Effects of three cytochrome P450 inhibitors, ketoconazole, fluconazole, and paroxetine, on the pharmacokinetics of lasofoxifene.

AIMS: Two studies were conduced to assess the effects of ketoconazole, a CYP3A4/5 inhibitor; fluconazole, a CYP2C9 inhibitor; and paroxetine, a CYP2D6 inhibitor, on lasofoxifene pharmacokinetics. METHODS: The first parallel group study was conducted in 45 healthy postmenopausal women (15 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) administered alone and in combination with ketoconazole (400 mg daily x 20 days) or fluconazole (400 mg daily x 20 days). Lasofoxifene was administered on day 2 and blood samples were collected serially for up to 456 h postdose (20 days). The second study enrolled 20 healthy postmenopausal women (10 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) alone and in combination with paroxetine (30 mg qd x 21 days). Lasofoxifene was given on day 8 of paroxetine treatment and blood samples were collected serially for up to 336 h postdose. RESULTS: All subjects completed the study and the treatments were well tolerated. Lasofoxifene C(max) and AUC ratios [90% confidence interval (CI)] with/without ketoconazole were 111% (98.4, 127) and 120% (105, 136), respectively, and were 91.3% (80.3, 104) and 104% (91.4, 118), respectively, with/without fluconazole. Lasofoxifene C(max) and AUC ratios (90% CI) with/without paroxetine were 118% (95.4, 146) and 135% (120, 152), respectively. CONCLUSIONS: Coadministration of potent inhibitors of CYP3A4/5 and CYP2D6, but not CYP2C9, resulted in a moderate increase in lasofoxifene exposure. No dosage adjustment should be required when lasofoxifene is coadministered with ketoconazole, fluconazole, paroxetine or other agents that inhibit these CYP enzymes.

Pharmacokinetics of clinafloxacin after single and multiple doses.

Clinafloxacin (CI-960) is a potent broad-spectrum, fluoroquinolone antibiotic that has been studied for parenteral and oral administration in patients with serious infections. The objectives of these studies were to examine the pharmacokinetics and safety of clinafloxacin following administration of single and twice-daily intravenous (i.v.) and oral doses to volunteers. Plasma and urine samples were assayed by validated liquid chromatographic methods, and pharmacokinetic parameter values were determined by noncompartmental methods. Safety was evaluated by clinical observation and laboratory tests. Absorption was rapid after oral administration, with maximum concentrations in plasma (C(max)) generally occurring within 2 h. Concentrations in plasma declined biexponentially, with an average terminal half-life of 4 to 6 h after single doses and 5 to 7 h after multiple doses. Increases in C(max) and area under the concentration-time curves (AUC) were generally proportional to the dose. The volume of distribution was much greater than total body water. Approximately 40 to 75% of the clinafloxacin doses were excreted unchanged into urine. Absolute bioavailability of orally administered clinafloxacin was approximately 90% and did not change with increasing dose. Therefore, switching patients from i.v. to oral dosing should achieve similar concentrations in plasma. The tolerability of clinafloxacin was acceptable. No serious adverse events occurred. C(max) values and minimum plasma clinafloxacin concentrations during multiple dosing exceeded MICs for a wide range of organisms.

Clinafloxacin pharmacokinetics in subjects with various degrees of renal function.

