Safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate active ulcerative colitis: results of a randomized, double-blind study.

OBJECTIVES: : A multicenter, double-blind study was conducted to evaluate the safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate ulcerative colitis (UC). PATIENTS AND METHODS: : Sixty-eight patients, 5 to 17 years of age, with mild-to-moderate active UC based on the modified Sutherland UC activity index (MUCAI) were randomized to receive oral balsalazide 2.25 or 6.75 g/day for 8 weeks. The primary endpoint was clinical improvement (reduction of the MUCAI score by > or =3 points from baseline). Clinical remission (MUCAI score of 0 or 1 for stool frequency) and histological improvement after 8 weeks were also assessed. Pharmacokinetic parameters for balsalazide, 5-aminosalicylic acid, and N-acetyl-5-aminosalicylic acid were determined at 2 weeks. Adverse events and laboratory changes were monitored throughout the study. RESULTS: : Clinical improvement was achieved by 45% and 37% of patients and clinical remission by 12% and 9% of patients receiving 6.75 and 2.25 g/day, respectively. Improvement in histologic grade was achieved by 8 of 16 (50%) and 3 of 10 (30%) patients receiving 6.75 and 2.25 g/day, respectively. No significant differences were seen in efficacy. Pharmacokinetics in 12 patients were characterized by large interpatient variability and low systemic exposure. Adverse events were similar between the treatment groups, the most common being headache and abdominal pain. No clinically significant changes were observed in laboratory values, including those indicative of hepatic or renal toxicity. CONCLUSIONS: : Balsalazide is well tolerated and improves the signs and symptoms of mild-to-moderate active UC in pediatric patients 5 to 17 years of age.

Oxymorphone extended release does not affect CYP2C9 or CYP3A4 metabolic pathways.

Two 14-day, randomized, open-label, parallel-group studies examined the effects of extended-release (ER) oxymorphone on CYP2C9 or CYP3A4 metabolic activities in healthy subjects. On days -1, 7, and 14, subjects received either a CYP2C9 probe (tolbutamide 500 mg) or CYP3A4 probes (midazolam and [14C N-methyl]-erythromycin for the erythromycin breath test). Subjects were randomized to 5 groups: high-dose oxymorphone ER (3 x 20 mg q12h) + naltrexone (50 mg q24h); low-dose oxymorphone ER (10-20 mg q12h); rifampin (2 x 300 mg q24h), an inducer of CYP2C9 and CYP3A4 activities; naltrexone (50 mg q24h); or CYP probes alone (controls). Probe metabolism was significantly altered by rifampin on days 7 and 14 (P < .05), whereas probe metabolism was not significantly affected by low-dose oxymorphone ER or by high-dose oxymorphone ER plus naltrexone. Oxymorphone ER exhibits a minimal potential for causing metabolic drug-drug interactions mediated by CYP2C9 or CYP3A4.

The use of roxifiban (DMP754), a novel oral platelet glycoprotein IIb/IIIa receptor inhibitor, in patients with stable coronary artery disease.

INTRODUCTION: Intravenous platelet glycoprotein (GP) IIb/IIIa receptor inhibitors have a significant beneficial impact on the outcomes of patients undergoing high-risk coronary interventions and in the stabilization of patients with unstable angina pectoris refractory to conventional medical treatment. The role of long-term treatment with oral platelet GP IIb/IIIa receptor inhibitors in patients with coronary artery disease is unproven. This study examined the dose-response effect on inhibition of platelet aggregation by roxifiban (DMP754), a novel oral platelet GP IIb/IIIa receptor inhibitor, and its safety and tolerability in patients with a history of chronic stable angina pectoris. METHODS: Ninety-eight patients were randomized to receive either a placebo or 1 of 8 oral dosages of roxifiban. Twenty-two patients were enrolled in multiple-dose regimens, bringing the total study population to 120. The oral dosages were 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, or 2.5 mg/day for up to 30 days. RESULTS: Pharmacodynamic response of roxifiban was clearly dose-dependent. Platelet aggregation inhibition in response to 10 micromol/L slope adenosine diphosphate was sustained throughout the study period (up to 1 month). No serious adverse events, including significant major bleeding events, were associated with roxifiban treatment. Minor bleeding was reported in 5% of participants in the placebo group (1 of 21 cases) versus 26% in the study group (26 of 99 cases). Incidence of minor bleeding associated with roxifiban 2 and 2.5 mg/day was significantly (p < or = 0.05) greater than that with placebo. Adverse events, including gastrointestinal disorders, platelet and clotting disorders, and urinary tract disorders, were observed in 1 of 21 cases (5%) in the placebo group and in 12 of 99 cases (12%) in the study group. Reversible thrombocytopenia without other complications developed in two patients. CONCLUSIONS: Roxifiban-induced inhibition of platelet aggregation was dose-dependent and sustained throughout the study period: higher drug dosages correlated with higher levels of platelet inhibition and higher incidence of minor bleeding events. No serious adverse events were observed at any dosage. Thus, roxifiban appears to be a potent oral platelet GP IIb/IIIa receptor inhibitor that is clinically well-tolerated and deserves further study as a new treatment strategy in patients with chronic stable angina pectoris.

