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Objectives In two separate trials, we studied the concomitant administration of atosiban with labetalol and betamethasone to determine any possibility of a clinically relevant pharmacokinetic interaction. Design Study 1 was an open-label, single dose atosiban, multiple dose labetalol, interaction study. Study 2 was an open-label, randomised, three-period crossover pharmacokinetic study. Setting The studies were carried out at the Clinical Pharmacology Unit of AAI Deutschland GmbH & Co KG, Neu-Ulm, Germany. Population The study population consisted of healthy female volunteers. Methods In Study 1, 14 healthy female volunteers participated. On study day 1, a 12-hour intravenous infusion of 114.75 mg atosiban was administered; on days 2–4, participants received labetalol orally (100 mg twice daily), and on study day 5 they received the combined treatment. In Study 2, a total of 18 healthy female volunteers received, on three separate occasions, a 12-hour intravenous infusion of 114.75 mg atosiban, a single intramuscular injection of 12 mg betamethasone or the two drugs in combination. Main outcome measure For Study 1, the outcome parameter for atosiban was area under the plasma concentration–time curve (AUC); the study parameters for labetalol were AUC, maximum plasma concentration ( Cmax) and time to Cmax ( tmax). In Study 2, AUC, Cmax and time to Cmax ( tmax) were assessed for atosiban and betamethasone. Results Labetalol had no clinically relevant influence on the bioavailability (AUC) of atosiban. For labetalol, the co-administration with atosiban did not affect the extent of bioavailability, however, Cmax decreased by 36% and tmax increased by 45 minutes. The Cmin was not affected by atosiban. The betamethasone and atosiban combination led to similar mean plasma concentration–time curves as the administration of each substance alone. Pharmacokinetic parameters (AUC, Cmax, tmax) did not differ markedly between treatments and all 90% CIs for ratios between treatments were fully within limits (80–125%). The co-administration of atosiban with labetalol or betamethasone resulted in similar tolerability to each substance alone. Conclusion The co-administration of atosiban with betamethasone or labetalol had no clinically relevant influence on their bioavailability or tolerability. [ABSTRACT FROM AUTHOR]

To evaluate the influence of renal impairment on the pharmacokinetics of desmopressin.Twenty-four subjects were enrolled in the study, 18 with varying degrees of renal impairment and six healthy volunteers. Each subject received a single intravenous dose of 2 µg desmopressin. Blood and urine samples were collected for 24 h and assayed for desmopressin by radioimmunoassay. Plasma concentrations and the amounts of desmopressin excreted in the urine were analysed simultaneously by use of mixed effects modelling.Only mild adverse events were observed. Both the renal and the nonrenal clearance of desmopressin were found to vary with the creatinine clearance (CrCL). A decrease of 1.67% in the CrCL (corresponding to 1 ml min−1 from 60 ml min−1) was found to cause a 1.74% decrease in the renal clearance and a 0.93% decrease in the nonrenal clearance. The fall in renal clearance caused the amount of desmopressin excreted in urine to decrease from 47% in healthy subjects to 21% in the patients with severe renal impairment. The mean systemic clearance of desmopressin was 10 litres h−1 in healthy subjects and 2.9 litres h−1 in patients with severe renal impairment (difference−7.5 litres h−1, 95% CI[−11;−4.3] litres h−1). Correspondingly, the mean terminal half-life, was 3.7 h in healthy subjects and 10 h in patients with severe renal impairment (difference 6.7 h, 95% CI[4.0; 9.4] h).Although desmopressin appears to be safe and well-tolerated by patients with impaired renal function, great caution should be exercised when titrating towards an efficient dosage regimen if patients with moderately or severely impaired renal function are to be treated with desmopressin at all. [ABSTRACT FROM AUTHOR]