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Background and Objectives: Two studies were conducted to investigate whether the pharmacokinetics of the atypical antipsychotic aripiprazole were altered in individuals with hepatic or renal impairment compared with those with normal hepatic or renal function.Study Design: Two open-label, single-dose studies.Study Setting: Clinical research unit.Patients: Study 1: Subjects with normal hepatic function (n = 6) and subjects with hepatic impairment (Child-Pugh class A [mild, n = 8], B [moderate, n = 8] or C [severe, n = 3]). Study 2: Subjects with normal renal function (creatinine clearance >80 mL/min; n = 7) and subjects with severe renal impairment (creatinine clearance <30 mL/min; n = 6).Treatment: Single oral dose of aripiprazole 15 mg. PHARMACOKINETIC ANALYSES: Noncompartmental pharmacokinetic analysis was performed using plasma aripiprazole and dehydro-aripiprazole concentration-time data.Main Outcome Measures: Study 1 (hepatic impairment study): apparent oral clearance of unbound drug (CL/Fu) and the maximum plasma concentration (Cmax) of aripiprazole; Study 2 (renal impairment study): CL/Fu, Cmax and renal clearance (CL(R)). Safety assessments included 12-lead ECGs, vital sign monitoring, clinical laboratory measurements and assessment of adverse events.fResults: In the hepatic impairment study, the mean total Cmax of aripiprazole was significantly lower in subjects with severe hepatic impairment compared with those with normal hepatic function (p = 0.04). The fraction of aripiprazole unbound (fu) was significantly greater for subjects with mild (p = 0.02) or severe hepatic impairment (p < 0.01) but not for those with moderate hepatic impairment (p = 0.09) compared with healthy controls. There were no meaningful differences in either the Cmax of unbound aripiprazole or CL/Fu between groups. The mean CL(R) of aripiprazole was negligible (0.04 mL/h/kg in controls and 0.19 mL/h/kg in patients with severe hepatic impairment). In the renal impairment study, the mean total Cmax values were numerically higher (approximately 40%) and the area under the plasma aripiprazole concentration-time curve from time zero to infinity was lower (approximately 19%) in renally impaired subjects versus those with normal renal function; the fu was comparable between groups. Aripiprazole CL(R) was approximately 3-fold higher in renally impaired subjects, but this difference was not statistically significant. No deaths or serious adverse events were reported during either study.Conclusion: A single aripiprazole 15-mg dose was well tolerated. There were no meaningful differences in aripiprazole pharmacokinetics between groups of subjects with normal hepatic or renal function and those with either hepatic or renal impairment. Adjustment of the aripiprazole dose does not appear to be required in populations with hepatic or renal impairment. [ABSTRACT FROM AUTHOR]

Two 14-day, placebo-controlled, double-blind studies evaluated the fasting pharmacokinetics, safety, and tolerability of aripiprazole, a new antipsychotic, in healthy male subjects. In Study 1, 37 subjects were randomized to aripiprazole 5 mg, 10 mg, 15 mg, 20 mg, or placebo once daily. In Study 2, 11 subjects were randomized to aripiprazole, titrated from 10 to 30 mg/day, or placebo. Aripiprazole had linear pharmacokinetics over 5 to 30 mg/day, which were described by a two-compartment open model, with first-order absorption. In Study 1, mean elimination half-life ranged from 47 to 68 hours with aripiprazole, with apparent systemic clearance (CL/F) of approximately 3.45 L/h. In Study 2, mean elimination half-life was 59 hours (CL/F approximately 4.0 L/h). Adverse events were generally mild to moderate, were transient in nature, and commonly occurred within the first 3 days of dosing. Clinical laboratory assessments, electrocardiogram, electroencephalogram, and prolactin levels showed no clinically significant changes during the studies. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of toborinone was studied in subjects with congestive heart failure (CHF) and concomitant renal and/or hepatic disease. At the time of admission, subjects were grouped based on estimated creatinine clearance and serum bilirubin. Glomerular filtration rate was assessed using iothalamate clearance. Hepatic function was assessed using the caffeine metabolism test and indocyanine green clearance. No significant differences were observed in mean toborinone pharmacokinetic parameters among the four study groups. Positive correlations were observed between toborinone clearance and the measured indices of renal and hepatic function: creatinine clearance, iothalamate renal clearance, paraxanthine/caffeine ratio, and indocyanine green clearance. Toborinone clearance decreased with decreasing creatinine clearance, decreasing glomerular filtration rate, decreasing demethylation metabolic activity, and decreasing hepatic bloodflow, although no significant differences were observed in any mean toborinone pharmacokinetic parameters evaluated among the four study groups. [ABSTRACT FROM AUTHOR]

This study investigated the effects of the concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6. In period 1, a single dose of 3.5 mg/kg theophylline was administered orally. In period 2, a single dose of 1.0 microg/kg/min toborinone was infused over 6 hours. In period 3, 3.5 mg/kg theophylline was coadministered with 1.0 microg/kg/min toborinone. Serial blood and pooled urine samples were collected before and after toborinone administration for the quantification of toborinone and its metabolites in plasma and urine. Serial blood samples were collected before and after theophylline administration for the quantification of theophylline and its metabolites in plasma. No significant differences were observed in toborinone pharmacokinetics between poor and extensive metabolizers via CYP2D6. Toborinone coadministration with theophylline did not result in a substantive effect on the disposition of theophylline and vice versa. [ABSTRACT FROM AUTHOR]

The pharmacokinetic and pharmacodynamic interactions between tolvaptan and furosemide or hydrochlorothiazide (HCTZ) were determined in a single-center, randomized, open-label, parallel-arm, 3-period crossover study conducted in healthy white (Caucasian) men. A total of 12 subjects were enrolled in the study, with 6 subjects assigned to each of two treatment arms. Subjects in Arm 1 received 30 mg of tolvaptan, 80 mg of furosemide, and 30 mg of tolvaptan + 80 mg of furosemide. Subjects in Arm 2 received 30 mg of tolvaptan, 100 mg of HCTZ, and 30 mg pf tolvaptan + 100 mg of HCTZ. Doses were separated by a 48-hour washout. Blood and urine samples were collected at scheduled timepoints during the 24 hours after administration of study drug for the determination of pharmacokinetic and pharmacodynamic parameters. No clinically significant changes were noted in the pharmacokinetic profiles of tolvaptan and furosemide or tolvaptan and HCTZ when coadministered. Free water clearance, 24-hour urine volume, plasma sodium and argentine vasopressin concentrations, and plasma osmolality were higher, and urine osmolality was lower when tolvaptan was administered either alone or in combination with furosemide or HCTZ, compared with furosemide or HCTZ administered alone. At 24 hours postdose, plasma renin activity was increased after furosemide or HCTZ administered alone or with tolvaptan, but it was unchanged after tolvaptan alone. Tolvaptan did not significantly affect the natriuretic activity of furosemide or HCTZ. Furosemide and HCTZ did not significantly affect the aquaretic activity of tolvaptan. Tolvaptan administered alone or in combination with furosemide or HCTZ was safe and well tolerated at the given doses.

Fluid retention and extracellular volume expansion are frequently encountered complications of congestive heart failure (HF) that can cause morbidity and mortality. Tolvaptan (Otsuka) is an orally administered nonpeptide vasopressin (VP) V2 receptor antagonist that inhibits water reabsorption in the kidney by competitively blocking VP binding, resulting in water diuresis without significantly changing total electrolyte excretion. In the 24-hour period following a 30-mg dose of tolvaptan, urine excretion rate increases and declines as plasma concentrations rise and fall; this uneven effect results in 80% of daily urine output in the first 12 hours. Therefore, the current study was designed to assess the pharmacodynamic effects, pharmacokinetics, and clinical safety of tolvaptan 30 mg QD plus placebo versus 15 mg BID over 7 days in patients with NYHA Class II/III heart failure and persistent fluid overload, SBP > or = 90 mm Hg, and a serum creatinine < or = 3.0 mg/dL. Patients were withdrawn from diuretics for 48 hours before randomization. Statistics were performed with ANCOVA for continuous variables and Mantel-Haenszel mean score test stratified by center for categorical variables. Thirty-nine of 40 patients completed days 1 and 7. There were no significant clinical, pharmacokinetic, or pharmacodynamic differences between the dosing regimens over time. Based on these findings, tolvaptan 30 mg was chosen as the comparator for placebo in a large phase 3 survival trial.

