Bioavailability investigation of a new tilidine/naloxone liquid formulation compared to a reference formulation

An oral solution available as ethanol-free droplets of the fixed drug combination tilidine-HCl 50 mg/naloxone-HCl 4 mg (CAS 27107-79-5 and CAS 465-65-6, respectively; Tilidin-ratiopharm plus Tropfen) was investigated in 12 healthy volunteers together with an ethanol-containing reference preparation for comparable bioavailability. The study was conducted in an open, randomized, two-way cross-over design applying single doses of 20 droplets (equivalent to 50 mg tilidine-HCl/4 mg naloxone-HCl) of either formulation in the fasting state. The drug plasma profiles were monitored for a period of 48 h by means of LC-MS/MS for tilidine and its active metabolite nortilidine, whereas GC-MS was employed in order to determine naloxone and its phase I metabolite, 6-beta-naloxole. Maximum concentrations (Cmax) achieved were 22.28 ng/ml (tilidine) and 92.78 ng/ml (nortilidine) for the test preparation. Corresponding values for the reference preparation were 24.95 ng/ml (tilidine) and 100.73 ng/ml (nortilidine). The extent of drug absorption (AUC0-infinity) amounted to 38.83 ng h/ml and 467.63 ng h/ml for the prodrug tilidine and the metabolite nortilidine of the test preparation and corresponded well to 43.81 ng h/ml and 493.85 ng h/ml of the reference. Regarding the rate of drug absorption, essentially identical tmax and Rabs values for both tilidine and nortilidine of either preparation in addition pointed to well comparable liquid formulations and equipotent analgesia may be inferred from opioid pharmakokinetic profiles. Pharmacokinetics of the opioid antagonist naloxone and 6-beta-naloxole were also determined and resulted in well coinciding profiles for both preparations. Thus despite the fact that only minimum oral naloxone bioavailabilities were observed, plasma level monitoring of naloxone and 6-beta-naloxole allowed for demonstration of systemic exposure of opioid antagonistic compounds throughout a period of 2-3 h after oral drug administration. Due to the limited number of subjects involved, the primary aim of the study did not consist in demonstration of drug bioequivalence. Rather a comparable bioavailability between preparations was assumed if AUC and Cmax point estimators of 90% confidence intervals would be contained within a 0.80-1.20 range. The study outcome revealed that all four investigated analytes met this requirement, whilst nortilidine pharmacokinetic parameters even fulfilled commonly accepted bioequivalence criteria, i.e. inclusion of 90% confidence intervals of AUC- and Cmax-ratios within acceptance limits of 80% and 125%. Increased data variation observed with bioavailability parameters of tilidine, naloxone and 6-beta-naloxole prevented their bioequivalence demonstration based on only 12 study participants. In conclusion, single doses of two different tilidine/naloxone 50 mg/4 mg liquid formulations revealed well comparable bioavailability for all 4 analytes investigated. Both treatments were fairly well tolerated. Most frequently reported adverse events were dizziness, headache and nausea, which all recovered without sequelae and necessity of concomitant treatment.