In vivo evaluation of drug-drug interactions linked to UGT inhibition: the effect of probenecid on dalcetrapib pharmacokinetics.

OBJECTIVE: To assess the effect of the UGT inhibitor probenecid on the pharmacokinetics of dalcetrapib, an investigational drug whose pharmacologically active thiol form undergoes glucuronidation (fm UGT ≥ 0.25). MATERIALS AND METHODS: A two-way crossover study in 20 healthy subjects. Subjects received a single 600 mg dose of dalcetrapib with or without probenecid (500 mg 4 times daily for 6 days). RESULTS: AUC∞ and Cmax of dalcetrapib thiol were increased by 14% and 21%, respectively, by co-administration of probenecid. CONCLUSIONS: This case study illustrates the difficulty in predicting clinically relevant drug-drug interactions for UGT substrates based only on the fraction metabolized by glucuronidation.

Safety, tolerability, and pharmacokinetics of intravenous oseltamivir: single- and multiple-dose phase I studies with healthy volunteers.

There is an unmet need for an intravenous (i.v.) neuraminidase inhibitor, particularly for patients with severe influenza who cannot take oral medication. Two phase I pharmacokinetic and safety studies of i.v. oseltamivir were carried out in healthy volunteers. The first was an open-label, randomized, four-period, two-sequence, single-dose trial of 100 mg, 200 mg, and 400 mg oseltamivir i.v. over 2 h and a 75-mg oral dose of oseltamivir. The second was a double-blind, placebo-controlled, parallel-group, multiple-dose study in which participants were randomized to 100 mg or 200 mg oseltamivir or placebo (normal saline) i.v. over 2 h every 12 h for 5 days. Exposure to the active metabolite oseltamivir carboxylate (OC) after dosing achieved with 100 mg oseltamivir administered i.v. over 2 h was comparable to that achieved with 75 mg administered orally. Single i.v. doses of oseltamivir up to 400 mg were well tolerated with no new safety signals. Multiple-dose data confirmed good tolerability of 100 mg and 200 mg oseltamivir and showed efficacious OC exposures with 100 mg i.v. over 2 h twice daily for 5 days. These results support further exploration of i.v. oseltamivir as an influenza treatment option for patients unable to take oral medication.

Effect of oseltamivir treatment on anticoagulation: a cross-over study in warfarinized patients.

AIM: To investigate whether oseltamivir enhances the anticoagulant effect of warfarin and to evaluate any pharmacokinetic (PK) interaction between the agents. METHODS: Twenty volunteers (mean age 62 years) receiving daily warfarin and with INR values of 2.0-3.5 during the previous 2 weeks were randomized to concomitant oseltamivir 75 mg twice daily for 4.5 days or warfarin alone in a two-way cross-over design with a 4-8 day wash-out. Anticoagulant effects were assessed by calculating overall [AUEC(0,96 h)] and observed maximum effect (E(max) ) increase from baseline in INR, decrease from baseline in factor VIIa, and change in vitamin K1 concentrations. Plasma pharmacokinetics of (R)- and (S)-warfarin and oseltamivir were also assessed. RESULTS: For both treatments, changes in INR and factor VIIa during treatment were small; for net AUEC(0,96 h), least square mean values were -9.53 (oseltamivir + warfarin) and -1.69 h (warfarin alone) for INR (difference -7.84 h, 90% CI -18.86, 3.17 h), and 1.56 and 0.54 kIU l⁻¹ h, respectively, for factor VIIa (difference, 1.01 kIU l⁻¹ h; 90% CI -1.18, 3.21). Differences between the treatments in E(max) increase from baseline for INR, decrease from baseline for factor VIIa and change from baseline in vitamin K1 concentration were not statistically significant. Oseltamivir did not alter warfarin pharmacokinetics. Oseltamivir was well tolerated in this study with no clinically significant adverse safety findings. CONCLUSION: Concomitant administration of oseltamivir for 4.5 days to volunteers on daily warfarin had little or no effect on warfarin pharmacokinetics and no effect on pharmacodynamics.