Effect of antacid suspension on the pharmacokinetics of ibuprofen

The effect of antacid administration on the pharmacokinetics of ibuprofen was evaluated in a randomized, crossover study of eight healthy volunteers. Doses of 62 mL of aluminum and magnesium hydroxide suspension and single doses of ibuprofen 400 mg were used. Subjects received each of the following treatments at one-week intervals: ibuprofen alone; ibuprofen administered concurrently with one dose of antacid; antacid administered one hour after the ibuprofen dose; and antacid administered concurrently with the ibuprofen dose, plus three more antacid doses given every five hours. Blood samples were taken at various time intervals up to 24 hours after the ibuprofen dose. Serum samples were assayed for ibuprofen content using high-performance liquid chromatography. Values for AUC, Cmax, tmax, and k were not significantly different among treatment groups. The ranges of mean (+/- S.D.) values were 113.97 +/- 21.5 to 127.53 +/- 29.3 micrograms.hr/mL for AUC, 35.30 +/- 6.40 to 41.00 +/- 10.00 micrograms/mL for Cmax, 0.95 +/- 0.30 to 1.28 +/- 0.54 hr for tmax, and 0.346 +/- 0.026 to 0.388 +/- 0.040 hr-1 for k. For the doses used, concurrent administration of aluminum and magnesium hydroxide suspension and ibuprofen does not alter ibuprofen pharmacokinetics.     

The influence of gastric emptying on droxicam pharmacokinetics

Droxicam is a new nonsteroidal anti-inflammatory drug that is a pro-drug of piroxicam. The influence of gastric emptying rate on droxicam pharmacokinetics has been investigated in eight healthy male volunteers. A single, 20 mg dose was administered p.o. together with 1500 mg of paracetamol. Gastric transit was experimentally modified by administration of propantheline (45 mg, p.o.) or metoclopramide (10 mg, i.v.) simultaneously with the droxicam and the paracetamol. Plasma levels of paracetamol were used as markers of gastric transit. The plasma concentrations of piroxicam, the active substance from droxicam, were determined by a high-performance liquid chromatographic method. The pharmacokinetic parameters of droxicam were: Cmax = 1.03 +/- 0.16 micrograms/mL (mean +/- SD). Tmax = 11.1 +/- 5.7 hr, AUC = 115.7 +/- 29.6 micrograms hr/mL, T 1/2 a = 2.64 +/- 0.72 hr. T 1/2 el = 73.6 +/- 16.7 hr, CL/F = 3.06 +/- 0.80 mL/min and MRT = 111.1 +/- 23.5 hr. Following modification of gastric emptying, only Tmax (droxicam + metoclopramide = 25.0 +/- 10.8 hr and droxicam + propantheline = 20.8 +/- 8.8 hr) underwent significant change (P less than 0.05). These results indicate that absorption rate of droxicam has been modified but bioavailability does not suffer modification in conditions of altered gastric emptying.     

Effect of sodium/potassium salt (potash) on the bioavailability of ibuprofen in healthy human volunteers.

The influence of sodium/potassium salt water extract incorporated in a traditional meal on the bioavailability of Ibuprofen tablets 400mg dose was studied in 6 healthy human volunteers. There was a statistically significant decrease in the plasma levels of ibuprofen, and its metabolites, hydroxy-ibuprofen and carboxy-ibuprofen, respectively, when the meal containing sodium/potassium salt extract was administered with the ibuprofen tablets than when taken under fasting state or with the meal without the fruit extract. The Cmax, AUC0-6hr and Ka for ibuprofen decreased from 38.04 +/- 0.70microg/ml to 20.06 +/- 1.21microg/ml (p<0.05); 28.030 +/- 2.40microg/ml.hr to 14.180 +/- 1.12microg/ml.hr (p<0.05) and 1.048 +/- 0.02hr(-1) to 0.602 +/- 0.03hr(-1). Similarly, the Cmax for hydroxy-ibuprofen and carboxy-ibuprofen decreases from 43.04 +/- 0.76microg/ml to 27.21 +/- 0.24microg/ml (p<0.05) and 48 +/- 0.71microg/ml to 31.08 +/- 0.12microg/ml (p<0.05) respectively; while AUC0-6hr for hydroxy-ibuprofen decreased from 34.120 +/- 0.49microg/ml.hr to 16.410 +/- 0.27microg/ml.hr while that of carboxy-ibuprofen decreased from 36.121 +/- 1.97microg/ml.hr to 19.278 +/- 0.92microg/ml.hr respectively. The Kel for hydroxy-ibuprofen increased from 0.71 +/- 0.94 hr(-1) to 0.81 +/- 0.21 hr(-1) (p<0.05) respectively. The study has indicated that sodium/potassium salt extract significantly decreased the bioavailability of ibuprofen.     