Background: Tolvaptan, a nonpeptide selective vasopressin receptor (V2) antagonist, is in development for the treatment of congestive heart failure and hyponatremia. Tolvaptan is primarily metabolized via CYP3A4. This study was conducted to determine the extent of the pharmacokinetic interaction between tolvaptan and steady state amiodarone, an antiarrhythmic drug commonly prescribed for patients with congestive heart failure and a known inhibitor of other drugs metabolized by CYP3A4., Methods: This was a multicenter, open-label, 1-arm, 3-period, sequential treatment study conducted in 11 men (10) and women aged 49 to 80 years. They were primarily Caucasian (20) subjects, with a history of cardiac arrhythmias who were otherwise healthy. Subjects were to have been on oral amiodarone maintenance therapy of 200 mg/day for at least 10 months. All subjects took 200 mg amiodarone once daily on each study day; on days 3 and 4, they were also coadministered 30 and 90 mg of tolvaptan, respectively. The plasma concentrations of amiodarone and its metabolite desethylamiodarone were determined for 24 hours postdose on days 2, 3, and 4, tolvaptan concentrations were determined for 24 hours postdose on days 3 and 4., Results: As determined by the ratio of the geometric means and 90% confidence intervals (0.5 to 2.0) for the maximal plasma concentration and the area under the curve during the dosing interval for both amiodarone and desethylamiodarone, tolvaptan coadministration had no effect on either amiodarone and desethylamiodarone disposition, as all the geometric mean ratios (amiodarone + tolvaptan [30 or 90 mg] vs amiodarone alone) were approximately 1., Conclusion: Tolvaptan coadministration does not alter steady-state amiodarone or desethylamiodarone concentrations. Tolvaptan concentrations did not appear to be different from historical controls. The most frequently reported adverse event was polyuria (15 of 21 subjects for amiodarone + 30 mg tolvaptan); an expected outcome due to the known potent aquaretic action of tolvaptan. The combination of amiodarone and tolvaptan was well tolerated.

Vesnarinone, a positive inotropic drug developed for congestive heart failure, and its metabolites (OPC-8230, OPC-18136, OPC-18137) were analyzed in human dialysate and urine (plus an additional metabolite: OPC-18692 in urine) samples using a modification to a previously published LC-MS/MS assay for the analysis of human plasma and urine samples. OPC-8192, a structural analogue of vesnarinone, was used as the internal standard. The analytes of interest were extracted from human dialysate or urine by a solid phase extraction method using a pre-conditioned C-18 extraction column. The analytes were then resolved by a 7 min gradient elution on a reverse phase high performance liquid chromatographic column. Vesnarinone and metabolites were detected on a PE/Sciex API III+Biomolecular Mass analyzer in MS/MS mode using a Turbo IonSpray interface. The linear range of quantitation in dialysate was 2.00-100.00 ng/ml for vesnarinone and 0.50-25.00 ng/ml for each metabolite. In urine, the linear range was of 0.50-25.00 microg/ml for vesnarinone and 0.10-5.00 microg/ml for the metabolites. This method was used to support the analysis of urine and dialysate samples from renally impaired patients who are on vesnarinone treatment.

Subjects enrolled in studies are not always screened for routine habits such as smoking. Personal history is not always reliable and therefore an objective biomarker is necessary to screen for smokers. The objectives of this article were to review the metabolism of nicotine and other metabolic considerations associated with smoking; to review some of the routine methods used to assess exposure to nicotine-containing products; to revisit cotinine breakpoints utilized to distinguish smokers from non-smokers during screening for clinical trials; to assess the utility of screening questions regarding smoking practices; and to recommend standards for clinical pharmacology studies. The results indicated that cotinine levels serve as a useful biomarker of tobacco exposure; racial issues may be clinically relevant in determining smoking status; cessation of smoking should occur at least 14 days prior to the start of the study; adverse effects from nicotine withdrawal such as craving, hunger and weight gain may persist for more than 6 months; potential metabolic interactions via cytochrome P2A6 and P1A2 need to be considered when designing a study; and the use of a single calibrator as a breakpoint is acceptable if a categorical outcome such as 'smoker' versus 'non-smoker' is desired. Nicotine from food products is not expected to impact assay sensitivity or to be clinically relevant; a serum cotinine concentration of 10 ng ml(-1) be employed as a breakpoint for non-smokers versus smokers; other non-invasive alternatives are collection of urine, saliva, or hair (with suggested breakpoints of 200 ng ml(-1), 5 ng ml(-1) and 0.3 ng mg(-1), respectively; screening questions be accompanied by testing for cotinine; and the inclusion of smokers in studies should be considered once the impact of smoking on the targeted population is understood.

The commonly used antitussive dextromethorphan can be used to simultaneously assess potential cytochrome P450 3A (CYP3A) and CYP2D6 inhibition during drug development. The metabolism of dextromethorphan to dextrorphan and subsequently to 3-hydroxymorphinan are via the 2D6 pathway, while the metabolism of dextromethorphan to 3-methoxymorphinan is via the 3A pathway. A sensitive and specific LC-MS/MS assay has been developed to determine the human urine concentrations of dextromethorphan and three metabolites (dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan) in support of drug interaction studies. Urine samples (0.5 ml), after enzymatic hydrolysis of the conjugates and containing 3-ethylmorphine as an internal standard, were extracted with chloroform under basic conditions. Following concentration and reconstitution, the samples were analyzed by LC-MS/MS. The assay was linear over the range of 5.00-500 ng/ml for dextromethorphan and 3-methoxymorphinan; and 200-3000 ng/ml for dextrorphan and 3-hydroxymorphinan using a Perkin-Elmer Sciex triple quadrupole mass spectrometer (API 300). The intra- and inter-day relative standard deviation (RSD) across three validation runs over the entire concentration range for all analytes was less than 15%. Accuracy determined at three or four concentrations (9.00, 200, and 400 ng/ml for dextromethorphan and 3-methoxymorphinan; 250, 400, 1300 and 2500 ng/ml for dextrorphan and 3-hydroxymorphinan) ranged between 96.3 and 113.8%. The stability of analytes in urine was demonstrated for 9 months at -20 degrees C, 24 h under ambient conditions and for up to three freeze/thaw cycles. The method described herein is suitable for the rapid and efficient measurement of dextromethorphan and different metabolites to estimate potential CYP3A inhibition by drug candidates and for screening of extensive and poor metabolizers of CYP2D6 in the heterogeneous population. The method has subsequently been validated on a Sciex API 3000 with lower limit of quantitation; 1.00 ng/ml for dextromethorphan and 3-methoxymorphinan; 60.0 ng/ml for dextrorphan and 100 ng/ml for 3-hydroxymorphinan.

An LC/MS/MS method for the simultaneous determination of cilostazol, a quinolinone derivative, and three active metabolites, OPC-13015, OPC-13213, and OPC-13217, in human plasma was developed and validated. Cilostazol, its metabolites, and the internal standard, OPC-3930 were extracted from human plasma by liquid-liquid partitioning followed by solid-phase extraction (SPE) on a Sep-Pak silica column. The eluent from the SPE column was then evaporated and the residue reconstituted in a mixture of methanol/ammonium acetate buffer (pH 6.5) (2:8 v/v). The analytes in the reconstituted solution were resolved using reversed-phase chromatography on a Supelcosil LC-18-DB HPLC column by an 17.5-min gradient elution. Cilostazol, its metabolites, and the internal standard were detected by tandem mass spectrometry with a Turbo Ionspray interface in the positive ion mode. The method was validated over a linear range of 5.0-1200.0 ng/ml for all the analytes. This method was demonstrated to be specific for the analytes of interest with no interference from endogenous substances in human plasma or from several potential concomitant medications. For cilostazol and its metabolites, the accuracy (relative recovery) of this method was between 92.1 and 106.4%, and the precision (%CV) was between 4.6 and 6.5%. During the validation, standard curve correlation coefficients equalled or exceeded 0.999 for cilostazol and its metabolites. These data demonstrate the reliability and precision of the method. The method was successfully cross-validated with an established HPLC method.

