43, 83) by 08.00 h and 20.00 h dosing, respectively (P = 0.04). CONCLUSION: These results indicate that a higher dose of oral D3 is more effective and safe after dosing at evening in patients with renal osteodystrophy.     

Pharmacokinetics and pharmacodynamics of single-dose oral tolvaptan in fasted and non-fasted states in healthy Caucasian and Japanese male subjects

Purpose

To compare the pharmacokinetics and pharmacodynamics of tolvaptan in Caucasian and Japanese healthy male subjects under fasting and non-fasting conditions.

Methods

This was a single-center, parallel-group, randomized, open-label, three-period crossover trial of single oral doses of tolvaptan 30?mg under fasting and non-fasting [a high-fat, high-calorie meal (HFM) or Japanese standard meal] conditions in 25 healthy male Caucasian subjects and 24 healthy male Japanese subjects. Pharmacodynamic endpoints were urine volume and fluid balance for 0 to 24?h postdose.

Results

In the fasted state, the plasma tolvaptan C_max and AUC_∞ geometric mean ratios (90 % confidence interval) were 1.105 (0.845–1.444) and 1.145 (0.843–1.554) for Japanese compared to Caucasian subjects. A HFM increased the C_max and AUC_∞ values by about 1.15-fold in both Japanese and Caucasian subjects.. Twenty-four-hour urine volumes paralleled pharmacokinetic changes, but the increases were not clinically significant. Fluid balance in the Japanese men was 1.4- to 2.0-fold more negative than that in the Caucasian men.

Conclusion

Tolvaptan pharmacokinetics is not clinically significantly affected by race. Body weight is a factor that affects exposure. Tolvaptan can be administered with or without food.     

Differences in lercanidipine systemic exposure when administered according to labelling: in fasting state and 15 minutes before food intake

Purpose

The aim of this study was to compare the systemic exposure of lercanidipine (Zanidip) after oral administration in the fasted state and 15?min before food intake (meals) to investigate if the recommendations in the Summary of Product Characteristics (SPC) with respect to the intake of meals are adequate.

Methods

The results of three pilot bioequivalence studies performed to develop a lercanidipine generic product, where Zanidip was administered consistently as reference product in the fasted state or 15?min before a standard breakfast, were compared to estimate the drug–food interaction and the similarity of the methods of administration defined in the SPC.

Results

The ingestion of a standard (non-high-fat, non-high-calorie) meal 15?min after drug intake increased the area under the concentration–time curve (AUC_0-t) of S-lercanidipine by 1.78-fold [90% confidence interval (CI) 1.48–2.15, P?max) of S-lercanidipine by 1.82-fold (90% CI 1.46–2.28, P?Conclusions As intake with a carbohydrate-rich meal is not recommended in the SPC of Zanidip because a twofold difference was considered to be clinically relevant, the intake of lercanidipine only 15?min before food intake does not seem to be consistent with this recommendation. The Marketing Authorisation Holder should clarify the dosing instructions in relation to meals and identify a sufficient time-lapse to ensure an exposure similar to that obtained in phase III clinical efficacy studies.     

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem in healthy subjects

AIMS: To assess the effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem. METHODS: In a randomized cross-over study with two phases, 10 healthy subjects ingested 10 mg of zolpidem with or without oral voriconazole pretreatment. The concentrations of zolpidem were measured in plasma up to 24 h and pharmacodynamic variables were monitored for 12 h. RESULTS: Voriconazole increased the peak plasma concentration of zolpidem by 1.23-fold [P < 0.05; 90% confidence interval (CI) 1.05, 1.45] and the area under the plasma zolpidem concentration-time curve by 1.48-fold (P < 0.001; 90% CI 1.29, 1.74). The time to peak plasma zolpidem concentration was unchanged by voriconazole but the half-life was prolonged from 3.2 to 4.1 h (P < 0.01; 95% CI on the difference 0.27, 1.45). The pharmacodynamics of zolpidem were unaffected by voriconazole. CONCLUSION: Voriconazole caused a moderate increase in exposure to zolpidem in healthy young subjects but no clear pharmacodynamic changes were observed between the groups.     