Triazolam kinetics: interaction with cimetidine, propranolol, and the combination

Nineteen healthy volunteers received a single 0.5-mg oral dose of triazolam on four occasions under the following conditions: (1) triazolam alone; (2) triazolam with cimetidine, 300 mg four times daily; (3) triazolam with propranolol, 40 mg four times daily; (4) triazolam with both cimetidine and propranolol. Triazolam kinetics were determined from multiple plasma concentrations measured during 24 hours after each dose. Compared with control, peak plasma triazolam concentration (Cmax) was significantly increased by cimetidine (5.4 versus 3.9 ng/mL), total area under the plasma concentration curve (AUC) increased (21.3 versus 16.1 ng/mL X hr), and oral clearance decreased (485 versus 668 mL/min). However triazolam half-life was not increased. During propranolol alone, triazolam Cmax (4.1 ng/mL), AUC (14.3 ng/mL X hr), and clearance (759 mL/min) did not differ significantly from control, whereas kinetic variables for triazolam with cimetidine plus propranolol were similar to those with cimetidine alone. Plasma free fraction for triazolam (17 to 18% unbound) did not differ significantly among the four treatment conditions. Mean steady-state plasma cimetidine concentrations during trials 2 and 4 were similar (1.04 versus .98 micrograms/mL), whereas plasma propranolol was significantly higher during cimetidine plus propranolol than with propranolol alone (47 versus 29 ng/ml, P less than .001). Thus cimetidine coadministration significantly inhibits triazolam clearance, causing increased triazolam AUC and Cmax, but without a prolongation in half-life. Propranolol itself does not impair triazolam clearance, nor does propranolol potentiate the inhibitory effect of cimetidine alone.     

Pharmacokinetic properties of mezlocillin in ambulatory elderly subjects

Twelve healthy ambulatory elderly subjects (mean age, 73-78 years) randomly received either a 4-g or 5-g dose of mezlocillin intravenously. One week later the regimen was repeated and patients crossed over to the other dose. Peak serum concentrations were 165 mg/L and 281 mg/L for the 4-g and 5-g doses, respectively. For both doses, differences in t1/2 beta (1.32 hr vs 1.13 hr), AUC (275 mg.hr/L vs 403 mg.hr/L), CL (207 mL/min vs 174 mL/min), CLR (59 mL/min vs 45 mL/min), CLNR (152 mL/min vs 130 mL/min) were not statistically significant. The differences in Varea (22.4L vs 168.8L, P less than or equal to .01) and Cmax (216.6 mg/L vs 317 mg/L, P less than or equal to .05) were statistically significant. Comparison with pharmacokinetic parameters obtained in younger subjects following the 5-g dose reveals that in the elderly the AUC, Varea, and CLNR are higher whereas the CL and CLR are lower. The elderly demonstrated an increase in nonrenal clearance compared with young subjects that is not fully compensatory. The increased AUC in the elderly group suggests that clinical studies examining mezlocillin doses and dose intervals in the treatment of serious infections are warranted in infected elderly patients.     

Pharmacokinetic profile of OPC-8212 in humans: a new, nonglycosidic, inotropic agent