A high performance liquid chromatography (HPLC) method with ultraviolet detection for the simultaneous quantification of cilostazol, and its known metabolites in human urine was developed and validated. Cilostazol, its metabolites and the internal standard OPC-3930 (structural analogue of cilostazol) were extracted from human urine using liquid-liquid extraction with chloroform. The organic extract was then evaporated and the residue was reconstituted in 8% acetonitrile in ammonium acetate buffer (pH 6.5). The reconstituted solution was injected onto an HPLC system and was subjected to reverse-phase HPLC on a 5-microm ODS column. A gradient mobile phase with different percentages of acetonitrile in acetate buffer (pH 6.5) was used for the resolution of analytes. Cilostazol, its metabolites and the internal standard were well resolved at baseline with adequate resolution from constituents of human urine. The lower limit of quantification was 100 ng/ml for cilostazol and all metabolites. The method was validated for a linear range of 100-3000 ng/ml for all the metabolites and cilostazol. The overall accuracy (% relative recovery) of this method ranged from 86.1 to 116.8% for all the analytes with overall precision (%CV) being 0.8-19.7%. The long-term stability of clinical urine samples was established for at least 3 months at -20 degrees C in a storage freezer. During validation, calibration curves had correlation coefficients greater than or equal to 0.995 for cilostazol and the seven tested metabolites. The method was successfully used for the analysis of cilostazol and its metabolites in urine samples from clinical studies, demonstrating the reliability and robustness of the method.

1. Cilostazol (OPC-13013) undergoes extensive hepatic metabolism. The hydroxylation of the quinone moiety of cilostazol to OPC-13326 was the predominant route in all the liver preparations studies. The hydroxylation of the hexane moiety to OPC-13217 was the second most predominant route in vitro. 2. Ketoconazole (1 microM) was the most potent inhibitor of both quinone and hexane hydroxylation. Both the CYP2D6 inhibitor quinidine (0.1 microM) and the CYP2C19 inhibitor omeprazole (10 microM) failed to consistently inhibit metabolism of cilostazol via either of these two predominant routes. 3. Data obtained from a bank of pre-characterized human liver microsomes demonstrated a stronger correlation (r2=0.68, P < 0.01) between metabolism of cilostazol to OPC-13326 and metabolism of felodipine, a CYP3A probe, that with probes for any other isoform. Cimetidine demonstrated concentration-dependent competitive inhibition of the metabolism of cilostazol by both routes. 4. Kinetic data demonstrated a Km value of 101 microM for cilostazol, suggesting a relatively low affinity of cilostazol for CYP3A. While recombinant CYP1A2, CYP2D6 and CYP2C19 were also able to catalyze formation of specific cilostazol metabolites, they did not appear to contribute significantly to cilostazol metabolism in whole human liver microsomes.

Vesnarinone is an orally administered inotropic agent that is metabolized in vitro by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1. The purpose of this study was to assess the contribution of CYP2E1 activity to the disposition of vesnarinone in humans by characterizing the pharmacokinetics before and after disulfiram-mediated CYP2E1 inhibition. The pharmacokinetics of vesnarinone 60 mg were determined in normal healthy volunteers (N = 7) before and after daily disulfiram administration (250 mg). Chlorzoxazone 250 mg was also administered before, during, and after disulfiram administration to serve as a positive control for CYP2E1 inhibition. Disulfiram treatment decreased 6-hydroxychlorzoxazone formation clearance by nearly 95% but effected only a modest decrease in vesnarinone apparent oral clearance (5.7 +/- 1.0 vs. 5.0 +/- 0.5 ml/min; p = 0.022). In contrast to the modest effect on the parent drug, disulfiram treatment substantially increased plasma concentrations of the primary metabolite OPC-18692. The Cmax of OPC-18692 was increased approximately 7-fold, and the area under the plasma concentration-time curve was increased 18-fold (2.9 +/- 0.9 vs. 53.7 +/- 33.2 micrograms.h/ml; p = 0.006). The results indicate that CYP2E1 inhibition has only a modest, clinically insignificant effect on vesnarinone disposition but markedly increases plasma concentrations of the OPC-18692 metabolite. The pharmacological properties of this metabolite have not been fully defined; thus, the clinical importance of this observation depends on whether this metabolite contributes to any of the toxicity associated with vesnarinone administration.

A high-performance liquid chromatographic (HPLC) method for the simultaneous determination of cilostazol, a quinolinone derivative, and its known metabolites OPC-13015, OPC-13213, OPC-13217, OPC-13366, OPC-13269, OPC-13326 and OPC-13388 in human plasma was developed and validated. Cilostazol, its metabolites and two internal standards, OPC-3930 and OPC-13112, were extracted from human plasma by a combination of liquid-liquid and liquid-solid phase extractions, with combined organic solvents of n-butanol, methanol, chloroform, methyl-tert.-butyl ether, and a Sep-Pak silica column. The combined extract was then evaporated and the residue was reconstituted in ammonium acetate buffer (pH 6.5). The reconstituted solution was injected onto a HPLC system and was subjected to reversed-phase HPLC on a 5 microm ODS-80TM column to obtain quality chromatograph and good peak resolution. A gradient mobile phase with different percentages of acetonitrile in acetate buffer (pH 6.5) was used for the resolution of analytes. Cilostazol, its metabolites and the two internal standards were well separated at baseline from each other with resolution factor being 74 and 138. This HPLC method was demonstrated to be specific for all analytes of interest with no significant interference from the endogenous substances of human plasma. The lower limit of quantitation was 20 ng/ml for cilostazol and all metabolites. The method was validated initially for an extended linear range of 20-600 ng/ml for all metabolites and cilostazol, and has been revised later for a linear range of 20-1200 ng/ml for cilostazol and two major and active metabolites OPC-13015 and OPC-13213. The overall accuracy (relative recovery) of this method was established to be 98.5% to 104.9% for analytes with overall precision (CV) being 1.5% to 9.0%. The long-term stability of clinical plasma samples was established for at least one year at -20 degrees C. Two internal standards of OPC-3930 and OPC-13112 were evaluated and validated. However, the data indicated that there was no significant difference for all accuracy and precision obtained by using either OPC-3930 or OPC-13112. OPC-3930 was chosen as the internal standard for the analysis of plasma samples from clinical studies due to its shorter retention time. During the validation standard curves had correlation coefficients greater than or equal to 0.998 for cilostazol and the seven metabolites. These data clearly demonstrate the reliability and reproducibility of the method.

Objective: In vitro results suggest that cilostazol is metabolised by cytochrome P450 (CYP) isoforms 1A2, 2D6, 3A and 2C19. This study investigated the role of CYP3A inhibition on the metabolism of cilostazol., Design: The study was conducted as a single-centre, open-label, nonrandomised, 2-period, crossover pharmacokinetic trial. A single dose of cilostazol 100 mg was administered orally on days 1 and 15. Erythromycin (150 mg orally 3 times daily) was administered on days 8 to 20. 14C-erythromycin (3 microns Ci) was administered intravenously on days 1 and 15 one hour before cilostazol administration to determine baseline and the inhibitory effect of erythromycin treatment on CYP3A activity., Study Participants: 16 healthy nonsmoking male volunteers., Main Outcome Measures: Serial blood and pooled urine samples were collected before and after cilostazol administration to quantitate cilostazol and its metabolites. Serial exhalation samples were collected after intravenous 14C-erythromycin administration and radioactivity was quantitated by scintillation counting. Pharmacokinetics were determined by noncompartmental methods and compared before and after erythromycin administration. Tolerability assessments included adverse events, laboratory tests, vital signs and electrocardiographs., Results: Following erythromycin coadministration, cilostazol maximum plasma concentration (Cmax), area under the plasma concentration-time curve at time t (AUCt), and area under the curve from zero to infinity (AUC infinity) increased significantly by 47, 87, and 73%, respectively, and an approximately 50% reduction in unbound clearance was observed for the major circulating metabolite of cilostazol, OPC-13015. Cmax decreased significantly (p < 0.001) by 24%, while AUCt increased by 8%; this increase was not significant. For the second major metabolite, OPC-13213, the Cmax and AUCt increased by 29 and 141%, respectively (p < 0.001)., Conclusions: In vivo results are in agreement with previous in vitro human microsome studies, indicating that cilostazol is metabolised to OPC-13015 via CYP3A. In addition, OPC-13213 concentrations increased after inhibition of CYP3A because of inhibition of sequential metabolism of OPC-13213 via CYP3A. A starting dose for cilostazol of 50 mg twice daily should be considered during coadministration of inhibitors of CYP3A.