The effect of the fat content of food on the pharmacokinetics and pharmacodynamics of SDZ FOX 988, an antidiabetic agent,in the dog

SDZ FOX 988 (FOX 988) is being developed for the treatment of type II diabetes. The objective of this study was to examine the effect of the fat content of food on the pharmacokinetics and pharmacodynamics of FOX 988 following oral administration in the dog. In a randomized, cross-over design, four dogs received a single 10 mg kg^?1 dose of ¹⁴C-FOX 988 suspension concomitantly with food containing 10% fat or 40% fat, or with the 10% fat food at 4 h post-dose. Serial blood, urine, and fecal samples were collected for 96 h and analyzed for total radioactivity. Blod concentrations of 53–450, the active metabolite of FOX 988, were also determined. Serum concentrations of β-hydroxybutyrate and glucose, pharmacological markers for the antidiabetic effects, were measured serially for 24 h after dosing. The animals receiving the low-fat meal at dosing and at 4 h post-dose exhibited similar extents of absorption, as shown by similar AUC values and urianry radioactivity recovery. Administration of the high-fat meal at dosing significantly enhanced the absorption of FOX 988 and resulted in high blood concentrations of 53–450. However, no significant differences in the pharmacological activity of the drug were observed among the three treatments.     

Ibopamine (SK&F 100168) pharmacokinetics in relation to the timing of meals.

The effect of the timing of a standard meal relative to a single oral dose of 200 mg ibopamine, on the appearance of its pharmacologically active metabolite, epinine, in plasma was investigated in a randomised crossover study in 12 healthy volunteers. After a 12 h fast, ibopamine was administered either in the fasting state (no meal), or 1 h before, 0.5 h before, immediately after, 2 h after or 3 h after a standardised meal. Blood samples taken immediately before and at intervals for 3 h after dosing were analysed for free epinine. Maximum concentration (Cmax), time to Cmax(tmax), and area under the concentration-time curve (AUC) for free epinine in plasma were calculated. When compared with the fasting state, Cmax and AUC0-3h were significantly reduced when ibopamine was given immediately after or 2 h after a meal. AUC was also reduced for ibopamine given 0.5 h before a meal. tmax was significantly delayed when ibopamine was given immediately after, or 2 or 3 h after a meal. Thus, administration of ibopamine with or shortly after a meal reduced the rate and extent of appearance of free epinine in plasma. The clinical significance of reduced epinine levels on acute dosing in the presence of food is unknown.     

6-Thioguanine in children with acute lymphoblastic leukaemia: influence of food on parent drug pharmacokinetics and 6-thioguanine nucleotide concentrations

AIMS: Since relatively little is known about the pharmacokinetics of 6-thioguanine (6TG) in children receiving 6-thioguanine for maintenance therapy of acute lymphoblastic leukaemia (ALL), we studied plasma drug concentrations under standardized conditions and investigated the effect of food on parent drug pharmacokinetics and the accumulation of the active metabolites 6-thioguanine nucleotides (6-TGNs) in red cells. METHODS: Single oral doses of 40 mg of 6-TG were administered both in the fasting and fed state to children with ALL. Pharmacokinetic sampling was performed up to 6 h post dose. Daily oral doses of 40 mg m(-2) of 6-TG were administered both fasting and after food over two 4 week periods. Twice weekly samples were taken for metabolite concentrations. The study design was cross-over with each child receiving dosing in either fasted or after food over a 4 week period in each phase. RESULTS: Eleven patients were studied. A wide interindividual variation in Cmax (median 313 pmol ml(-1), range 51-737) and AUC (median 586 pmol ml(-1) h, range 156-1306) was observed in the fasted state. Concomitant food administration resulted in a significant reduction in Cmax (median 71 vs 313 pmol ml(-1), P = 0.006, CI from 36 to 426), AUC (median 200 vs 586 pmol ml(-1) h, P = 0.006, 95% CI from 109 to 692), and time to reach Cmax (median 1.5 vs 3 h, P = 0.013, 95% CI from 0.74 to 2.73). There was no difference in the steady state concentration of red cell 6-TGNs observed after a 4 week period of 6-TG administered fasting or after food. CONCLUSIONS: Children with ALL demonstrate significant interindividual variation in 6-TG pharmacokinetics. Although there would appear to be a reduction in parent drug Cmax and AUC with food there was no difference in 6-TGN concentrations after 4 weeks of 6-TG. Taking the drug on an empty stomach may not be necessary.     