Prospective testing for drug-dependent antibodies reduces the incidence of thrombocytopenia observed with the small molecule glycoprotein IIb/IIIa antagonist roxifiban: implications for the etiology of thrombocytopenia.

Thrombocytopenia is a relatively common side effect observed during glycoprotein (GP) IIb/IIIa antagonist therapy. With the oral antagonist roxifiban, we observed thrombocytopenia, defined as 50% reduction of platelets over predose values or below 90 000/microL (9 x 10(10)/L), with a frequency of 2% (8 of 386). Thrombocytopenia occurred either early (days 2 to 4) or delayed (days 11 to 16). No additional cases were observed with up to 6 months of treatment. Retrospective analysis provided evidence for drug-dependent antibodies (DDABs) to GP IIb/IIIa in 5 of 6 subjects, suggestive of an immune etiology of thrombocytopenia. The hypothesis that excluding patients based on positive DDAB reaction would reduce the frequency of thrombocytopenia was tested. Patients were screened for DDABs during the study qualification period and, overall, 3.9% of the patients were excluded based on pre-existing DDAB concentrations above a statistically defined medical decision limit. An additional 2.6% were excluded based on therapy-related antibody production during the first 2 weeks. With antibody testing, 0.2% of patients (2 of 1044) developed immune-mediated thrombocytopenia. One case developed a rapidly increasing antibody concentration and presented with thrombocytopenia despite discontinuation of roxifiban therapy. The second case was related to a false-negative test result. The frequency of thrombocytopenia was statistically significantly reduced from 2% to 0.2% (P =.0007) comparing nonscreened and screened patients. Testing for DDABs can reduce the frequency of thrombocytopenia in patients treated with roxifiban and, by analogy, other GP IIb/IIIa antagonists. Thus, DDAB testing may be employed to increase the safety of GP IIb/IIIa antagonists.

A double antibody radioimmunoassay for the determination of XV459, the active hydrolysis metabolite of roxifiban, in human plasma.

A radioimmunoassay (RIA) was developed for the determination of XV459, the active hydrolysis metabolite of the oral prodrug roxifiban (DMP 754), in human plasma. XV459 is a potent antagonist of the glycoprotein IIb/IIIa receptor. The method utilizes a competitive double antibody format employing an 125I-labeled XV459 analogue tracer which competes with XV459 for antibody binding sites and a second antibody precipitation step to separate antibody bound analyte from free analyte. The method has a validated lower quantification limit of 0.35 ng/ml (0.81 nM) using 12.5 microl of plasma and with dilution can accommodate clinical plasma samples ranging up to 48.0 ng/ml (110.7 nM). Cross-validation to an existing quantitative liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method showed good correlation (r(2)=0.98). The RIA has been successfully used to assay over 10000 clinical samples with sensitivity and specificity comparable to the LC-MS/MS method, but with faster turn around time and at greatly reduced costs.

Integrated pharmacokinetic/pharmacodynamic model of XV459, a potent and specific GPIIb/IIIa inhibitor, in healthy male volunteers.