Clinical doses are developed for the oral coadministration of radiolabeled and nonlabeled forms of a poorly soluble investigational compound: OPC-41061. The release rates of the labeled and nonlabeled forms are equated and matched to the release rate of the polymer spray-dried form of the drug in the proposed market product. The study involves the physicochemical characterization of the powders using thermal analysis and dissolution testing, development and extemporaneous manufacture of liquid-filled soft gelatin capsules, and dissolution and stability testing of the final dosage form. Thermal analysis indicated that the labeled powder was amorphous and that the nonlabeled powder, which had been jet-milled, was crystalline. Dissolution testing of the jet-milled and spray-dried powders indicated that the former was released at a significantly slower rate. A liquid formulation containing 25% dimethyl acetamide and 75% polyethylene glycol 400 (PEG 400) solubilized the desired dose of 60 mg and exhibited a drug profile that was similar to the spray-dried formulation. The final formulation was a soft gelatin capsule containing 60 mg of drug, including 100 microCi radioactivity, dissolved in 0.8 ml of a 25% dimethyl acetamide/75% PEG 400 solution. The formulation was chemically and physically stable for a period greater than the duration of the study.

Objective: To assess the effects of cilostazol on lovastatin pharmacokinetics., Design: This was a single-centre, open-label, multiple dose, sequential treatment study. Participants received single oral doses of lovastatin 80 mg on days 1, 7 and 9, as well as oral cilostazol 100 mg twice daily on days 2 to 8, followed by a single oral 150 mg cilostazol dose on day 9., Study Participants: 15 healthy, nonsmoking male or female volunteers (aged 18 to 60 years) were enrolled, and 12 completed the study., Main Outcome Measures: Pharmacokinetic parameters were calculated using plasma concentrations of lovastatin and its beta-hydroxy metabolite and of cilostazol and its metabolites. Differences in the pharmacokinetics of each drug when given alone or in combination were assessed by analysis of variance., Results: The maximum observed plasma concentration (Cmax) of lovastatin or its metabolite did not differ significantly when lovastatin was given alone and when it was given with 100 mg of cilostazol. The mean ratios of the area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUCt) for lovastatin coadministered with 100 mg of cilostazol to that with lovastatin given alone were 1.6 for lovastatin and 1.7 for its metabolite. With 150 mg of cilostazol, lovastatin Cmax did not change, whereas Cmax of the metabolite increased 2.2-fold. The mean AUCt ratios for lovastatin given with 150 mg cilostazol/lovastatin given alone were 1.6 and 2.0 for lovastatin and its metabolite, respectively. All increases in lovastatin and metabolite AUC were statistically significant, except for the 1.6-fold increase in lovastatin AUC with 150 mg of cilostazol. Maximum steady-state plasma drug concentration (Cssmax) and AUC during a dosage interval (AUC tau) for cilostazol 100 mg twice daily decreased 14 and 15%, respectively, upon lovastatin coadministration., Conclusions: Lovastatin and metabolite exposure is increased only by up to 2-fold when cilostazol is coadministered, which is considerably less than that observed for potent CYP3A inhibitors such as itraconazole and grapefruit juice. Absorption of cilostazol decreased approximately 15% when it was given with lovastatin. No dosage adjustments are necessary for cilostazol when coadministered with lovastatin, whereas lovastatin dose reductions may be needed when the 2 drugs are given together.

Objectives: The objectives of this research were to (1) assess the relative bioavailability following administration of a 100 mg cilostazol suspension versus 100 mg tablet; (2) assess dosage form equivalency (2 x 50 mg compared with 1 x 100 mg); (3) compare the relative bioavailability following a single 50 mg dose of cilostazol administered as an ethanolic solution versus a 50 mg tablet; and (4) determine the effects of high fat diet on the pharmacokinetics of cilostazol following a single dose of 100 mg cilostazol in the fed or fasted state. Results were compiled from 3 separate studies to address these objectives., Design: All studies involved healthy adult males receiving single oral doses of cilostazol in the fed or fasted state. The fed state consisted of administering cilostazol after ingestion of a high fat meal. One study compared the relative bioavailability of 100 mg suspension and 2 x 50 mg tablet versus 100 mg tablet in a randomised crossover design. The study involving administration of a 50 mg cilostazol ethanolic solution was a single treatment study. The effects of food on the pharmacokinetics of cilostazol after administration of 100 mg cilostazol in the fed or fasted state as well as the pharmacokinetic profile following administration of a single 50 mg oral dose of cilostazol were assessed in a randomised crossover design., Study Participants: All participants were healthy nonsmoking males aged between 19 and 48 years whose bodyweight was within 15% of ideal bodyweight., Main Outcome Measures: Noncompartmental pharmacokinetic parameters were determined for each study participant., Results: The area under the plasma concentration-time curve (AUC) parameters were within the 80 to 125% criterion for bioequivalence for the cilostazol and its primary metabolite, OPC-13015. The maximum observed plasma concentrations (Cmax) for these formulations were not equivalent and indicated that the absorption of cilostazol from a suspension is more rapid than from a tablet. The apparent terminal half-lives (t1/2z) of cilostazol and OPC-13015 were shorter after administration of the suspension compared with the tablet. Cmax and AUC following administration of a single 50 mg cilostazol tablet were approximately 80% of that from the same dose administered as an ethanolic solution. The t1/2z of cilostazol decreased from 15.5 hours after a tablet to 2.5 hours after an ethanolic solution. Upon coadministration with a high fat meal, the Cmax of cilostazol increased 90% and AUC infinity increased 25% (p < 0.05). The t1/2z decreased from 15.1 +/- 14.5 hours (mean +/- SD) in the fasted state to 5.4 +/- 2.0 hours in the fed state. Single oral doses of 50 and 100 mg cilostazol were well tolerated., Conclusions: The relative bioavailability of the 100 mg cilostazol tablet versus an oral 100 mg cilostazol suspension is 100%. The 2 x 50 mg and 1 x 100 mg tablets are considered to be bioequivalent. The absorption following administration of 50 mg cilostazol ethanolic solution is faster and appears to be greater than that after administration of the 50 mg tablet. Coadministration of food increases the rate and extent of cilostazol absorption. The oral pharmacokinetics of cilostazol and metabolites are absorption-rate limited. The significant differences in the t1/2z observed when comparing cilostazol tablet, suspension, and solution as well as the effects of food suggest 'flip-flop' pharmacokinetics.