Effects of foods on the pharmacokinetics and clinical efficacy of quazepam.

The effects of foods on the pharmacokinetics and clinical efficacy of quazepam, a benzodiazepine derivative, in healthy persons were examined. Six healthy Japanese male subjects were randomly divided into three groups and each subject was treated with quazepam under the following three conditions by the crossover method. For the fasting state, subjects were administered 15 mg quazepam 11 hours after a meal. For the postprandial state, subjects were administered 15 mg or 30 mg quazepam 2 hours after a meal. Mean peak plasma concentration (Cmax) of quazepam was significantly higher [1.6-2.8 fold] with administration 2 hours after a meal than 11 hours after a meal. However, in regard to 15 mg of quazepam administration, the area under the curve (AUC) did not differ between administration 2 hours after a meal and 11 hours after a meal. In addition, differences were observed neither in other pharmacokinetic parameters or blood metabolite concentration under all of the study conditions, nor in clinical evaluation of subjective symptoms, complete blood count, or biochemical analyses between administrations 2 and 11 hrs after a meal. The present study showed that administration 2 hours after a meal did not affect subjective symptoms or physical functions so much; therefore it suggested favorable tolerance of this drug. However, it was also suggested that, in actual clinical use, it is important to evaluate the physical function including measurements of vital signs and hematological test results, carefully considering the effects of foods and daily life-style.     

Within- and between- subject variability in methadone pharmacokinetics and pharmacodynamics in methadone maintenance subjects

AIMS: To investigate within- and between-subject variability of the pharmacodynamics and pharmacokinetics of (R)- and (S)-methadone in methadone maintenance subjects at steady-state. METHODS: Six non-holder subjects were studied on three occasions at 7-16 day intervals; doses (20-170 mg/day) remained unchanged. Blood samples and pharmacodynamic data were collected 10-12 times over a 24-h inter-dosing interval. All pharmacodynamic data were expressed as the area under the end-point versus time curve. Using analyses of variance with mixed effects, best estimates were made of the ratio of between- to within-subject variation, with corresponding 95% confidence intervals (CI) for within-subject variation at the average value. RESULTS: Subjects were relatively consistent between occasions, whereas there was much greater between-subject variability (P < 0.02) for all measures. Estimates of the ratio of between- to within-subject variation ranged from 2.2-12.8 for pharmacodynamic measures, and 1.3-7.9 for pharmacokinetic parameters. For pain, total mood disturbance, withdrawal, pupil size and respiration rate, 95% CI for within-subject measures ranged < or = 2-fold, while this was greater for subjective direct opioid effects (4.2-fold). For CL/F of the active (R)-methadone, the variance ratio was 4.9 (P < 0.0003), with 95% CI for within-subject measures ranging < or = 2-fold. (S)-methadone CL/F demonstrated greater within-subject variability (3.4-fold), possibly contributing to a smaller (2.7; P < 0.0003) ratio of between- to within-subject variance. CONCLUSIONS: Non-holder methadone maintenance treatment participants appear to respond consistently with respect to pharmacokinetics and pharmacodynamics over a 1-2 month period. Such knowledge may help prescribers to determine whether alternative dosing regimens or treatments might be more appropriate in this population.     

Effect of timing of dosing in relation to food intake on the pharmacokinetics of esomeprazole

AIM: To investigate the pharmacokinetics of esomeprazole before a high-fat meal vs. fasting. METHODS: This open-label, randomized, crossover study consisted of two 5-day dosing periods of esomeprazole 40 mg per day. On days 1 and 5, subjects received esomeprazole 15 min before a high-fat meal (fed) or 4 h before a non-high-fat meal (fasting). RESULTS: On days 1 and 5, ratio of fed to fasting area under the plasma concentration-time curve [0.56, 90% confidence interval (CI) 0.50, 0.64, and 0.78, 90% CI 0.74, 0.82, respectively] and peak plasma concentration (0.34, 90% CI 0.28, 0.41, and 0.47, 90% CI 0.41, 0.52, respectively) were outside of the limits of bioequivalence. CONCLUSIONS: Esomeprazole bioavailability was reduced when taken within 15 min before eating a high-fat meal vs. that while fasting.     