OPC-8212, a new inotropic agent, was administered orally as a single 7.5-, 15-, 30-, 60-, 120-, or 240-mg dose in a sequentially ascending order to 21 male healthy volunteers to determine the pharmacokinetic profile. Each volunteer received one of the six doses after an overnight fast. After the single-dose study was completed and the safety and tolerability were ascertained, 3 of the 21 volunteers participated in a 15-day repeated-dose (30 mg once daily) study to determine the steady-state kinetic profile. The AUC0-infinity and Cmax values were proportional to doses (mg or mg/kg, P less than .001). The mean elimination t1/2, apparent oral clearance (CL/F) and percentage fraction of dose excreted unchanged in urine up to 336 hours postdose (fe0-336) appeared to be comparable among the six single doses examined. The overall mean (+/- SEM) kinetic parameters obtained from the 21 subjects were: 44.7 +/- 1.2 hours for t1/2, 0.284 +/- 0.018 L/hr or 4.49 +/- 0.28 mL/hr/kg for CL/F, and 17.7 +/- 0.9% for fe0-336. A steady state of the drug appeared to be attained by about day 9 after the initiation of the repeated dosing: the mean postdose 2- and 24-hour plasma drug concentrations observed during days 9 to 15 ranged from 6.3 +/- 0.5 micrograms/mL to 6.9 +/- 0.6 micrograms/mL and from 3.6 +/- 0.7 micrograms/mL to 4.0 +/- 0.6 micrograms/mL, respectively. The mean fraction of the daily dose excreted unchanged in urine over the dosing interval (fe0-r) during days 9 to 15 ranged from 19.2 +/- 1.4% to 25.6 +/- 0.6%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Apparent reduced absorption of gemfibrozil when given with colestipol

Colestipol and gemfibrozil may be used in combination to lower serum cholesterol and triglycerides. Since colestipol is known to bind certain anionic drugs, we studied the effect of colestipol on the pharmacokinetics of gemfibrozil in 10 patients with elevated serum cholesterol and triglycerides. Each patient received 600 mg of gemfibrozil by mouth during four different studies. Gemfibrozil was given randomly either alone, with, 2 hours before, or 2 hours after 5 grams of colestipol. The serum gemfibrozil concentration time curves were similar when gemfibrozil was given alone or two hours before or after colestipol. There was also no statistical difference in peak gemfibrozil concentration (Cmax), time to Cmax (tmax), area under the curve (AUC), or serum elimination half-life (t1/2) between any of these three treatments. However, when colestipol was given with gemfibrozil, there was a decrease in AUC (43.6 +/- 21.9 mg*hr/L) compared with gemfibrozil given alone (62.6 +/- 10.3 mg*hr/L) which was statistically different by both ANOVA and paired t-test. This finding suggests a decrease in gemfibrozil bioavailability. Cmax when colestipol was given with gemfibrozil (14.7 +/- 6.6 mg/L) was not statistically different from gemfibrozil alone (20.1 +/- 4.9 mg/L). However, the mean serum concentrations when gemfibrozil was given with colestipol were significantly lower at the 0.5, 1.0 and 1.5 hour sampling times when compared to the other regimens. Gemfibrozil serum elimination half-life was not significantly altered by combination with colestipol. The data suggest a reduction of gemfibrozil bioavailability when colestipol is administered concomitantly. Separating the administration of these two drugs by at least two hours will avoid this drug interaction.     

Pharmacokinetics and urinary excretion of eprosartan in Chinese healthy volunteers of different gender

The study aims to evaluate the pharmacokinetics and urinary excretion of eprosartan in Chinese healthy volunteers and to study the effect of gender on pharmacokinetics of eprosartan. Twenty healthy volunteers (ten men and ten women) were recruited for an open trial and received a single dose of 600 mg eprosartan. Using a validated LC/MS/MS method, plasma and urinary concentrations of eprosartan were determined. The following pharmacokinetic parameters were elucidated after administration: the area under the plasma concentration versus time curve from 0 to 32 h (AUC0-32h) 14818.75 +/- 7312.11 ng x h/mL, the area under the plasma concentration versus time curve from 0 to infinite (AUC(0-infinity)) 15081.62 +/- 7379.63 ng x h/mL, peak plasma concentration (Cmax) 3664.25 x 1653.94 ng x h/mL, time to Cmax (Tmax) 1.63 +/- 0.46 h, elimination half-life (t(1/2)) 8.03 +/- 4.04 h, apparent clearance (CL/F) 47.84 +/- 19.21 L/h, apparent volume of distribution of the central compartment (V/F) 537.21 +/- 287.91 L, renal clearance (CLr) 1.33 +/- 0.41 L/h, amount of unchanged eprosartan excreted into urine 18.44 +/- 6.43 mg and fraction of unchanged eprosartan excreted into urine 3.07 +/- 1.07%. Our results also indicated that no gender differences were observed in the pharmacokinetics of eprosartan in Chinese healthy volunteers.     