Objective: In vitro results suggest that cilostazol is metabolised by cytochrome P450 (CYP) isoforms 1A2, 2D6, 3A4 and 2C19. This study was designed to evaluate the effect of concomitant administration of omeprazole (a CYP2C19 inhibitor) on the pharmacokinetics of a single 100 mg oral dose of cilostazol., Design: This study was conducted as a single-centre, open-label, nonrandomised, 2-period, crossover pharmacokinetic trial. A single 100 mg dose of cilostazol was administered orally on days 0 and 14. Oral omeprazole (40 mg every day) was administered on days 7 to 18., Study Participants: 20 healthy nonsmoking male and female volunteers., Main Outcome Measures: Serial blood samples were collected before and after cilostazol administration to characterise the pharmacokinetics of cilostazol and its metabolites., Results: Following omeprazole coadministration, the increases in cilostazol maximum plasma concentration (Cmax) and area under the plasma concentration-time curve at time t (AUCt) were 18% (p = 0.062) and 26% (p < 0.001), respectively. For the 2 major circulating metabolites, OPC-13015 and OPC-13213, the OPC-13015 Cmax and AUCt increased by 29 and 69%, respectively (p < 0.001). However, for OPC-13213, the Cmax and AUCt decreased by 22 and 31%, respectively (p < 0.001). The plasma protein binding of cilostazol was unaffected by coadministration of omeprazole., Conclusions: Coadministration of cilostazol with omeprazole resulted in an increase in the systemic exposure of cilostazol and its active metabolite, OPC-13015, by 26 and 69%, respectively. For the other active metabolite, OPC-13213, systemic exposure decreased by 31% because of inhibition of cilostazol metabolism to this metabolite. These changes in systemic exposure were well tolerated. A dose of 50 mg cilostazol twice a day should be considered during coadministration of inhibitors of CYP2C19, such as omeprazole.

Objective: The pharmacokinetic profiles of cilostazol and its metabolites following a single oral dose of cilostazol 100 mg were compared between individuals with impaired and normal liver function., Design: The study was conducted as a single-centre, open-label, single dose pharmacokinetic and tolerability trial., Study Participants: 12 patients with impaired and compensated liver function were compared with 12 volunteers with normal liver function. Participants in each group were matched for gender, age and weight. Of the 12 patients with hepatic impairment examined in this study, 10 had mild impairment (Child-Pugh class A) and 2 had moderate impairment (Child-Pugh class B)., Main Outcome Measures: Blood and urine were collected up to 144 hours after drug administration. Pharmacokinetics were determined by noncompartmental methods., Results: Protein binding did not differ between the groups (95.2% healthy volunteers, 94.6% hepatically impaired patients). Mean +/- SD unbound oral clearance of cilostazol decreased by 8.6% because of hepatic impairment (3380 +/- 1400 ml/min in healthy volunteers, 3260 +/- 2030 ml/min in hepatically impaired patients). Total urinary excretion of metabolites was significantly higher in healthy volunteers (26 vs 17% of dose). Overall, the pharmacokinetics of cilostazol and its metabolites, OPC-13213 and OPC-13015, were not substantially different in those with mild and moderate hepatic disease compared with values in healthy volunteers. Except for terminal-phase disposition half-life and apparent terminal-phase volume of distribution for cilostazol, the ratios of geometric means of pharmacokinetic parameters for plasma cilostazol, OPC-13213 and OPC-13015 in those with hepatic impairment versus healthy volunteers were close to 100%., Conclusions: Based on the results of the pharmacokinetic analysis, dose adjustment in patients with mild hepatic impairment is not necessary. However, caution should be exercised when cilostazol is administered to patients with moderate or severe hepatic impairment.

Objective: In vitro results are inconclusive as to whether cilostazol is metabolised by cytochrome P450 isoenzyme 2D6 (CYP2D6). The goals of this study were (1) to assure the dose of quinidine and timing relative to cilostazol used in this study were adequate to cause inhibition of CYP2D6, (2) to evaluate carryover effects of quinidine administration, and (3) to evaluate the effect of CYP2D6 deficiency and administration of quinidine (a CYP2D6 inhibitor) on the pharmacokinetics of a single 100 mg oral dose of cilostazol., Design: This study was conducted as a single-centre, open-label, randomised sequence, 2-period, crossover pharmacokinetic trial. Water alone (treatment without quinidine) or two 200 mg oral doses of quinidine sulfate with water were administered 25 hours and 1 hour prior to a single 100 mg dose of cilostazol in period 1. Study participants were crossed over to opposite treatment in period 2. Metoprolol 25 mg, used as a positive control, was administered 1 hour after quinidine sulfate with water or using water alone to assess the magnitude of CYP2D6 inhibition by quinidine., Study Participants: 22 healthy nonsmoking Caucasian (14 male and 8 female) volunteers participated in the study., Main Outcome Measures: Serial blood and urine samples were collected at predose and after cilostazol administration to characterise cilostazol and its metabolite pharmacokinetics. Additional plasma samples were taken to assess the pharmacokinetics of quinidine. Urine samples were collected to measure metoprolol and hydroxymetoprolol., Results: Administration of metoprolol with quinidine caused a significant (p < 0.001) decrease in the urinary 4-hydroxymetoprolol/metoprolol ratio compared with administration of metoprolol alone (42-fold decrease, 0.065 vs 2.707). Hence, quinidine effectively converted extensive metabolisers of CYP2D6 to poor metabolisers of CYP2D6. The 21-day washout period was adequate to have complete recovery from quinidine inhibition of CYP2D6. The analysis of variance demonstrated that the mean maximum plasma concentration (Cmax) for cilostazol, both adjusted and unadjusted for the free fraction, was higher in the control group than in the quinidine group (p = 0.023). However, the time to Cmax (p = 0.669), the area under the plasma concentration-time curve from time zero to infinity (AUC infinity; p = 0.133), and the apparent oral clearance (p = 0.135) were unchanged. The geometric mean ratios (90% confidence interval) comparing with quinidine (test) and without quinidine (reference) coadministration for Cmax and AUC infinity are 0.86 (0.77, 0.95) and 0.92 (0.84, 1.00), respectively. Similar patterns were observed for OPC-13015 and OPC-13213 with regard to Cmax, area under the plasma concentration-time curve from time zero to the last measurable concentration at time t, and AUC infinity (where determinable). The slight decrease in the systemic availability of cilostazol and its metabolites was thought to be a result of the increased gastrointestinal motility secondary to quinidine., Conclusions: Administration of quinidine sulfate 200 mg profoundly inhibited CYP2D6-mediated metabolism. The effects of quinidine inhibition of CYP2D6 metabolism were completely reversible during the 21-day washout period. Coadministration of quinidine with cilostazol had no substantial effect on cilostazol or its metabolites (OPC-13015 and OPC-13213). Hence, CYP2D6 does not have a significant contribution in the metabolic elimination of cilostazol.

Objective: To evaluate the effect of cilostazol administration on warfarin pharmacokinetics and pharmacodynamics following a single 25 mg dose of warfarin., Design: A randomised double-blind 2-period crossover with healthy volunteers receiving either 100 mg cilostazol twice daily for 13 days or matching placebo twice daily for 13 days, and the other treatment 21 days later. A single 25 mg dose of warfarin was given 14 days prior to the start of the study, and 7 days after the cilostazol and placebo treatments., Study Participants: 15 normal healthy male volunteers., Outcome Measures: Noncompartmental pharmacokinetic parameters for (R)- and (S)-warfarin, the area under the curve of the prothrombin time (AUCPT), activated partial thromboplastin time (AUCaPTT), Ivy bleeding times, unbound fraction (fu) of cilostazol, and warfarin were determined for each individual., Results: For (R)- and (S)-warfarin, the 90% confidence intervals for the ratios of the geometric means (90% CI) of the maximum plasma concentration and area under the plasma concentration-time curve were between 0.88 to 1.03. The 90% CI for the AUCPT and AUCaPTT was between 0.95 and 1.06. For Ivy bleeding time, the 90% CI for the ratios of the geometric means ranged between 0.71 and 1.22. The fu of cilostazol did not differ significantly between the 2 treatments. There was a 17% increase in the fu of warfarin (p < 0.05), which was not clinically significant., Conclusions: Coadministration of warfarin with twice daily administration of cilostazol 100 mg did not alter (R)- and (S)-warfarin pharmacokinetics, prothrombin time, partial thromboplastin time, Ivy bleeding times, or cilostazol protein binding.