Effect of food on the absorption of frusemide and bumetanide in man

1 The influence of food on the absorption of frusemide and bumetanide was compared in two separate randomized crossover studies. 2 On three separate occasions frusemide 40  mg was administered to eight healthy male volunteers intravenously, orally in the fasting state and orally after a standard breakfast. Blood and urine were collected at intervals over 8  h and urine alone for a further 16  h. The study was then repeated in nine healthy volunteers using intravenous and oral bumetanide 2  mg. 3 Breakfast significantly reduced the peak plasma concentration of frusemide from 2.35±0.49 to 0.51±0.19  mg l⁻¹ (95% confidence intervals (95% CI)=1.39 to 2.28  mg l⁻¹) and delayed the time to peak concentration from 0.69±0.21 to 1.91±0.93  h (95% CI=0.41 to 2.03  h). The oral bioavailability of frusemide was significantly reduced by approximately 30% (75.6±10.6 to 43.2±16.8%; 95% CI=13.5 to 51.4%). 4 With bumetanide, the meal also significantly reduced the peak concentration from 0.097±0.015 to 0.036±0.012  mg l⁻¹ (95% CI=0.048 to 0.073  mg l⁻¹) and delayed the time to peak from 0.53±0.08 to 1.36±0.72  h (95% CI=0.23 to 1.44  h). However, food had no statistically significant effect on the bioavailability and urinary recovery of bumetanide. 5 In this study, the absorption of bumetanide was affected less than frusemide by food.     

Clofibrate raises human 24 h intragastric acidity but does not affect plasma gastrin concentration.

1. We studied the effects of acute oral dosing with clofibrate (500 mg four times daily) on 24 h intragastric acidity and plasma gastrin concentration in 12 healthy female subjects. 2. The 24 h integrated intragastric acidity rose from 429 mmol l-1 h (95% CI 296-479) before dosing to 527 mmol l-1 h (95% CI 385-664) on the day of dosing (+23%; P = 0.041), but no change was observed in the 24 h integrated plasma gastrin concentration: 420 pmol l-1 h (95% CI 282-499) before and 389 pmol l-1 h (95% CI 249-489) during dosing (P = 0.182). 3. We conclude that clofibrate has no acute antisecretory effect on the human stomach, and that human gastrin-induced enterochromaffin-like cell proliferation is unlikely with this drug.     

Single oral dose pharmacokinetics of quazepam is influenced by CYP2C19 activity

The effects of cytochrome P450 (CYP)2C19 activity and cigarette smoking on the single oral dose pharmacokinetics of quazepam were studied in 20 healthy Japanese volunteers. Twelve subjects were extensive metabolizers (EMs), and 8 subjects were poor metabolizers (PMs) by CYP2C19 as determined by the PCR-based genotyping. Nine subjects were smokers (>10 cigarettes/d), and 11 subjects were nonsmokers. The subjects received a single oral 20-mg dose of quazepam, and blood samplings and evaluation of psychomotor function were conducted up to 72 hours after dosing. Plasma concentrations of quazepam and its active metabolite 2-oxoquazepam (OQ) were measured by HPLC. There were significant differences between EMs and PMs in the peak plasma concentration (mean +/- SD: 34.5 +/- 16.6 versus 66.2 +/- 19.2 ng/mL, P < 0.01) and total area under the plasma concentration-time curve (490.1 +/- 277.5 vs 812.1 +/- 267.2 ng x h/mL, P < 0.05) of quazepam. The pharmacokinetic parameters of OQ and pharmacodynamic parameters were not different between the 2 groups. Smoking status did not affect the pharmacokinetic parameters of quazepam and OQ or pharmacodynamic parameters. The present study suggests that the single oral dose pharmacokinetics of quazepam are influenced by CYP2C19 activity but not by cigarette smoking.     