Roxifiban is an oral prodrug of XV459, a potent and specific inhibitor of the glycoprotein (GP) IIb/IIIa receptor previously under investigation for the treatment of peripheral arterial disease and acute coronary care syndrome. The objective of the present analysis was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that would be used to guide dose selection in Phase 2. This was a randomized, sequential, rising multiple-dose study in 41 healthy male volunteers given doses of 0.5 to 1.25 mg daily for 7 to 10 days. Total XV459 was measured in plasma by a sensitive and specific LC/MS/MS method. The percent inhibition of platelet aggregation (%IPA) was evaluated in citrated plasma in response to 10 microM ADP using the initial slope of the response. The resulting PK data were fit to a two-compartment model with first-order absorption and saturable oral absorption. The pharmacodynamics was modeled using a direct sigmoidal Emax model. Modeling was performed using NONMEM V. Intersubject variability was moderate in both PK and PD (15.3%-18.5%), except for V2/F (64.8%). Residual variability was low at 11.8%. Platelet count influenced both CL/F and EC50. Age and weight did not explain any additional variability in either PK or PD. The model was shown to produce realistic data when used for simulation. Overall, the results suggest that XV459 concentrations in the range of 10 to 20 ng/ml will yield %IPA values in the range of 40% to 80% inhibition. Because of the pharmacodynamically mediated PK of XV459 (due to platelet binding), the EC50 and CL/F are negatively correlated, limiting the utility of plasma concentration monitoring.

Safety, tolerability, pharmacokinetics, and time course of pharmacologic response of the active metabolite of roxifiban, XV459, a glycoprotein IIb/IIIa antagonist, following oral administration in healthy volunteers.

Roxifiban is an esterprodrug that is hydrolyzed, after oral administration, to the active glycoprotein (GP) IIb/IIIa antagonist, XV459. The objectives of the study were to investigate the safety, tolerability, pharmacokinetics, and the time course of the pharmacologic response of XV459 in escalating doses of roxifiban and to assess the effect of age, loading dose of roxifiban, and aspirin pretreatment on XV459 pharmacokinetics, pharmacologic response, and safety profile in a five-part double-blind, placebo-controlled study. Healthy male volunteers (ages 18-46 years) received 7 (0.75-1.5 mg; n = 20) and 10 (0.75-1.0 mg; n = 8) multiple, oral, qd doses of roxifiban or placebo (n = 5). Healthy older male and female volunteers (ages 47-75 years) received roxifiban qd doses (0.5-0.75 mg; n = 8) or placebo (n = 3) for 7 days. Healthy male subjects (ages 18-46 years; n = 16) received a 1.5 or 1.0 mg loading dose either with or without pretreatment of 325 mg aspirin once daily for 3 days followed by single daily doses of 1.0 mg roxifiban for 6 days. Measurable plasma concentrations of XV459 appeared rapidly and were sustained throughout the dosing interval of 24 hours. The pharmacokinetics of XV459 were nonlinear. Systemic exposure of XV459 plateaued at the 1-mg dose level; plasma concentrations approached steady state in 4 to 6 days for doses greater than 1.0 mg. The time course of pharmacologic response as measured by the inhibition of platelet aggregation in response to an ex vivo 10 microM adenosine 5'-diphosphate (ADP) agonist correlated closely to the plasma concentration of XV459. Potent inhibition of ADP-induced platelet aggregation (IPA) persisted over the entire dosing interval. A clear dose response was achieved with roxifiban doses of 0.5 and 1.0 mg. For doses greater than 1.0 mg, a dose-proportional increase in IPA was not observed. Both the pharmacokinetics and pharmacologic response of XV459 exhibited low intraindividual variability (coefficient of variation [CV] < 15%) and higher interindividual variability (CV < 30%). Pretreatment with aspirin and/or a loading dose of 1.5 mg roxifiban had no significant effect on the pharmacokinetics and pharmacologic response of XV459. A dose-related increase in template bleeding time was observed at 1.25- and 1.5-mg doses of roxifiban, as compared to placebo. However, these bleeding time increases in the 1.25- and 1.5-mg dose groups were not significantly different from those at the lower dose groups. Overall, once-daily oral administration of roxifiban was fairly well tolerated and provided sustained systemic drug exposure and pharmacologic response over the entire administration interval.