Objective: The pharmacokinetics of cilostazol were studied in patients with mild, moderate and severe renal impairment and in healthy volunteers after administration of 50 mg single and multiple doses of cilostazol., Design: This was an open-label, single and multiple dose study administering 50 mg cilostazol every 12 hours to healthy volunteers and patients with varying degrees of renal impairment., Participants: 6 normal volunteers [creatinine clearance (CLCR) > or = 90 ml/min]; 6 patients with mild (CLCR 50 to 89 ml/min), 5 with moderate (CLCR 26 to 49 ml/min) and 6 with severe (CLCR 5 to 25 ml/min) renal impairment., Outcome Measures: Noncompartmental pharmacokinetic parameters were determined for each study participant., Results: At steady state, in the severe renal disease group, cilostazol and OPC-13015 peak concentrations (Cmax) were 29 and 41% lower and the areas under the concentration-time curve over the dosage interval (AUC tau) 39 and 47% lower than in the healthy volunteers. Cmax and AUC tau of OPC-13213 were significantly higher, 173 and 209%, respectively, than those in the healthy volunteers. The accumulation ratios were not significantly different between the various renal function groups for cilostazol and its metabolites. The estimated pharmacological activity of cilostazol and its metabolites was similar between the normal volunteers and those with severe renal impairment., Conclusions: A dosage reduction in renally impaired patients is not supported by the pharmacokinetics of cilostazol and its metabolites in this patient group.

Objective: To study the pharmacokinetics of cilostazol following single oral administration of 50 to 200 mg in healthy young males, and after repeated oral administration of 100 mg every 12 hours to patients with peripheral arterial disease (PAD)., Design: The healthy male single dose study was a single-centre, randomised sequence, open-label, incomplete block, 3-period, 4-treatment, crossover design. The patient study was a single-centre, multiple dose, open-label study., Study Participants: 20 healthy nonsmoking male volunteers were enrolled and successfully completed the single dose study. 26 patients (21 males, 5 females) with intermittent claudication resulting from PAD were enrolled and completed the single/multiple dose study., Main Outcome Measures: Noncompartmental pharmacokinetic parameters, the area under the plasma concentration-time curve from zero to the time of last measurable plasma concentration, and maximum plasma concentration., Results: Peak plasma concentrations of cilostazol occurred about 3 hours after drug administration and then declined biexponentially with concentrations detectable (> 20 micrograms/L) in the plasma for at least 36 hours postdose. The apparent elimination half-life of cilostazol (approximately 11 hours) was similar after a single dose or after multiple doses, with steady state being reached within 4 days. Cilostazol accumulated 1.7-fold following multiple dose administration. The apparent volume of distribution (Vz/F; 2.76 L/kg) suggested extensive distribution of cilostazol in the tissues. The oral clearance of cilostazol (CL/F; 0.18 L/h/kg) was much lower than liver blood flow, indicating a low extraction ratio drug, and hence low probability of a significant first-pass effect. None of the administered doses were recovered in the urine as unchanged cilostazol, suggesting that metabolism, rather than urinary excretion, is the major elimination route. Following single oral doses of 50 to 200 mg, the plasma concentrations of cilostazol and its metabolites increased less than proportionally to the dose. The pharmacokinetics of cilostazol in normal healthy volunteers are predictive of those in patients with PAD. Single oral doses of 50 to 200 mg cilostazol as well as 100 mg cilostazol every 12 hours were well tolerated., Conclusion: The plasma concentration of cilostazol and its metabolites increased less than proportionally with increasing doses. The relatively low plasma clearance and high volume of distribution of cilostazol suggest a low first-pass effect and extensive distribution. The pharmacokinetics of cilostazol in normal volunteers is predictive of that in patients with PAD. Cilostazol was well tolerated in healthy volunteers and patients with intermittent claudication resulting from PAD.

An LC/MS/MS assay was developed and successfully used to quantitate vesnarinone and its principal metabolites (OPC-8230, OPC-18136, and OPC-18137) in human plasma and urine. Samples were pre-treated with liquid-solid extraction followed by simultaneous monitoring of primary and daughter ions which were used for the identification and quantitation of the analytes on LC/MS/MS. This assay offers advantages of specificity, speed and greater sensitivity over the previously developed HPLC-UV assay. The lower limit of quantitation is 500 ng x ml(-1) for vesnarinone and 20 ng x ml(-1) for OPC-8230, OPC-18137, and OPC-18136 in plasma. Methodology is similar for the estimation of these analytes in urine with the lower limit of quantitation being 500 ng x ml(-1) for vesnarinone and 100 ng x ml(-1) for each metabolite. Ascorbic acid was added to stabilize the analytes from degradation. This LC/MS/MS method was developed to overcome many practical problems associated with the HPLC method. The LC/MS/MS method offers the flexibility of analyzing additional metabolites and changing the linearity range to accommodate the differences in linear range (200-10000 ng x ml(-1) for vesnarinone and 20-1000 for metabolites) for the analytes.

Objective: This study evaluated the effects of repeated oral drug administration with cilostazol alone and with aspirin (acetylsalicylic acid) on platelet aggregation, coagulation and bleeding time as well as the cilostazol-aspirin pharmacokinetic interaction in healthy males., Design: This was a randomised, double-blind, placebo-controlled, crossover study. Participants received either cilostazol 100 mg or placebo twice a day for 10 days; aspirin 325 mg/day was coadministered for the last 5 days. After a 14-day washout period, participants received the alternative treatment., Study Participants: 12 healthy male volunteers were enrolled., Main Outcome Measures: Differences in bleeding times, platelet aggregation, prothrombin time (PT) and activated partial thromboplastin time (aPTT) between cilostazol with aspirin and cilostazol alone. Noncompartmental pharmacokinetic parameters were determined for each study participant., Results: Cilostazol, with or without aspirin, caused no changes in PT, aPTT or bleeding time. There was a 23 to 35% increase in inhibition of ADP-induced ex vivo platelet aggregation by cilostazol plus aspirin when compared with aspirin alone. There was no additive or synergistic effect on arachidonic acid-induced platelet aggregation. Statistically significant but clinically insignificant increases in the area under the plasma concentration-time curve to the last measurable plasma concentration and trough concentrations of cilostazol and its metabolites (OPC-13015 and OPC-13213) occurred after aspirin coadministration, with no differences observed in the maximum plasma concentration Drug-related adverse events were generally mild, the most frequent being headache., Conclusions: Cilostazol and aspirin coadministration did not cause clinically significant changes in PT, aPTT, bleeding time, platelet aggregation or plasma concentrations of cilostazol and its 2 active metabolites. Cilostazol was generally well tolerated with or without aspirin.

A high-performance liquid chromatography-ultraviolet (HPLC-UV) method for the quantitation of cilostazol and four of its principal metabolites (i.e. OPC-13015, OPC-13213, OPC-13217 and OPC-13326) in human liver microsomal solutions was developed and validated. Cilostazol, its metabolites, and the internal standard (OPC-3930), were analyzed by protein precipitation followed by reverse-phase HPLC separation on a TSK-Gel ODS-80TM (150 x 4.6 mm, 5 microm) column and a Cosmil C-18 column (150 x 4.6 mm, 5 microm) in tandem and UV detection at 254 nm. An 80 min gradient elution of mobile phase acetonitrile in acetate buffer (pH = 6.50) was used to obtain quality chromatography and peak resolution. All the analytes were separated from each other, with the resolution being 2.43-17.59. The components of liver microsomal incubation mixture and five metabolic inhibitor probes (quinidine sulfate, diethyl dithiocarbamate (DEDTC), omeprazole, ketoconazole and furafylline) did not interfere with this analytical method. The LOQ was 1000 ng ml(-1) for cilostazol and 100 ng ml(-1) for each of the metabolites. This method has been validated for linear ranges of 100-4000 ng ml(-1) for OPC-13213, OPC-13217 and OPC-13326; 100-2000 ng ml(-1) for OPC-13015; and 1000-20000 ng ml(-1) for cilostazol. The percent relative recovery of this method was established to be 81.2-101.0% for analytes, with the precision (% coefficient of variation (CV)) being 2.8-7.7%. The autosampler stability of the analytes was evaluated and it was found that all analytes were stable at room temperature for a period of at least 17 h. This assay has been shown to be precise, accurate and reproducible.