The effect of dosing regimen on the pharmacokinetics of risedronate

AIMS: To examine the effect of timing of a risedronate dose relative to food intake on the rate and extent of risedronate absorption following single-dose, oral administration to healthy male and female volunteers. METHODS: A single-dose, randomized, parallel study design was conducted with volunteers assigned to four treatment groups (31 or 32 subjects per group, 127 subjects total). Each subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h and were dosed 1 and 0.5 h, respectively, before a high-fat breakfast; and Group 4 was dosed 2 h after a standard dinner. Blood and urine samples were collected for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous analysis of risedronate serum concentration and urinary excretion rate-time data. RESULTS: Extent of risedronate absorption (AUC and Ae ) was comparable (P=0.4) in subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a significantly greater extent of absorption occurred when risedronate was given 1 or 4 h prior to a meal (1.4- to 2.3-fold greater). Administration 0.5, 1, or 4 h prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8-, 3.5-, and 4.1-fold greater, respectively) when compared with 2 h after dinner. CONCLUSIONS: The comparable extent of risedronate absorption when administered either 0.5-1 h before breakfast or 2 h after an evening meal support previous clinical studies where risedronate was found to have similar effectiveness using these dosing regimens. This flexibility in the timing of risedronate administration may provide patients an alternative means to achieve the desired efficacy while maintaining their normal daily routine.     

Absence of circadian variation in the pharmacokinetics of lopinavir/ritonavir given as a once daily dosing regimen in HIV-1-infected patients

AIMS: To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening. METHODS: This was a randomized, two-way, cross-over study in HIV+ subjects. In each subject the pharmacokinetics of each drug were characterized after 2 weeks of LPV/r 800/200 mg administered once daily at 08.00 h and 19.00 h. On study days, LPV/r was taken with a standardized meal (800 kCal, 25% from fat) after fasting for at least 5 h. LPV/r concentrations were measured by LC-MS/MS, and the data were analyzed by noncompartmental pharmacokinetic analysis. RESULTS: Fourteen subjects completed the study (all men, mean age/weight 44 year/81 kg). The median (interquartile range) LPV AUC(0,24 h), maximum plasma concentration (C(max)) and concentration at the end of the dosing interval (C(24 h)) after am and pm dosing was, respectively, 143 (116-214) mg l(-1) h, 12.8 (10.3-17.2) mg l(-1), 1.34 (0.58-3.25) mg l(-1), and 171 (120-232) mg l(-1) h, 12.9 (8.22-16.3) mg l(-1), 1.15 (0.59-1.98) mg l(-1). The geometric mean ratio (GMR, am : pm) and 95% CI of the LPV AUC(0,24 h), C(max), and C(24 h) was 0.91 (0.79, 1.06), 1.11 (0.94, 1.32), and 1.19 (0.72, 1.96), respectively. The median ritonavir C(max) after am and pm dosing was 1.05 and 0.90 mg l(-1), respectively. The GMR (95% CI) of the RTV AUC(0,24 h), C(max), and C(24 h) was 0.93 (0.80, 1.08), 1.27 (1.00, 1.63), and 1.04 (0.68, 1.60), respectively. Administration of LPV/r in a once-daily regimen was generally well tolerated. CONCLUSIONS: No differences were observed in the pharmacokinetics of LPV/r after am or pm dosing with food, which suggests that this once daily combination, can be taken in the morning or evening. Such flexibility in dosing may improve adherence.     

Effect of food on the pharmacokinetics of the oral phosphodiesterase 5 inhibitor udenafil for the treatment of erectile dysfunction

AIMS

Udenafil is a cyclic guanosine 3′,5′-monophosphate-specific phosphodiesterase type 5 (PDE5) inhibitor developed for the treatment of erectile dysfunction. The aim was to evaluate the effect of food on the pharmacokinetics of udenafil.

METHODS

An open, randomized, three-way crossover study was conducted. Fifteen healthy male volunteers received a single 200-mg oral dose of udenafil while fasting, after a low-fat meal, and after a high-fat meal separated by 7-day washout periods. Serial blood samples were taken up to 48 h after oral administration.

RESULTS

Under fasting conditions, udenafil was rapidly absorbed and t_max was observed typically 1.5 h after administration. The mean t_max values after a low-fat meal and a high-fat meal were 2.6 and 2.1 h, respectively. The ratios (90% confidence intervals) of the geometric means compared with the fasting condition for C_max and AUC_last were 0.79 (0.70, 0.90) and 0.96 (0.89, 1.03) in the low fat-fed condition, respectively, and 1.01 (0.89, 1.15) and 1.03 (0.96, 1.11), respectively, in the high fat-fed condition.

CONCLUSIONS

The t_max of udenafil was delayed under the fed conditions. However, although the C_max was reduced by approximately 21% in the low fat-fed state, overall bioavailability was not affected when taken with food.