As the primary route for elimination of clinafloxacin is renal clearance (CL(R)) of unchanged drug, studies were conducted to determine the pharmacokinetic profile of clinafloxacin following administration to young and elderly subjects, subjects with various degrees of renal function, and subjects requiring dialysis. These were open-label studies in which subjects received single oral clinafloxacin doses. Sixteen young subjects (18 to 35 years old) and 16 elderly subjects (>65 years old) were enrolled in a study comparing pharmacokinetic profiles of clinafloxacin in young and elderly subjects. Twenty subjects having various degrees of renal function were enrolled into one of three groups based on degree of renal function as measured by creatinine clearance (CL(CR)). Twelve subjects with severe renal impairment requiring dialysis enrolled in a third study. Clinafloxacin was generally well tolerated by all subjects. Clinafloxacin pharmacokinetic profiles in elderly subjects were dependent only on age-related decreases in renal function. Clinafloxacin maximum concentrations in plasma, areas under the concentration-time curves, and terminal elimination half-life values increased with decreasing CL(CR) values. Total apparent body clearance of clinafloxacin from the plasma after oral administration (CL(oral)) and CL(R) were dependent on CL(CR) according to the following relationships: CL(oral) = 2.3. CL(CR) + 77 and CL(R) = 1.74. CL(CR). Hemodialysis had no significant effect on clinafloxacin clearance. Based on the relationship between CL(CR) and clinafloxacin CL(oral) and CL(R) values, the clinafloxacin dose should be halved in patients having a CL(CR) of <40 ml/min. Further dose adjustment is not warranted in patients requiring hemodialysis.

Drug interactions with clinafloxacin.

Many fluoroquinolone antibiotics are inhibitors of cytochrome P450 enzyme systems and may produce potentially important drug interactions when administered with other drugs. Studies were conducted to determine the effect of clinafloxacin on the pharmacokinetics of theophylline, caffeine, warfarin, and phenytoin, as well as the effect of phenytoin on the pharmacokinetics of clinafloxacin. Concomitant administration of 200 or 400 mg of clinafloxacin reduces mean theophylline clearance by approximately 50 and 70%, respectively, and reduces mean caffeine clearance by 84%. (R)-Warfarin concentrations in plasma during clinafloxacin administration are 32% higher and (S)-warfarin concentrations do not change during clinafloxacin treatment. An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration.

Effect of food on absorption of Dilantin Kapseals and Mylan extended phenytoin sodium capsules.

BACKGROUND: Because of phenytoin's narrow therapeutic index and nonlinear pharmacokinetics, food-induced alterations in absorption may markedly influence drug concentrations and, in turn, safety and effectiveness. Potential food-associated differences between 100-mg Mylan (Mylan Pharmaceuticals) extended-release phenytoin sodium capsules and Parke-Davis 100-mg Dilantin Kapseals were examined. METHODS: A single-dose, two-way crossover study was conducted in 24 healthy subjects to determine the effect of a high-fat meal on the pharmacokinetics of both formulations. Pharmacokinetic parameters were estimated by noncompartmental methods. The impact of switching products on steady-state phenytoin concentrations was investigated through simulation using pharmacokinetic data previously obtained from 30 epileptic patients. RESULTS: Based on AUC(0-infinity), bioavailability of the Mylan product administered with food was 13% lower than that observed with Dilantin Kapseals. Simulations of substituting the Mylan product for Dilantin suggested that the 13% decrease in bioavailability would result in a median 37% decrease (range 19 to 58%) in plasma phenytoin concentrations when the drug is given with food; in 46% of patients, phenytoin concentrations would likely fall below the therapeutic range of 10 to 20 mg/L. Simulations of substituting Dilantin for the Mylan product suggested that the 15% increase in bioavailability would result in a median 102% increase (range 24 to >150%) in plasma phenytoin concentrations, with 84% of patients having phenytoin concentrations above the therapeutic range. CONCLUSIONS: Results suggest that when taking phenytoin sodium with food, product switches may result in either side effects or loss of seizure control.

Effect of food on the bioavailability of 100-mg dilantin Kapseals.

The authors examined the effect of food on the bioavailability of Dilantin Kapseals in a nonblinded, single 100-mg dose, randomized, crossover trial. Drug was administered after an 8-hour fast and after a high-fat meal. Differences in mean dietary state values were +6% for maximum concentrations (C(max)) and -2% for area under the curve. Associated 90% CI were within US Food and Drug Administration criteria, confirming the absence of a food effect. Thus, patients may take 100-mg Dilantin Kapseals without regard to meals.

Single-dose gabapentin pharmacokinetics and safety in healthy infants and children.