Fosinopril: pharmacokinetics and pharmacodynamics in Chinese subjects

This study examined thepharmacokinetics and pharmacodynamics of fosinopril (IVand oral) in Chinese subjects to determine whether they were different from a group of somewhat heavier and older Western control subjects previously published using the same methods. It was an open-label, randomized, balanced, two-way crossover study comparing oral and IV pharmacokinetics in 12 healthy Chinese subjects in a clinic in Taiwan. Each subject received 10 mg of oral fosinopril or 7.5 mg of IV fosinoprilatin a randomized sequence with sampling for fosinoprilat concentrations over 48 hours. Standard pharmacokinetics, including AUC, Cmax Tmax, T 1/2, Vss, bioavailability, total clearance, and renal and nonrenal clearance, were determined as well as pharmacodynamic effects on angiotensin-converting enzyme (ACE) activity. Following oral administration of 10 mg fosinopril, AUC0-T and AUCinf were 1,556 +/- 586 ng x hr/mL and 1,636 +/- 620 ng x hr/mL, respectively; T 1/2 was 17.4 +/- 11.4 hr; Cmax was 183.4 +/- 59.4 ng/mL; and median Tmax was 4.0 hr, with > 99% protein binding. Following IV administration of 7.5 mg fosinoprilat, AUC0-T and AUCinf were 7,727 +/- 2,638 ng x hr/mL and 7,816 +/- 2,693 ng x hr/mL, respectively; T 1/2 was 13.0 +/- 5.2 hr; and median Tmax was 4.0 hr, with 99.5% +/- 0.22% protein binding and a Vss of 5,850 +/- 2,780 mL. Bioavailability was 22.3% +/- 7.9%. Percent urinary excretion was 7.6% +/- 2.6% after oral dosing and 42.6% +/- 6.1% after IV dosing. After IV, dosing total clearance was 1,088 +/- 439 mL/hr, renal clearance was 472 +/- 213 mL/hr, and nonrenal clearance was 617 +/- 246 mL/hr. ACE inhibition was essentially complete through 12 hours and markedly reduced through 24 hours. Compared to a somewhat heavier and older previously reported control group, pharmacokinetic values were similar except for a slightly lower AUC and total clearance in Chinese and a statistically significantly lower nonrenal clearance. Pharmacodynamic effects on ACE activity were essentially identical. There is no reason to expect significant differences in fosinopril dosing or effect in a Chinese population compared to a Western population.     

Pharmacokinetic studies on oral antibiotics in pediatrics. I. A pharmacokinetic study on cefixime in pediatrics

A pharmacokinetic study on cefixime (CFIX) 5% granules for pediatric use was performed, and pharmacokinetic parameter were calculated. 1. Six school children were administered orally with CFIX granules at a dose level of 3 mg/kg either at 30 minutes before meal or at 30 minutes after meal on a crossover design, and serum concentrations and urinary excretion rates of CFIX were determined. Tmax, Cmax, T 1/2 and urinary excretion rate (0-12 hours) following the administration before meal were 3.33 +/- 0.42 hours, 1.03 +/- 0.17 micrograms/ml, 2.31 +/- 0.26 hours and 15.3 +/- 2.2%, respectively, Tmax, Cmax, T 1/2 and urinary excretion rate following the the administration after meal were 4.00 +/- 0.52 hours, 0.90 +/- 0.09 micrograms/ml, 3.11 +/- 0.21 hours and 11.3 +/- 1.6%, respectively. Earlier Tmax, higher Cmax and higher urinary excretion rate were observed when the drug was administered before meal than when administered after meal. These differences between the 2 groups were not statistically significant. 2. Five school children were administered orally with CFIX granules at 30 minutes after meal at a dose level of either 3 mg/kg or 6 mg/kg on a crossover design, and serum concentrations and urinary excretion rates of CFIX were determined. Cmax and AUC at a dose level of 3 mg/kg were 1.01 +/- 0.26 mg/ml and 5.86 +/- 1.13 micrograms.hr/ml, respectively, and Cmax and AUC at a dose level of 6 mg/kg were 1.76 +/- 0.29 micrograms/ml, 12.54 +/- 1.77 micrograms.hr/ml, respectively. A dose response relationship was thus observed. Seven infants (3 mg/kg) and 3 infants (6 mg/kg) were administered orally with CFIX granules at 30 minutes after meal. Cmax and AUC at a dose level of 3 mg/kg were 2.45 +/- 0.26 micrograms/ml, 33.50 +/- 7.62 micrograms.hr/ml, respectively, and Cmax and AUC at a dose level of 6 mg/kg were 4.42 +/- 0.98 micrograms/ml, 66.85 +/- 25.19 micrograms.hr/ml, respectively. A dose response was observed. 3. Eleven school children, 5 younger children and 7 infants were administered orally with CFIX granules at a dose level of 3 mg/kg at 30 minutes after meal, and serum concentrations and urinary excretion rates of CFIX were determined. Tmax in school children, younger children and infants were 3.82 +/- 0.33 hours, 5.20 +/- 0.49 hours and 5.43 +/- 0.37 hours, respectively. Earlier Tmax's were observed in school children than in other children. Cmax in school children, younger children and infants were 0.95 +/- 0.12 micrograms/ml, 0.56 +/- 0.06 micrograms/ml and 2.45 +/- 0.26 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

