Pharmacokinetics, safety, and tolerability of R411, a dual alpha4beta1-alpha4beta7 integrin antagonist after oral administration at single and multiple once-daily ascending doses in healthy volunteers.

R411 is a dual alpha4beta1-alpha4beta7 integrin antagonist under development for the treatment of chronic asthma. The objective of this study was to investigate the pharmacokinetics and safety of R411 and its active metabolite, RO0270608, in humans. A 3-part phase I trial was conducted in 132 healthy volunteers: (1) 12 subjects received 200 mg R411 as a single oral dose or 100 mg RO0270608 as an intravenous infusion in a 1-sequence crossover design; (2) 7 groups of 10 subjects received 1 of 7 single oral doses of R411 (10-1200 mg) in a parallel, placebo-controlled, ascending adaptive dose design; and (3) 5 groups of 10 subjects each received repeated oral qd doses of R411 (50-900 mg) for up to 3 weeks in a parallel, placebo-controlled, ascending adaptive dose design. The absolute bioavailability of RO0270608 (mean +/- standard deviation) after oral administration of R411 was 27% +/- 4%, and the terminal half-life was 7.33 +/- 2.29 hours. After IV infusion of RO0270608, total clearance (mean +/- standard deviation) was 19.4 +/- 7.1 L/h, and the volume of distribution was 93.1 +/- 36.1 L. After single ascending oral doses of R411, area under the concentration-time curve from 0 to infinity of active metabolite RO0270608 increased proportionally from 150 to 1200 mg (P > .05). Following repeated administration, the oral clearance was independent of time. No drug accumulation was observed, and no safety concerns were revealed up to a dose of 900 mg after up to 3 weeks of treatment.

Ganciclovir pharmacokinetic parameters do not change when extending valganciclovir cytomegalovirus prophylaxis from 100 to 200 days.

BACKGROUND: A 3-month course of prophylaxis is usually recommended for cytomegalovirus (CMV) D+/R- renal transplant recipients. Based on recent data, up to 6 months of prophylaxis may be used. A subanalysis was performed to evaluate the pharmacokinetics of ganciclovir after valganciclovir administration and to perform an exploratory pharmacokinetic/pharmacodynamic analysis. METHODS: In Improved Protection Against Cytomegalovirus in Transplant, a phase III, randomized, double blind, placebo-controlled, multicenter study, 318 CMV D+/R- kidney transplant recipients received valganciclovir prophylaxis (900 mg once daily) for 200 or 100 days. A population pharmacokinetic analysis was conducted on a subgroup of patients (n=120). The relationships between ganciclovir exposure (AUC0-24 hr) and clinical outcomes were explored. RESULTS: The final population parameter estimates (95% confidence interval) were as follows: apparent clearance of ganciclovir, 12 L/hr (11.3-12.7 L/hr); volume of distribution, 18.5 L (14.4-22.6 L); and peripheral volume, 44.4 L (40.2-48.6 L). No differences were apparent between the two treatment groups and these estimates. These results are consistent with previously published pharmacokinetic models. There were no direct correlations between the likelihood of developing hematologic adverse events and ganciclovir exposure at the time of the event. The incidence of CMV disease was not correlated with ganciclovir exposure. CONCLUSION: The pharmacokinetics of ganciclovir were similar between the two dosing groups (100 vs. 200 days), with the majority of patients achieving an area under the concentration time curve in the target therapeutic range (40-60 µg hr/mL). The fact that the majority of patients were within the target therapeutic range and the absence of a control arm (no treatment) precluded any attempt to validate a correlation with clinical parameters (i.e., CMV disease).