Gabapentin (Neurontin) is a gamma-aminobutyric acid analogue indicated in adults for adjunctive treatment of partial seizures with or without secondary generalization. Two studies were conducted to determine the single-dose pharmacokinetics of gabapentin in healthy subjects age 1 month to 12 years and to guide dose selection in safety and efficacy trials in pediatric patients. Forty-eight subjects were given single oral doses of gabapentin (10 mg/kg) while fasting. Enrollment was homogeneously distributed throughout the age range. Plasma samples were drawn predose and then serially for 24 hours postdose. Single doses of gabapentin were well tolerated by healthy pediatric subjects. Plots of pharmacokinetic parameters versus age suggested significant differences between younger (1 month to < 5 years) and older (> or =5 to 12 years) subjects. Mean area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) was 25.6 microg x h/mL in younger subjects and 36.0 microg x h/mL in older subjects (p < 0.001). Corresponding mean peak plasma concentrations (Cmax) were 3.74 and 4.52 microg/ml (p < 0.05). Oral clearance (normalized for body weight) was 7.40 and 4.41 mL/min/kg in younger subjects and older subjects, respectively (p < 0.001). It was concluded that children between 1 month and < 5 years of age require approximately 30% higher daily doses of gabapentin than those > or =5 to 12 years of age.

Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion.

The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.

Pharmacokinetics of clinafloxacin enantiomers in humans.

The pharmacokinetics of R-clinafloxacin and S-clinafloxacin enantiomers of the broad-spectrum fluoroquinolone antibiotic, clinafloxacin, were characterized in selected volunteer subjects and patients after the administration of oral and intravenous doses of racemic drug. The absorption of each enantiomer was rapid and nearly complete after a single, oral 400 mg racemic dose. The mean (+/- SD) bioavailability of R-clinafloxacin was 87.5% +/- 4.8% compared to 86.2% +/- 5.8% for S-clinafloxacin. The mean Cmax of each enantiomer was 1.19 micrograms/mL, with plasma concentrations of each enantiomer remaining above 0.1 microgram/mL for at least 12 hours. No notable differences in the disposition of R-clinafloxacin and S-clinafloxacin were observed. After a single 400 mg intravenous dose of racemic drug, mean (+/- SD) t1/2 was 5.6 +/- 0.3 hours and 5.7 +/- 0.4 hours, plasma Cl was 329 +/- 49 mL/min and 314 +/- 45 mL/min, and Vdss was 138 +/- 18 L and 134 +/- 16 L for R- and S-clinafloxacin, respectively. Two healthy volunteers each received a single 400 mg oral dose of racemic clinafloxacin (alone) and with oral administration of 1 gm probenecid separated by a 1-week washout period between treatments. With probenecid coadministration, the increase in AUC0-infinity was 75% and 83% for R-clinafloxacin and was 71% and 75% for S-clinafloxacin in each subject, respectively. Probenecid increased the total exposure (AUC) of both R-clinafloxacin and S-clinafloxacin, although it had no stereo-selective effects on the disposition of either enantiomer. The antimicrobial potency of the isomers was also evaluated. In vitro susceptibility testing showed that the two compounds were comparable in their inhibitory activities, as all MICs were within twofold for each organism tested. These results demonstrate that in addition to their similar antimicrobial potency, R- and S-clinafloxacin have nearly identical disposition characteristics and are eliminated by similar mechanisms that display no apparent enantioselectivity in man.

Clinical pharmacokinetics of troglitazone.