Bioequivalence and pharmacokinetics of 70 mg alendronate sodium tablets by measuring alendronate in plasma

The bioequivalence and pharmacokinetics of alendronate sodium tablets were examined by determining the plasma concentration of alendronate. Two groups, consisting of 24 healthy volunteers, each received a 70 mg reference alendronate sodium tablet and a test tablet in a 2x2 crossover study. There was a 6-day washout period between doses. The plasma alendronate concentration was monitored for 7 h after the dose, using HPLC-Fluorescence Detector (FD). The area under the plasma concentration-time curve from time 0 to the last sampling time at 7 h (AUC(0-7h) was calculated using the linear-log trapezoidal rule. The maximum plasma drug concentration (Cmax) and the time to reach Cmax (Tmax) were derived from the plasma concentration-time data. Analysis of variance was performed using logarithmically transformed AUC(0-7h) and Cmax, and untransformed Tmax. For the test medication versus the reference medication, the AUC(0-7h) were 87.63 +/- 29.27 vs. 102.44 +/- 69.96 ng x h x mL(-1) and the Cmax values were 34.29 +/- 13.77 vs. 38.47 +/- 24.39 ng x mL(-1), respectively. The 90% confidence intervals of the mean differences of the logarithmic transformed AUC(0-7h) and Cmax values were log 0.8234-log 1.1597 and log 0.8222-log 1.1409, respectively, satisfying the bioequivalence criteria guidelines of both the U.S. Food and Drug Administration and the Korea Food and Drug Administration. The other pharmacokinetic parameters for the test drug versus reference drug, respectively, were: t(1/2), 1.87 +/- 0.62 vs. 1.77 +/- 0.54 h; V/F, 2061.30 +/- 986.49 vs. 2576.45 +/- 1826.05 L; CL/F, 835.32 +/- 357.35 vs. 889.48 +/- 485.87 L x h(-1); K(el), 0.42 +/- 0.14 vs. 0.40 +/- 0.18 h(-1); Ka, 4.46 +/- 3.63 vs. 3.80 +/- 3.64 h(-1); and Tlag, 0.19 +/- 0.09 vs. 0.18 +/- 0.06 h. These results indicated that two alendronate formulations (70-mg alendronate sodium) were biologically equivalent and can be prescribed interchangeably.     

Pharmacokinetics and dose proportionality of domperidone in healthy volunteers

Domperidone is a potent gastrokinetic agent and antinauseant currently undergoing clinical trials in the United States. The bioequivalence of 20 mg of domperidone given as free-base tablets and maleate salt tablets, and the bioavailability of base and maleate tablets relative to a solution, were studied in 21 fasting men using a crossover design. Plasma samples collected for up to 48 hours were analyzed for domperidone levels, using a sensitive and specific radioimmunoassay (RIA). The absorption of domperidone was very rapid, with mean peak plasma concentration (Cmax) values of 18.8, 15.0, and 20.7 ng/mL attained at 0.9, 1.2, and 0.6 hours after the administration of base tablet, maleate tablet, and solution, respectively. The mean elimination half-life (t1/2) ranged from 12.6 to 16.0 hours. The mean oral clearance (CL/F) after the solution dose was 4,735 +/- 2,017 mL/min and the mean apparent volume of distribution (Vd/F) was 6,272 +/- 5,100 L, indicating an extensive distribution of domperidone in the body. The area under the plasma concentration-time curve (AUC) data demonstrated bioequivalence of base and maleate tablets. The relative bioavailability for base tablet and maleate tablet was 107 +/- 50% and 116 +/- 47%, respectively, of that of the solution. Dose proportionality of domperidone was also studied in 12 subjects at solution doses of 10, 20, and 40 mg. Linear correlations between the dose and Cmax and AUC values were observed. Mean CL/F remained relatively constant after doses of 10, 20, and 40 mg (5,255 +/- 3,159, 4,842 +/- 1,774, and 4,380 +/- 1,289 mL/min, respectively), indicating linear pharmacokinetics of domperidone over the dose range studied.     