The effect of famotidine, an H2 receptor blocker, on the oral absorption and pharmacokinetics of the novel agent vesnarinone was investigated after oral administration of 60 mg vesnarinone with and without pretreatment with intravenous famotidine. The single-blind, randomized, two-way crossover study was conducted in 12 volunteers, with a washout period of 7 days between the two treatments. A pH monitor was used to ensure that gastric pH of the subjects was < or = 3 in the absence of and > or = 5 in the presence of famotidine. A significant decrease in maximum concentration (Cmax) and increase in time to Cmax (tmax) was observed for vesnarinone during treatment with famotidine, whereas area under the concentration-time curve (AUC) was similar for both treatments. The physicochemical properties of the drug support the above observations. Therefore, therapies that increase gastric pH will affect the rate but not the extent of absorption of vesnarinone or the safety or efficacy profile of vesnarinone.

Cilostazol is being developed for the treatment of intermittent claudication due to peripheral arterial disease (PAD). This study was conducted to investigate the effects of age and gender on the pharmacokinetics of cilostazol after multiple-dose administration. It was an open label, multiple-dose study of cilostazol administered to male and female subjects 50 years of age and older at a dose of 100 mg (oral tablet) twice daily for 7 days. Equal numbers of healthy male and female (7 per group), nonsmoking subjects stratified into age groups of 50 to 59 years, 60 to 69 years, and 70 years or older were enrolled. Serial plasma samples were obtained. Data were analyzed by model-independent methods. Cilostazol was absorbed at a moderate rate, with peak plasma concentrations occurring at an overall mean of 2.4 hours after administration. Cilostazol is extensively bound (95%), primarily to albumin. A trend toward increasing cilostazol free fraction with age was observed in the male subjects, which was explained by a decrease in plasma albumin concentration with age. Differences in plasma protein binding between age and gender groups (less than 15%) are not expected to have any clinical significance. Plasma cilostazol concentrations reached steady state by day 4. The pharmacokinetic characteristics of cilostazol were not affected by age or gender.

Two open crossover studies were conducted to investigate the effects of food or concomitant treatment with the histamine H2-receptor antagonist famotidine on the pharmacokinetics of the new fluoroquinolone grepafloxacin. Each study involved 16 healthy male volunteers. In the first study, participants received grepafloxacin 600 mg, either after fasting or after consumption of a standard high-fat meal. There were no significant differences in any pharmacokinetic parameter under the fasting or nonfasting conditions. In the second study, participants received grepafloxacin 400 mg, either alone or after infusion of famotidine 20 mg; additional doses of famotidine were given, if necessary, to maintain intragastric pH above 6. Famotidine treatment had no significant effect on grepafloxacin pharmacokinetics. The results of these studies indicate that neither food nor the elevation of gastric pH influence the absorption or bioavailability of grepafloxacin. Therefore, grepafloxacin can be administered with or without food.

The pharmacokinetics of grepafloxacin in healthy male subjects following single oral administration of doses ranging from 200 to 1200 mg, and following repeated oral administration of 400 and 800 mg doses are reported. Plasma levels of grepafloxacin reached a peak within 2 hours (on average) following drug administration and then declined bi-exponentially with concentrations being detectable (> 5 micrograms/L) in the plasma for at least up to 72 hours postdose. The high values for the apparent volume of distribution (5 to 8 L/kg) suggested extensive distribution of grepafloxacin in the tissues. Only a small percentage of the administered dose (ranging from 6% to 9.5%) was recovered in the urine as unchanged grepafloxacin, suggesting that metabolism, rather than urinary excretion, is the major elimination route. The half-life of grepafloxacin was about 12 hours after single doses and about 15 hours after repeat doses. The trough levels increased significantly over the first 3 days of repeat administration; thereafter, the changes were small, with steady-state being reached by the fifth day. The area under the concentration-time curve (AUC24 h) values observed on days 7 and 14 of repeat administration, at each dose level, were similar, suggesting that steady-state is maintained. The area values increased more than proportionally after administration of increasing single and repeat doses, suggesting nonlinear kinetics. The elimination half-life and renal clearance did not change with increasing doses. Saturation in the metabolism of grepafloxacin and possibly in the distribution into a peripheral compartment, as suggested by a decrease in the total plasma clearance and in the apparent volume of distribution, could be the origin of the nonlinear kinetics. However, this deviation from linearity is unlikely to be of clinical significance, since it was very small over the recommended range of therapeutic doses (400 to 600 mg once daily). Compared with other quinolones, grepafloxacin showed the longest half-life and the highest apparent volume of distribution. These features, together with the excellent bactericidal activity of grepafloxacin, support the recommended dosage regimen of grepafloxacin for the treatment of respiratory tract infections and sexually transmitted diseases.

Grepafloxacin is mainly (approximately 90%) excreted by nonrenal mechanisms. The effect of renal impairment on the pharmacokinetics of grepafloxacin was evaluated in an open-label study involving 20 adults, 15 of whom had some degree of renal impairment (creatinine clearance 7.5 to 64.0 ml/min). Of these 15, 3 had mild renal impairment, 6 had moderate renal impairment, and 6 had severe renal impairment. Grepafloxacin 400 mg was administered orally once daily for 7 days, and pharmacokinetic parameters were measured on days 1 and 7. The results show that both renal clearance and the amount of grepafloxacin excreted unchanged in urine, on day 1 and day 7, were significantly lower in individuals with severe renal impairment compared with those who were healthy. Renal clearance was 0.50 +/- 0.05 ml/min/kg in healthy individuals vs 0.15 +/- 0.05 ml/min/kg in patients with severe renal impairment on day 1, while the corresponding values on day 7 were 0.46 +/- 0.04 ml/min/kg vs 0.14 +/- 0.08 ml/min/kg, respectively. The percentage of grepafloxacin excreted unchanged in urine on day 1 was 5.1 +/- 3.0 in the healthy individuals and 1.5 +/- 0.7 in those with severe renal impairment. On day 7, the corresponding values were 7.9 +/- 1.9 and 2.9 +/- 2.2. No other significant pharmacokinetic differences occurred between the 2 groups. Accumulation during multiple dose administration did not vary with the degree of renal impairment. We conclude that the pharmacokinetics of grepafloxacin are not significantly different in individuals with varying degrees of renal impairment. Hence, dose adjustment is not necessary during treatment of patients with renal dysfunction.

Two phase I trials, each involving 16 healthy adult volunteers, were performed to investigate possible interactions between grepafloxacin and theophylline or warfarin. In the theophylline study, grepafloxacin 600 mg was administered once daily for 10 days to 12 volunteers who were receiving a maintenance dose of theophylline. This dose of theophylline was designed to produce mean serum theophylline concentrations of 7.5 mg/L; 4 volunteers received theophylline plus placebo. Pharmacokinetic parameters of theophylline were determined before grepafloxacin treatment and on day 10 of grepafloxacin or placebo administration. Peak theophylline concentrations and the area under the concentration-time curve increased significantly during grepafloxacin treatment, and apparent total clearance of theophylline was reduced by approximately 50%. No changes were observed in the placebo group and theophylline appeared to have no effect on the pharmacokinetics of grepafloxacin. In the warfarin study, grepafloxacin 600 mg was given once daily for 14 days to volunteers receiving a maintenance dose of warfarin. Warfarin was discontinued during the last 4 days of grepafloxacin administration. The pharmacodynamics of warfarin did not change after administration of grepafloxacin. Similarly, warfarin had no significant effect on the pharmacokinetics of grepafloxacin. We conclude that during treatment with grepafloxacin maintenance, doses of theophylline should be reduced by 50%, and we recommend that serum concentrations of theophylline be monitored during treatment with grepafloxacin. However, no dose adjustment is necessary for grepafloxacin when it is coadministered with theophylline, and dose adjustment does not seem to be required in concomitant treatment with grepafloxacin and warfarin.