Troglitazone is a new thiazolidinedione oral antidiabetic agent approved for use to improve glycaemic control in patients with type 2 diabetes. It is rapidly absorbed with an absolute bioavailability of between 40 and 50%. Food increases the absorption by 30 to 80%. The pharmacokinetics of troglitazone are linear over the clinical dosage range of 200 to 600 mg once daily. The mean elimination half-life ranges from 7.6 to 24 hours, which facilitates a once daily administration regimen. The pharmacokinetics of troglitazone are similar between patients with type 2 diabetes and healthy individuals. In humans, troglitazone undergoes metabolism by sulfation, glucuronidation and oxidation to form a sulfate conjugate (M1), glucuronide conjugate (M2) and quinone metabolite (M3), respectively. M1 and M3 are the major metabolites in plasma, and M2 is a minor metabolite. Age, gender, type 2 diabetes, renal impairment, smoking and race do not appear to influence the pharmacokinetics of troglitazone and its 2 major metabolites. In patients with hepatic impairment the plasma concentrations of troglitazone, M1 and M3 increase by 30%, 4-fold, and 2-fold, respectively. Cholestyramine decreases the absorption of troglitazone by 70%. Troglitazone may enhance the activities of cytochrome P450 (CYP) 3A and/or transporter(s) thereby reducing the plasma concentrations of terfenadine, cyclosporin, atorvastatin and fexofenadine. It also reduces the plasma concentrations of the oral contraceptive hormones ethinylestradiol, norethindrone and levonorgestrel. Troglitazone does not alter the pharmacokinetics of digoxin, glibenclamide (glyburide) or paracetamol (acetaminophen). There is no pharmacodynamic interaction between troglitazone and warfarin or alcohol (ethanol). Pharmacodynamic modelling showed that improvement in fasting glucose and triglyceride levels increased with dose from 200 to 600 mg. Knowledge of systemic troglitazone exposure within a dose group does not improve the prediction of glucose lowering response or adverse effects beyond those based on the administered dose.

Steady-state pharmacokinetics and dose proportionality of troglitazone and its metabolites.

This study evaluated the steady-state pharmacokinetics and dose proportionality of troglitazone, metabolite 1 (sulfate conjugate), and metabolite 3 (quinone metabolite) following administration of daily oral doses of 200, 400, and 600 mg troglitazone for 7 days (per dosing period) to 21 subjects. During each dosing period, plasma samples were collected predose on days 1, 5, 6 and 7 and serially for 24 hours on day 7. Steady-state plasma concentrations for troglitazone, metabolite 1, and metabolite 3 were achieved by day 7. Troglitazone was rapidly absorbed with mean tmax values of 2.7 to 2.9 hours. Mean Cmax and AUC(0-24) values for troglitazone, metabolite 1, and metabolite 3 increased proportionally with increasing troglitazone doses over the clinical dose range of 200 mg to 600 mg administered once daily. Mean troglitazone CL/F, percent fluctuation, and AUC ratios of metabolite 1 and metabolite 3 to troglitazone were similar across dose groups. These data suggest that the pharmacokinetics and disposition of troglitazone and its metabolites are independent of dose over the dose range studied. Thus, troglitazone, metabolite 1, and metabolite 3 displayed linear pharmacokinetics at steady-state.

Gabapentin does not interact with a contraceptive regimen of norethindrone acetate and ethinyl estradiol.

Anticonvulsants that induce hepatic metabolism increase clearance of oral contraceptive hormones and thereby cause contraceptive failure. Gabapentin is not metabolized in humans and has little liability for causing metabolic-based drug-drug interactions. In healthy women receiving 2.5 mg norethindrone acetate and 50 microg ethinyl estradiol daily for three consecutive menstrual cycles, concurrent gabapentin administration did not alter the steady-state pharmacokinetics of either hormone. Thus, gabapentin is unlikely to cause contraceptive failure.

PIP: Anticonvulsants that induce hepatic metabolism increase the clearance of synthetic estrogens and progestogens used in oral contraceptives (OCs), thereby potentiating contraceptive failure. In contrast, the anticonvulsant drug gabapentin is not metabolized in humans and has little liability for metabolic-based drug interactions. The present study sought to confirm whether concurrent administration of gabapentin would alter the pharmacokinetics of norethindrone acetate (2.5 mg) and ethinyl estradiol (50 mcg) in healthy US women. A total of 13 women were enrolled for three menstrual cycles each. Pharmacokinetic values did not change appreciably as a result of the addition of gabapentin. The rate and extent of absorption of both hormones were unaffected by the anticonvulsant. Gabapentin plasma concentration time profiles and pharmacokinetic values from this study were similar to historical values after administration of gabapentin alone. The observed lack of interaction between gabapentin and norethindrone acetate or ethinyl estradiol is consistent with the fact that gabapentin is not metabolized, is not an inducer or inhibitor of hepatic drug metabolizing enzymes, is absorbed via a specific transport system for amino acids, and is not bound to plasma proteins. Anticonvulsant drugs that do not interact with OCs should be considered for the treatment of epileptic women of childbearing age who are using this method of fertility control.