Comparative biological availability of two different ibuprofen granules]

Bioavailability of ibuprofen (CAS 15687-27-1) was investigated in 12 healthy volunteers who received 2 sachets of newly developed effervescent granules (Imbun), each containing 500 mg of ibuprofen lysine salt (corresponding to 292.6 mg of ibuprofen) as the test preparation and 1 sachet of commercially available granules containing 600 mg ibuprofen. Blood samples were withdrawn pre-dose and at 16 occasions until 10 h post dose. Ibuprofen plasma concentrations were assayed by HPLC using a proprietary column-switching technique. Maximum plasma concentrations, Cmax, and times of their occurrence, tmax, were taken from the plasma data directly, areas under the plasma level/time curves, AUC0-10, were calculated using the trapezoidal rule. Pharmacokinetic parameters were checked for significant differences using ANOVA with p = 0.05. When the test preparation was applied maximum ibuprofen levels of 60 +/- 17 micrograms/ml were reached at 27 +/- 17 min p. appl. while Cmax was 52 +/- 12 micrograms/ml at tmax = 94 +/- 27 min after application of the reference preparation. AUC values were 150 +/- 44 microgramsh/ml (test) and 148 +/- 33 microgramsh/ml (reference), respectively. Thus, relative bioavailability of ibuprofen was 101.8 +/- 16.3% (or 104.1 +/- 16.7% when the slight differences in doses were corrected for). Differences in extent of absorption as measured by AUC and Cmax proved to be insignificant whereas differences in absorption rate as measured by tmax were highly significant (p < 0.001).     

Relative bioavailability of three cefixime formulations

Three galenic formulations of cefixime (tablet, syrup and dry suspension) containing 200 mg each were compared with respect to their relative bioavailability in twelve healthy volunteers. All three formulations showed reliable absorption. Mean peak plasma concentrations were reached after 3.3-3.5 h, mean terminal half lives were 2.9-3.1 h. 18-24% of the dose administered were recovered unchanged in the urine. Best bioavailability was obtained with the dry suspension (AUC0-infinity = 25.8 +/- 7.0 micrograms/ml h; Cmax = 3.4 +/- 0.9 microgram/ml), followed by the tablet (AUC0-infinity = 20.9 +/- 8.1 micrograms/ml h; Cmax = 3.0 +/- 1.0 micrograms/ml) and the syrup which is based on triglycerides (AUC0-infinity = 17.8 +/- 5.9 micrograms/ml h; Cmax = 2.4 +/- 0.7 micrograms/ml). The statistical analysis resulted in bioinequivalence between dry suspension and syrup. It is concluded that best bioavailability of cefixime after oral administration is guaranteed when taken in an "aqueous medium" either as dry suspension or as tablet with "plenty of liquid".     

Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in children with HIV infection.

The pharmacokinetics of zidovudine (ZDV) and dideoxyinosine (ddI) were investigated following administration alone and in combination to children with symptomatic HIV disease. The children were studied on three separate occasions and received ZDV 200 mg m-2, ddI 100 mg m2 or a combination of ZDV 200 mg m-2 plus ddI 100 mg m-2. The administration of ddI did not significantly alter ZDV pharmacokinetics. The area under the curve (AUC) was 14.2 +/- 4.9 and 15.8 +/- 7.2 mumol l-1 h and elimination half-life (t1/2, z) was 1.4 +/- 0.4 and 1.2 +/- 0.2 h in the absence and presence of ddI respectively. The peak concentration (Cmax), time to peak (tmax) and apparent oral clearance (CL/F) were also unchanged. The administration of ZDV had no significant effect on ddI Cmax, tmax, t1/2,z, or CL/F, however the AUC was reduced by 19% (5.9 +/- 2.9 to 4.8 +/- 2.7 mumol l-1 h; P < 0.05). This study suggests that ZDV and ddI may be co-administered to children with symptomatic HIV disease without concern of a clinically relevant pharmacokinetic drug interaction.     