The pharmacokinetics of grepafloxacin, a new broad spectrum fluoroquinolone antibiotic, were studied in 2 trials involving 14 healthy volunteers, 10 individuals with mild (Child-Pugh Class A) impairment of liver function, and 12 with moderate (Child-Pugh Class B or C) hepatic impairment. All participants received an oral dose of grepafloxacin 400 mg, daily for 7 days, and plasma and urine grepafloxacin concentrations were measured over 7 days. The pooled data from participants with impaired liver function showed that, compared with healthy individuals, peak plasma grepafloxacin concentrations, area under the plasma concentration-time curve and proportion of the dose excreted in the urine were increased. In addition, apparent total clearance was reduced in the presence of hepatic dysfunction. Peak concentrations were increased by 36% and 48% in individuals with Class A and B disease, respectively; the corresponding reductions in clearance were 33% and 55%, respectively. Child-Pugh scores and components of the scores showed no correlation with any pharmacokinetic variables. Based on these findings, we recommend a daily grepafloxacin dose of 400 mg in patients with mild hepatic impairment, irrespective of the severity of infection. Grepafloxacin should not be used in patients with moderate or severe liver disease.

The effects of age and gender on the pharmacokinetics of the oral fluoroquinolone grepafloxacin were examined in 48 healthy middle-aged and elderly individuals, of whom half were male and half were female. Participants were stratified into 4 groups (each with n = 12), aged 40 to 49 years, 50 to 59 years, 60 to 69 years, and > 70 years. All received oral grepafloxacin 600 mg once daily for 7 days, and pharmacokinetic parameters were measured on days 1 and 7. Mean plasma grepafloxacin concentrations were consistently higher in females than in males. Peak concentrations, area under the concentration-time curve, apparent volume of distribution and apparent total clearance (but not renal clearance) differed significantly in females and males. There were no significant gender differences in the elimination half-life values. Further analysis of the data suggests that the gender-related pharmacokinetic differences were primarily due to differences in bodyweight, in particular to differences in lean body mass. The only parameters that changed significantly with age were renal clearance and the proportion of the dose excreted unchanged in the urine, but no clear trend was observed, and there was no correlation with creatinine clearance. We conclude that age and gender have no clinically significant effect on the pharmacokinetics of grepafloxacin. Dose adjustment on the basis of these factors does not therefore seem necessary.

This study explored the rectal route of administration for 2',3'-dideoxyinosine (ddI). Rats were given a rectal infusion of nonradiolabeled ddI (200 mg/kg in 0.7 mL saline) over 35 min along with an intravenous (iv) bolus injection of [8-(3)H]ddI (20 microCi, equivalent to 2.1 micrograms), which was used to calculate the absolute rectal bioavailability of ddI. Maximal plasma concentrations of rectally administered unlabeled ddI were 5.4 +/- 2.2 micrograms/mL and were reached at the end of the infusion. The rectal bioavailability averaged 15.6 +/- 4.4% (n = 9). The second aim of this study was to examine the kinetics of ddI absorption from the colorectal region. Analyses of the absorption rate-time profiles by the Loo-Riegelman and deconvolution methods showed biphasic absorption: a rapid phase during infusion and a slow phase postinfusion. These profiles were inconsistent with a mammillary model with absorption from a single site with one apparent rate constant. The model which gave the best fit for infusion and postinfusion data consisted of two different sites (colon and rectum) with different apparent absorption rate constants. The two sites were connected by a first-order transfer of drug solution from rectum to colon. The apparent absorption rate constant in the rectum was 39-fold higher than that in the colon. In conclusion, these results show absorption of ddI from the colorectal region and suggest the rectal route as an alternative to the oral route. The data further suggest different absorption sites in the colorectal region, with a more rapid absorption in the rectum than in the colon.

We previously reported a > 80% presystemic loss of 2',3'-dideoxyinosine (ddl) in rats after an oral dose. The present study investigated the extent of drug loss due to incomplete absorption and presystemic elimination by intestinal wall, liver and intestinal microflora. In vitro metabolism by tissue homogenates showed that the extraction by liver, duodenum, jejunum and ileum was 19.0, 0.5, 1.8 and 1.4%, respectively. Hence, metabolism by the intestinal wall contributed less to the first-pass metabolism than the liver. The in vivo first-pass elimination was determined by infusing ddl into the liver and different parts of the intestinal tract. The in vivo extractions of 12 and 200 mg kg-1 of ddl doses by the liver were 23 and 5%, indicating a concentration-dependent liver metabolism. The in vivo liver extraction at the low dose was similar to the in vitro extraction. The in vivo extraction was 10% in the duodenum and 73% in the ileum. The significantly higher in vivo intestinal extractions compared to the in vitro extractions indicate a loss due to factors in addition to intestinal wall enzyme metabolism. Incomplete absorption was ruled out, based on the undetectable excretion of ddl in feces after duodenal or ileal infusion. A 14% w/v solution of intestinal contents degraded ddl by 18 and 38% over 2 and 24 hr, respectively, at 37 degrees C. By linear extrapolation, a 100% w/v enzyme solution would degrade the entire dose within 1.5 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

5'-Deoxy-5-fluorouridine (dFUR) is used orally to treat human malignancies. This study compared the antitumor activity and toxicity of rectally and orally administered dFUR. A 7-day treatment of dFUR (350 or 700 mg/kg/day) was infused rectally over 30 min or administered by oral gavage (500 mg/kg/day) to rats bearing transplanted dimethylhydrazine-induced colon tumors. The oral treatment was previously shown to produce a 82% cure of the tumor-bearing animals. The tumor weight after 7 day treatment was compared to that before treatment. The size of the tumor in the saline-treated control group (N = 6) increased by 55%. The maximum tumor size reductions by drug treatments were 40% for the 350-mg/kg rectal dose (N = 5), greater than 99% for the 700-mg/kg rectal dose (N = 10), and 100% for the 500-mg/kg oral dose (N = 4). The 350-mg/kg rectal dose did not produce any cures, while the 700-mg/kg rectal dose produced 80% cures and the 500-mg/kg oral dose 100% cures. The cured animals remained tumor-free during the observation period of 163 to 243 days. The tumor-bearing rats were euthanized between 46 and 132 days when they appeared moribund or when the tumor began to ulcerate. The 700-mg/kg rectal and 500-mg/kg oral treatments produced greater weight loss than saline suggesting a drug-induced intestinal toxicity. After rectal drug treatment, the animal weight returned to pretreatment level within 3 days, indicating a rapidly reversible intestinal toxicity. The oral group suffered a greater weight loss than the rectal group and took more than 10 days to recover.2+his suggests that the intestinal

Uridine (UR) inhibits the metabolic activation of 5'-deoxy-5-fluorouridine (dFUR) to 5-fluorouracil (FU) by the intestinal pyrimidine nucleoside phosphorylases and could potentially reduce its intestinal toxicity. This study examined the effect of UR coadministration on the absorption and disposition of an oral dose of dFUR. Rats were given dFUR alone (500 mg kg-1) and dFUR (300 mg kg-1) plus UR (4.5 g kg-1) in a random crossover experiment. Simultaneous injection of a tracer dose of [6-3H]dFUR was used to asses the total body clearance (Cl) of dFUR. The absorption of UR was rapid and variable. The UR dose produced a maximal blood concentration of 80 micrograms/ml for UR and 100 micrograms/ml for its metabolite uracil (U). The absorption of dFUR was slower than UR, as indicated by its later time of maximal concentration. UR did not alter the Cl of dFUR, but reduced the absorption rate of dFUR from the gastrointestinal tract and significantly reduced the absolute oral bioavailability of dFUR from 55.2% to 33.4%. The effects of UR coadministration on the dFUR metabolite FU were opposite to those on dFUR; the FU availability was increased sixfold, and the elimination of FU was reduced. Based on the known competition between pyrimidine bases for their saturable metabolic enzymes, the increase in FU availability by UR coadministration was likely due to a competitive inhibition of FU metabolism by U. This study established the complex pharmacokinetic interactions between dFUR and UR and between their metabolites, which may be important in the modulation of dFUR activity by UR.