Effect of troglitazone on steady-state pharmacokinetics of digoxin.

Twelve healthy subjects participated in a study to determine the effect of multiple doses of troglitazone on the steady-state pharmacokinetics of digoxin. Subjects received digoxin 0.25 mg orally once daily on days 1 through 20 and 400 mg of troglitazone orally once daily on days 11 through 20. Serial plasma samples and 24-hour urine samples collected before and after the doses on days 10 and 20 were analyzed for digoxin using a radioimmunoassay method. Eleven subjects completed the study. Administration of multiple oral doses of digoxin and troglitazone was well tolerated. Mean values for maximum concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from 0 to 24 hours (AUC0-24) of digoxin on day 10 were similar to those on day 20. Mean day 10 digoxin values for minimum concentration (Cmin), apparent oral clearance (Cl/F), total urinary excretion from 0 to 24 hours (Ae0-24), and renal clearance (Clr) were also similar to corresponding values on day 20. Thus, concomitant administration of multiple-dose troglitazone does not alter the steady-state pharmacokinetics of digoxin.

Meta-analysis of steady-state pharmacokinetics of troglitazone and its metabolites.

The object of this study is to evaluate the effects of age, gender, age-by-gender interaction, Type II diabetes, body weight, race, smoking, and formulation on steady-state pharmacokinetics of troglitazone, Metabolite 1 (sulfate conjugate), and Metabolite 3 (quinone metabolite) following multiple-dose oral administration of troglitazone. Pharmacokinetic parameter estimates [Cl/F (apparent oral clearance), AUC0-24 (area under plasma concentration-time curve), and ratio of AUC for troglitazone to Metabolite 1 and to Metabolite 3] obtained from 84 healthy volunteers and 171 patients with Type II diabetes in 8 studies were analyzed using a graphical method (for race and smoking) or a weighted ANCOVA model incorporating gender, health status (healthy vs Type II diabetes), and formulation as main effects; age, age-by-gender interaction, and body weight as continuous covariates. Ratio of AUC for troglitazone to metabolites was also examined by inspection of log-probit plots. Age, gender, age-by-gender, Type II diabetes, and formulation had negligible effects on troglitazone Cl/F, AUC0-24 (all analytes), and AUC ratio of troglitazone to metabolites. Race and smoking did not appear to influence steady-state pharmacokinetics of troglitazone and its metabolites. Although body weight was a significant covariate for AUC0-24 and Cl/F, the explanatory power of the overall model was weak (R2 < 0.2). Log-probit plots did not reveal a polymorphic distribution in AUC ratio of troglitazone to Metabolite 1 or Metabolite 3. Based on pharmacokinetics, dose adjustment for troglitazone in relation to the demographic factors examined is not required due to their poor predictive ability on steady-state pharmacokinetics of troglitazone and its metabolites.

Lack of effect of type II diabetes on the pharmacokinetics of troglitazone in a multiple-dose study.