Omeprazole disposition in children following single-dose administration

Omeprazole is frequently used to treat gastroesophageal reflux in infants and children despite the lack of age-specific pharmacokinetic and dosing information in the approved product labeling. To address this challenge, the authors examined the potential influence of development and cytochrome P450 2C19 (CYP2C19) genotype on omeprazole disposition by conducting two pharmacokinetic (PK) studies in children and adolescents (ages 2-16 years) after a single oral 10- or 20-mg dose of the drug. Plasma omeprazole concentrations were determined by HPLC-MS from seven plasma samples obtained over a 6-hour postdose period. Pharmacokinetic parameters were determined by noncompartmental methods. Subjects were genotyped for CYP2C19 by PCR-RFLP. Data were available from 37 patients (19 female), 10 of whom were < or = 5 years of age. No drug-associated adverse events were observed. The numbers of functional CYP2C19 alleles per subject in the cohort were 2 (n = 25), 1 (n = 11), and 0 (n = 1). Pharmacokinetic parameters (mean +/- SD, range) were as follows: tmax (2.1 +/- 1.2, 1-6 h), Cmax (331.1 +/- 333.6, 20.8-885.8 ng/mL), AUC0-->infinity (809.5 +/- 893.8, 236.9-1330.9 ng/mL.h), t1/2 (0.98 +/- 0.22, 0.7-1.4 h), and CL/F (1.8 +/- 1.4, 0.3-5.8 L/h/kg). Comparison of mean AUC0-->infinity values normalized for dose (i.e., per 1 mg/kg) between subjects with one versus two functional CYP2C19 alleles revealed no statistically significant difference. In addition, the CL/F and apparent elimination rate constant (lambda z) for omeprazole were not significantly different for subjects with one versus two functional CYP2C19 alleles. No association between age and CL/F, t1/2, or lambda z was observed. The range of t1/2 values for omeprazole was similar to those reported in adults (1-1.5 h). CONCLUSIONS: (1) in children ages 2 to 16 years receiving 10 or 20 mg of omeprazole as a single oral dose, the PK are quite comparable to values reported for adults, and (2) in pediatric patients who are CYP2C19 extensive metabolizers, there was no association between genotype and the pharmacokinetics of omeprazole.     

The effect of antacid and ranitidine on droxicam pharmacokinetics.

Droxicam is a nonsteroidal anti-inflammatory drug that is a pro-drug of piroxicam. The influence of concomitant administration of antacid or ranitidine on droxicam pharmacokinetics has been investigated. On three separate phases, 15 healthy volunteers received a single oral 20-mg dose of droxicam either alone, with antacid (400 mg aluminum hydroxide + 400 mg magnesium hydroxide, three times/day), or with ranitidine (300 mg, two times/day) for 6 days. Piroxicam, the active substance from droxicam, was quantified by high-performance liquid chromatography. The pharmacokinetic parameters for droxicam given alone were: maximum peak plasma concentration (Cmax) = 1.53 +/- .21 micrograms/mL (mean +/- SD), time to peak concentration (Tmax) = 7.5 +/- 2.1 hr, t1/2a = 1.38 +/- .82 hour, t1/2el = 53.3 +/- 11.9 hr, Cl/F = 2.98 +/- .71 mL/min, volume of distribution (Vd/F) = 13.2 +/- 1.8 L and area under the curve (AUC) = 117.6 +/- 26.8 micrograms/hour/mL. The subject effect was significant for all the pharmacokinetic parameters except for the absorption half-life (P < .05). Concomitant antacid or ranitidine administration had no significant effect on any of the droxicam pharmacokinetic parameters. The results of this study suggest that antacid or ranitidine do not significantly alter the oral absorption or pharmacokinetic disposition of single-dose droxicam.     

