Effects of acid-reducing agents on the pharmacokinetics of lopinavir/ritonavir and ritonavir-boosted atazanavir.

A total of 71 HIV-negative healthy adults were randomized to 1 of 6 regimens to receive lopinavir/ritonavir tablets 400/100 mg twice daily (bid) or 800/200 mg once daily (qd) or atazanavir 300 mg + ritonavir 100 mg qd from study days 1 to 15 with a moderate-fat meal. One hour before breakfast, either omeprazole 40 mg qd was administered on study days 11 through 15, or a single dose of ranitidine 150 mg was administered on study day 11. Lopinavir, atazanavir, and ritonavir pharmacokinetics were determined on study days 10, 11, and 15 and compared using point estimates and 90% confidence intervals (CIs). The point estimates for lopinavir Cmax and AUCtau were in the range of 0.92 to 1.08, with 90% CI contained within the range of 0.80 to 1.25 after coadministration of omeprazole or ranitidine. The point estimates for atazanavir Cmax and AUCtau were decreased by 48% to 62% with the upper bound of the 90% CI

The effects of multiple doses of fenofibrate on the pharmacokinetics of pravastatin and its 3alpha-hydroxy isomeric metabolite.

Published data indicate that coadministration of multiple doses of the fibrate drug, gemfibrozil, led to a 202% increase in pravastatin systemic exposure (area under the plasma concentration-time curve, AUC). To evaluate the effects of another fibrate drug, fenofibrate, on the pharmacokinetics of pravastatin, 24 healthy subjects took pravastatin (40 mg once daily) on study days 1 to 15 and fenofibrate (160 mg once daily) on study days 6 to 15. Blood samples were collected for 24 hours after dosing on days 5, 6, and 15. Plasma concentrations of pravastatin and its active metabolite, 3alpha-hydroxy-iso-pravastatin, were measured, and pharmacokinetics was assessed. Safety assessments were based on adverse events, physical examinations, electrocardiogram results, vital signs, and clinical laboratory testing. Safety results were unremarkable. Coadministration of fenofibrate had modest effects on pravastatin and 3alpha-hydroxy-iso-pravastatin systemic exposures (AUC). Increases in pravastatin systemic exposures (19%-28%, on average) and 3alpha-hydroxy-iso-pravastatin systemic exposures (24%-39%, on average) were observed upon coadministration, but individual changes were variable. Pravastatin and 3alpha-hydroxy-iso-pravastatin systemic exposures were not statistically significantly different following the 1st and 10th doses of fenofibrate.

Anticoagulant efficacy of PEG-Hirudin in patients on maintenance hemodialysis.