Twelve patients with type II diabetes and 12 age-, weight-, and gender-matched healthy subjects participated in a study comparing the pharmacokinetics of troglitazone, metabolite 1 (sulfate conjugate), and metabolite 3 (quinone) after oral administration of 400 mg of troglitazone every morning for 15 days. Serial plasma samples collected after the dose on days 1 and 15 were analyzed for troglitazone, metabolite 1, and metabolite 3 using a validated HPLC method. Steady state plasma concentrations of troglitazone and its metabolites were achieved by the fifth day of troglitazone administration in both groups. Mean day 15 Cmax, tmax, AUC0-24, and Cl/F values of troglitazone were 1.54 micrograms/mL, 3.25 hours, 15.6 micrograms.hr/mL, and 461 mL/min, respectively, in patients with type II diabetes. Corresponding parameter values were 1.42 micrograms/mL, 2.63 hours, 12.5 micrograms.hr/mL, and 558 mL/min, respectively, in healthy subjects. Elimination t1/2 was approximately 24 hours in both groups. Mean day 15 pharmacokinetic parameter values for metabolite 1 and metabolite 3 were similar in the two groups. Ratio of AUC of metabolite 1 to troglitazone was 6.2 and 6.7, respectively, in patients and in healthy subjects. Ratio of AUC of metabolite 3 to troglitazone was 1.1 in both groups. Thus, steady-state pharmacokinetics and disposition of troglitazone and its metabolites in patients with type II diabetes were similar to those in healthy subjects.

A high-performance liquid chromatographic assay for the enantiomers of bevantolol in human plasma.

A method was developed and validated for the simultaneous analysis of (+)- and (-)-bevantolol in human plasma. The assay involves plasma protein precipitation, derivatization of racemic bevantolol to its diastereomeric thioureas with 2,3,4,5-tetra-o-acetyl-alpha-D-glucopyranosyl isothiocyanate, and solid-phase extraction of the diastereomers from 0.5 ml human plasma. Chromatographic separation was accomplished under isocratic conditions using a reversed-phase C-18 analytical column and mobile phase consisting of equal parts of 75 mM dibasic ammonium phosphate buffer (adjusted to pH 3.5 with phosphoric acid) and acetonitrile, with a detection wavelength of 220 nm. The absolute peak-height method was employed for quantitation. Retention times for the diastereomers of (+)- and (-)-bevantolol were 7.4 and 6.4 min, respectively. The method is suitable for the quantification of the enantiomers over a concentration range of 40 to 800 ng/ml per enantiomer.

Pharmacology, pharmacokinetics, and therapeutic use of meclofenamate sodium.

Meclofenamic acid is a nonsteroidal anti-inflammatory drug (NSAID) approved for use in arthritis (osteo and rheumatoid), analgesia (mild to moderate pain), dysmenorrhea, and heavy menstrual blood loss (menorrhagia). At least three different biochemical effects have been defined for meclofenamic acid. It is a potent inhibitor of the enzyme cyclooxygenase, thereby inhibiting the production of prostaglandins. It also inhibits the release of 5-HETE and LTB4 from human neutrophils stimulated with calcium ionophore and antagonizes the response of tissues to certain prostaglandins. These mechanisms may explain in part the pharmacological profile and clinical effectiveness of this compound. The rapid onset of activity of meclofenamic acid and its duration of action may be the result of its pharmacokinetic profile. Sodium meclofenamate is completely bioavailable from capsules relative to an oral suspension dosage form. Maximum meclofenamic acid plasma concentrations are achieved in 0.5-2 h following doses of capsules. Meclofenamic acid is extensively metabolized. One of the metabolites, metabolite 1, is approximately 20% as active as the parent compound in inhibiting cyclooxygenase activity in vitro. This metabolite accumulates in plasma during repeated dosing. It is possible that this metabolite may contribute to at least some of the activity observed following administration of sodium meclofenamate.

Gastrointestinal behavior of orally administered radiolabeled erythromycin pellets in man as determined by gamma scintigraphy.