Lack of clinically significant pharmacokinetic interactions between zonisamide and lamotrigine at steady state in patients with epilepsy

The present study was designed to assess the effect of the addition of zonisamide (ZNS) on lamotrigine (LTG) disposition and the safety of the combination under steady-state conditions in patients with epilepsy. A secondary objective was to characterize ZNS pharmacokinetics (PK) in the presence of LTG. Twenty subjects (male and female 18 to 55 years old) stabilized on LTG monotherapy (150-500 mg/d) took part in a 2-center, open-label, 1-way drug interaction study. ZNS was gradually increased to 200 mg twice daily over a 3-week period, and 3 PK profiles were performed: on days -7 and -1 to assess the PK of oral LTG administered alone and on day 35, after 14 days of ZNS at the maximal tolerated dose, to evaluate the effect of ZNS on LTG PK and to characterize ZNS PK in the presence of LTG. Eighteen subjects completed the study. Steady-state dosing of ZNS did not significantly affect the mean Cmin (mean +/- SD: 2.8 +/- 1.4 vs 3.5 +/- 2.4 microg/mL), Cmax (5.1 +/- 3.0 vs 5.1 +/- 3.0 microg/mL), AUC0-12 (45.5 +/- 22.6 vs 50.3 +/- 32.1 microg.h/mL), and CL/F (2778.5 +/- 1368.5 vs 3052.1 +/- 2744.9 mL/h) of LTG measured before (day -1) and after (day 35) ZNS administration, respectively. Further, 90% confidence intervals for the geometric mean ratios (day 35/day -1) fell within the no-effect range of 0.80-1.25. The fraction of dose of total and unconjugated LTG excreted in urine was not significantly different between baseline and ZNS treatment, but the renal clearance of LTG decreased significantly with ZNS dosing (P = 0.01). On the other hand, the PK parameters measured for ZNS in the presence of LTG were consistent with an absence of LTG effect on ZNS PK. The coadministration of ZNS and LTG was generally well tolerated. Steady-state safety and PK of LTG and ZNS are not affected significantly when these two drugs are coadministered at clinically relevant doses, indicating that no dosage adjustment of either drug should be required when they are used in combination.     

Pharmacokinetics of ibuprofen enantiomers in children with cystic fibrosis

Chiral inversion of R(-)- to S(+)-ibuprofen in children with cystic fibrosis was investigated. Children with cystic fibrosis (n = 38, ages 2-13 years) were administered a single oral dose of racemic ibuprofen (20 mg/kg), and the pharmacokinetics of ibuprofen was found to be stereoselective. Mean Cmax, AUC, apparent CL/F, and Varea/F of S-ibuprofen were significantly different from those of R-ibuprofen. The enantiomeric ratio of plasma AUC (S:R = 2.09:1) and of free and conjugated ibuprofen in urine (S:R = 13.9:1) of children with cystic fibrosis was not different from reported values for healthy children and adults. No significant gender difference was observed for any of the pharmacokinetic parameters determined. However, there was an inverse linear relationship between the CL/F of R-ibuprofen and age in children with cystic fibrosis. Apparent CL/F was higher in children with cystic fibrosis than previously reported for healthy children; therefore, higher doses of ibuprofen would be necessary for children with cystic fibrosis.     

The effect of antacid and cimetidine on the oral absorption of the antifungal agent SCH 39304

The single-dose pharmacokinetics of the antifungal agent SCH 39304 (Schering-Plough Corp., Kenilworth, NJ) were assessed alone and in combination with antacid and cimetidine. On three separate occasions nine healthy men received a single oral 50 mg dose of SCH 39304 either alone, with 60 mL antacid, or with oral cimetidine 300 mg four times a day for 4 days. Concomitant antacid or cimetidine administration had no significant effect on any of the SCH 39304 pharmacokinetic parameters studied. The oral absorption of SCH 39304, as assessed by the area under the plasma concentration-time curve (AUC) and the amount of drug recovered unchanged in the urine, was not affected by either antacid or cimetidine. The AUC0-1 for the drug given alone was 80.5 +/- 15.8 micrograms.hr/mL, compared to 81.4 +/- 12.7 and 79.7 +/- 9.6 micrograms.hr/mL with concomitant antacid and cimetidine, respectively. The amount of drug excreted in the urine (Ae0-1) was 22.7 +/- 5.1, 24.2 +/- 9.2, and 23.6 +/- 7.6 mg when the drug was given alone, with antacid, and with cimetidine, respectively. Antacid coadministration delayed absorption as evidenced by an increase in the tmax in 7 out of 9 subjects, although this did not reach statistical significance (P = .082, Wilcoxon test). We conclude that concomitant antacid or cimetidine does not alter the oral absorption or pharmacokinetic disposition of single-dose SCH 39304.