BACKGROUND: Heparins are currently the anticoagulants of choice in long-term hemodialysis (HD). Because of their shortcomings, including the increasing incidence of heparin-induced thrombocytopenia (HIT II), alternative anticoagulation is necessary. The study objectives were to provide safe and effective HD by investigating an appropriate PEG (polyethylene glycol)-Hirudin dosage regimen in patients on HD, as well as to compare the safety, tolerability, and efficacy of PEG-Hirudin with that of unfractionated heparin (UFH). METHODS: Twenty patients (12 males, 8 females, mean age 57.8 years) with end-stage renal disease (ESRD) took part in the study. Dialysis sessions lasting a mean of 4.3 hours (QB 250 to 300 mL/min, QD 500 mL/min) were performed 3 times a week with a Gambro GFS plus 16 dialyzer. Ten patients (group I) received UFH at 3 regular dialysis sessions (HD1-3) followed by 5 dialysis sessions using PEG-Hirudin (HD4-8). Another 10 patients (group II) received UFH at 3 regular dialysis sessions (HD1-3) followed by 10 sessions on PEG-Hirudin (HD4-13). The starting dose of PEG-Hirudin was a single bolus injection of 80 microg/kg BW (HD4), except for the first patient, who received 50 microg/kg BW followed by a 12 microg/kg bolus. Before each of the following sessions (HD5-13), an individualized PEG-Hirudin dose of between 26 to 65 microg/kg body weight (BW) (mean dose 41 microg/kg BW) was injected. PEG-Hirudin plasma and blood concentrations derived from anti-Iia activity and ecarin clotting time (ECT), respectively, activated partial thromboplastin time (aPTT), bleeding time, and arteriovenous (AV) fistula compression time were investigated to calculate the pharmacokinetic parameters or to assess anticoagulant efficacy. RESULTS: Mean predialysis PEG-Hirudin plasma concentrations increased up to a maximum of 488 ng/mL in group I (HD8) and up to 536 ng/mL in group II (HD8). Mean plasma concentrations measured at 5 minutes after the 1st (HD4), 5th (HD8), and 10th (HD13) PEG-Hirudin injection ranged from 1076 to 1298 ng/mL. Mean post-dialysis plasma levels ranged from 818 to 995 ng/mL. Mean predialysis aPTT was not affected by UFH, but was prolonged by 46 to 56 seconds by PEG-Hirudin. Five minutes after injecting PEG-Hirudin or UFH, mean aPTT was prolonged to a maximum of 85 and 188 seconds, respectively. Mean post-dialysis aPTT values ranged from 60 to 68 seconds after PEG-Hirudin and 34 to 46 seconds after UFH. PEG-Hirudin was well tolerated; no serious adverse events or bleeding complications were observed. Safety assessments yielded no significant difference between the two anticoagulants. CONCLUSION: This pilot study confirmed the usefulness and tolerability of a PEG-Hirudin dose regimen consisting of a single, fixed bolus dose of 80 microg/kg BW injected before starting the first dialysis session (HD4) and followed by a dose titration period over at least 4 sessions (HD5-8), which again was followed by a fixed maintenance dose period (HD9-13). On the basis of PEG-Hirudin data from patients with various degrees of renal insufficiency but not undergoing hemodialysis and prior recombinant-hirudin (r-hirudin) experience, patients were titrated into an EC-controlled dose range that proved to be efficacious enough to prevent clotting and safe enough to prevent bleeding. Due to the favorable pharmacokinetic properties of PEG-Hirudin, a residual anticoagulant effect is maintained in the intervals between dialysis sessions, and this permanent state of anticoagulation may prevent vascular access complications as well as other vascular events.

Effects of PEG-hirudin in clotting parameters and platelet function and its interaction with aspirin in healthy volunteers.

The purpose of this study was to investigate the pharmacodynamics of PEG-Hirudin and its potential interactions with acetylsalicylic acid (ASA 325 mg once daily from days 1-3). In a randomized, 2-way cross-over trial, 6 healthy volunteers received PEG-Hirudin (i.v. bolus of 0.2 mg/kg + 0.02 mg/kg/h for 24 hours) and placebo (i.v. bolus + 24-hour infusion). In a further randomized, 3-way cross-over trial another 9 healthy volunteers received ASA (325 mg) or oral placebo from days 1 to 3 and PEG-Hirudin (0.2 mg/kg + 0.02 mg/kg/h for 24 h) or i.v. placebo on day 3. Assessments included bleeding time (BT), collagen (1 microgram ml(-1))-induced platelet aggregation (CIPA), platelet adhesion, ecarin clotting time (ECT), activated clotting time (ACT), plasma anti-factor IIa activity (aIIa), and activated partial thromboplastin time (aPTT). Ten minutes after the PEG-Hirudin injection/starting the infusion, mean plasma concentration was 3.1 microgram/mL and aPTT, ECT, and ACT were prolonged up to 80, 309, and 233 seconds, respectively. During the last 8 hours of the 24-hour infusion mean PEG-Hirudin plasma concentration was 1.3 microgram/mL. In the interaction study, ASA significantly inhibited CIPA. At 6 hours after administration, on day 3 mean BT was 6.5 minutes after PEG-Hirudin alone, 18.2 minutes after ASA alone, and 32.9 minutes after combined administration of ASA and PEG-Hirudin. PEG-Hirudin (0.2 mg/kg + 0.02 mg/kg/h for 24 hours) administered alone or together with 325 mg ASA proved to be safe in healthy volunteers. Combined use of PEG-Hirudin and ASA significantly increased the mean bleeding time compared to ASA or PEG-Hirudin monodrug administration. None of the clotting parameters or platelet function tests correlated with the prolongation of the bleeding time.