The behavior of single 250-mg doses of a multiparticulate form of erythromycin base (ERYC(R)), each including five pellets radiolabeled with neutron-activated samarium-153, was observed by gamma scintigraphy in seven male subjects under fasting and nonfasting conditions. The residence time and locus of radiolabeled pellets within regions of the gastrointestinal tract were determined and were correlated with plasma concentrations of erythromycin at coincident time points. Administration of food 30 minutes postdosing reduced fasting plasma erythromycin Cmax and area under the plasma erythromycin versus time curve (AUC) values by 43% and 54%, respectively. Mean peak plasma concentration of erythromycin (Cmax) in the fasting state was 1.64 micrograms/mL versus 0.94 micrograms/mL in the nonfasting state. Total oral bioavailability, as determined by mean AUC (0-infinity) of the plasma erythromycin concentration versus time curve, was 7.6 hr/micrograms/mL in the fasted state, versus 3.5 hr/micrograms/mL in the nonfasting state. Mean time to peak plasma erythromycin concentration (tmax) in the fasting state was 3.3 hours, versus 2.3 hours in the nonfasting state. Plasma concentrations of erythromycin in both fasting and nonfasting states were within acceptable therapeutic ranges. Evidence provided by this study: 1) indicates that pellet erosion and absorption of active erythromycin base begins when the enteric-coated pellets reach the highly vascular mucosa of the jejunum and proximal ileum, and is essentially completed within the ileum, with a significant portion absorbed in the medial-to-distal ileum; 2) confirms that acceptable therapeutic plasma levels of erythromycin are attained in nonfasting subjects (Cmax = 0.94 microgram/mL) and that superior plasma erythromycin concentrations (Cmax = 1.64 micrograms/mL) are achieved by administration of the dose on an empty stomach 1 to 2 hours before or after meals; 3) corroborates other comparative studies reporting greater fasting bioavailability with this multiparticulate dosage form of erythromycin base than with reference single tablet or particle-in-tablet formulations; and 4) indicates that neutron activation of stable isotopes incorporated as a normal excipient in industrially-produced formulations provides an effective means for in vivo evaluation of dosage forms through gamma scintigraphy.

Pharmacokinetic profile of a 300-mg extended phenytoin sodium capsule (Dilantin) formulation.

The pharmacokinetic profile of a newly developed Dilantin 300-mg Kapseal formulation was compared with that of currently marketed Dilantin 100-mg Kapseals in both a 300-mg single-dose bioequivalence study in nine healthy volunteers and a once-daily 300-mg multiple-dose study in 18 patients with seizures. Results of these studies indicate the rate and extent of absorption of the 300-mg extended phenytoin (PHT) sodium capsule formulation are similar to that of 100-mg extended PHT sodium capsules based on PHT plasma maximum concentrations and time to achieve them (Cmax, tmax), and area under the curve (AUC) values and the urinary excretion of total hydroxy phenylhydantoin (HPPH) in the single-dose study and steady-state PHT plasma Cmax, tmax, minimum plasma concentrations (Cmin), and AUC values and urinary excretion of total HPPH in the multiple-dose study. Control of seizures in patients was equally maintained on a once-daily 300-mg multiple-dosing regimen administered as either one 300-mg extended PHT sodium capsule daily or three 100-mg extended PHT sodium capsules daily. Therefore, 300-mg extended PHT sodium capsules can be safely and effectively interchanged with three 100-mg extended PHT sodium capsules in patients requiring a once-daily 300-mg PHT sodium dosing regimen.

Effect of a high-fat meal on the bioavailability of a polymer-coated erythromycin particle tablet formulation.

The effect of food on the relative bioavailability of an erythromycin particles-in-tablet formulation was studied in 27 healthy volunteers, using a four-way, crossover study design with the following treatments: one or two erythromycin capsules USP (Eryc, Parke-Davis), or one polymer-coated erythromycin particles-in-tablet (PCE, Abbott) administered fasting or with a high-fat meal. Under fasting conditions the erythromycin particles-in-tablet and erythromycin capsule formulations are bioequivalent based on similar tmax and dose-normalized Cmax and AUC values. The rate and extent of absorption from the particles-in-tablet formulation, however, are dramatically reduced following administration with a meal. Mean Cmax and AUC values decreased by 73% and 72%, respectively, and seven subjects had no detectable erythromycin plasma concentrations for 16 hours following administration of the particles-in-tablet formulation with the high-fat meal. Greater than 40% of the subjects had nonfasting Cmax and AUC values that were less than 10% of those values following administration of the dose fasting. Cmax and AUC values in nonfasting subjects were within 75% to 125% of fasting values in only two and one of 27 subjects, respectively. The erythromycin particles-in-tablet formulation therefore should not be administered with meals.