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.

Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin.

BACKGROUND AND OBJECTIVE: Patients with type 2 diabetes mellitus often have impaired renal function or may have impaired hepatic function, which can pose significant safety and tolerability issues for antihyperglycaemic pharmacotherapies. Therefore, the pharmacokinetics and tolerability of saxagliptin and its pharmacologically active metabolite, 5-hydroxy saxagliptin, in nondiabetic subjects with mild, moderate or severe renal or hepatic impairment, or end-stage renal disease (ESRD) were compared with saxagliptin and metabolite pharmacokinetics and tolerability in healthy adult subjects. METHODS: Two open-label, parallel-group, single-dose studies were conducted. Subjects received a single oral dose of saxagliptin 10 mg (Onglyza™). RESULTS: Compared with healthy subjects, the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) for saxagliptin was 16%, 41% and 108% (2.1-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. AUC∞ values for 5-hydroxy saxagliptin were 67%, 192% (2.9-fold) and 347% (4.5-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. As creatinine clearance (CLCR) values decreased, saxagliptin and 5-hydroxy saxagliptin AUC∞ generally increased or became more variable. Twenty-three percent of the saxagliptin dose (measured as the sum of saxagliptin and 5-hydroxy saxagliptin) was cleared by haemodialysis in a 4-hour dialysis session. In the hepatic impairment study, the differences in exposure to saxagliptin and 5-hydroxy saxagliptin were less than 2-fold across all groups. As compared with healthy subjects matched for age, bodyweight, sex and smoking status, the AUC∞ values for saxagliptin were 10%, 38% and 77% higher in subjects with mild, moderate or severe hepatic impairment, respectively. These values were 22%, 7% and 33% lower, respectively, for 5-hydroxy saxagliptin compared with matched healthy subjects. CONCLUSIONS: One-half the usual dose of saxagliptin 5 mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate (CLCR 30-50 mL/min) or severe (CLCR<30 mL/min not on dialysis) renal impairment or ESRD, but no dose adjustment is recommended for those with mild renal impairment or any degree of hepatic impairment.

Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole.

BACKGROUND: Many medicines, including several cholesterol-lowering agents (eg, lovastatin, simvastatin), antihypertensives (eg, diltiazem, nifedipine, verapamil), and antifungals (eg, ketoconazole) are metabolized by and/or inhibit the cytochrome P450 (CYP) 3A4 metabolic pathway. These types of medicines are commonly coprescribed to treat comorbidities in patients with type 2 diabetes mellitus (T2DM) and the potential for drug-drug interactions of these medicines with new medicines for T2DM must be carefully evaluated. OBJECTIVE: To investigate the effects of CYP3A4 substrates or inhibitors, simvastatin (substrate), diltiazem (moderate inhibitor), and ketoconazole (strong inhibitor) on the pharmacokinetics and safety of saxagliptin, a CYP3A4/5 substrate; and the effects of saxagliptin on these agents in three separate studies. METHODS: Healthy subjects were administered saxagliptin 10 mg or 100 mg. Simvastatin, diltiazem extended-release, and ketoconazole doses of 40 mg once daily, 360 mg once daily, and 200 mg twice daily, respectively, were used to determine two-way pharmacokinetic interactions. RESULTS: Coadministration of simvastatin, diltiazem extended-release, or ketoconazole increased mean area under the concentration-time curve values (AUC) of saxagliptin by 12%, 109%, and 145%, respectively, versus saxagliptin alone. Mean exposure (AUC) of the CYP3A4-generated active metabolite of saxagliptin, 5-hydroxy saxagliptin, decreased with coadministration of simvastatin, diltiazem, and ketoconazole by 2%, 34%, and 88%, respectively. All adverse events were considered mild or moderate in all three studies; there were no serious adverse events or deaths. CONCLUSION: Saxagliptin, when coadministered with simvastatin, diltiazem extended-release, or ketoconazole, was safe and generally well tolerated in healthy subjects. Clinically meaningful interactions of saxagliptin with simvastatin and diltiazem extended-release are not expected. The dose of saxagliptin does not need to be adjusted when coadministered with a substrate or moderate inhibitor of CYP3A4. A limitation to the lowest clinical dose of saxagliptin (2.5 mg) is proposed when it is coadministered with a potent CYP3A4 inhibitor such as ketoconazole.

An open-label study of aripiprazole: pharmacokinetics, tolerability, and effectiveness in children and adolescents with conduct disorder.

OBJECTIVES: This study evaluated flexible-dose pharmacokinetics, safety, and effectiveness of aripiprazole in children and adolescents with conduct disorder (CD). METHODS: This open-label, 15-day, three-center study with an optional 36-month extension enrolled a total of 23 patients: 12 children (6-12 years) and 11 adolescents (13-17 years) with CD and a score of 2-3 on the Rating of Aggression Against People and/or Property (RAAPP). Initially, the protocol used the following dosing: subjects <25 kg, 2 mg/day; subjects 25-50 kg, 5 mg/day; subjects >50-70 kg, 10 mg/day; and subjects >70 kg, 15 mg/day. Due to vomiting and sedation, this schedule was revised to: <25 kg, 1 mg/day; 25-50 kg, 2 mg/day; >50-70 kg, 5 mg/day; and >70 kg, 10 mg/day. RESULTS: Aripiprazole pharmacokinetics were linear, and steady state appeared to be attained within 14 days. Both groups demonstrated improvements in RAAPP scores and Clinical Global Impressions-Severity (CGI-S) scores. Adverse events were similar to the known profile for aripiprazole in adults. CONCLUSION: The pharmacokinetics of aripiprazole in children and adolescents are linear and comparable with those in adults. Aripiprazole was generally well-tolerated in patients with CD, particularly after protocol adjustments, with improvements in aggressive behavior.

Effects of the glycoprotein IIb/IIIa antagonist Roxifiban on P-selectin expression, fibrinogen binding, and microaggregate formation in a phase I dose-finding study: no evidence for platelet activation during treatment with a glycoprotein IIb/IIIa antagonist.

The hypothesis that glycoprotein (GP) IIb/IIIa antagonists stimulate platelets is controversial. Here, we report the results of flow cytometric measurements of platelet activation markers in a phase I dose optimization study of Roxifiban, an orally active GP IIb/IIIa antagonist. Whole blood was collected at pre-dose and during the dosing interval directly into citrate fixative so that circulating levels of platelet activation could be assessed. P-selectin expression and fibrinogen binding of single platelets were unchanged at any of the dosing intervals compared to the pre-dose values, whereas microaggregate formation was reduced. Blood was also collected in hirudin to maintain physiological calcium concentrations and stimulated with platelet agonists to test whether GP IIb/IIIa antagonists lower the threshold for platelet activation. After stimulation with a concentration range of ADP and TRAP, P-selectin expression was not altered by Roxifiban administration compared to pre-dose levels. Fibrinogen binding and microaggregate formation were reduced by Roxifiban dosing in a dose-dependent manner. Inhibition of both parameters was retained at trough and no increase above pre-dose values was observed at any time. This study provides evidence for a dose-dependent inhibition of platelet functions by an orally active GP IIb/IIIa antagonist and does not detect paradoxical activation of platelets by a GP IIb/IIIa antagonist in humans.