Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study.

BACKGROUND: Cebranopadol is a nociceptin/orphanin FQ peptide/opioid receptor agonist with central antinociceptive activity. We hypothesize that this novel mechanism of action may lead to a lower risk of abuse compared with pure µ-opioid peptide receptor agonists. METHODS: We conducted a single-dose, nested-randomized, double-blind crossover study in nondependent recreational opioid users to evaluate the abuse potential of single doses of cebranopadol relative to hydromorphone immediate release and placebo. The study consisted of a qualification phase and a 7-period treatment phase (cebranopadol 200, 400, and 800 µg; hydromorphone 8 and 16 mg; and 2 placebos). The primary end point was the peak effect of drug liking at this moment, measured by visual analog scale (VAS). Various secondary end points (eg, VAS rating for good drug effects, high, bad drug effects, take drug again, drug similarity, and pupillometry) were also investigated. RESULTS: Forty-two subjects completed the study. Cebranopadol 200 and 400 µg did not differentiate from placebo on the abuse potential assessments and generated smaller responses than hydromorphone. Responses observed with cebranopadol 800 µg were similar to hydromorphone 8 mg and smaller than hydromorphone 16 mg. The maximum effect for VAS drug liking at this moment was delayed compared with hydromorphone (3 and 1.5 hours, respectively). Cebranopadol administration was safe; no serious adverse events or study discontinuation due to treatment-emergent adverse events occurred. CONCLUSIONS: These results confirm our hypothesis that cebranopadol, a nociceptin/orphanin FQ peptide/opioid receptor agonist, has lower abuse potential than hydromorphone immediate release, a pure µ-opioid peptide agonist.

Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency.

OBJECTIVES: Opioid-induced androgen deficiency (OPIAD) affects patients treated with opioid analgesics. The norepinephrine reuptake inhibitor (NRI) and µ-opioid receptor (MOR) agonist activities of tapentadol may result in tapentadol having less effect on serum androgen concentrations than analgesics acting through the MOR alone, such as morphine and oxycodone. The objectives of this publication are to 1) evaluate the effects of tapentadol (NUCYNTA and NUCYNTA extended release [ER]) on sex hormone concentrations in healthy male volunteers (vs placebo and morphine) and patients with osteoarthritis (vs placebo and oxycodone), and 2) present a mechanistic hypothesis explaining how the combined MOR agonist and NRI activities of tapentadol may result in less impact on androgen concentrations. METHODS: Three clinical studies were conducted: study 1 (single-dose comparison study vs morphine in healthy volunteers), study 2 (single-dose-escalation study in healthy volunteers without an active comparator), and study 3 (multiple-dose study vs oxycodone in patients with osteoarthritis). Studies 1 and 2 were conducted at medical research centers in Germany and the United Kingdom; study 3 was conducted at primary and secondary care centers and medical research centers in the United States. All three studies were randomized, double blind, and placebo controlled. Concentrations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH; study 3 only) were evaluated at 6 and 24 hours postdose in studies 1 and 2, respectively, and at varying time points postdose in study 3. RESULTS: In study 1, mean serum total testosterone concentrations in healthy male volunteers were similar at baseline for all treatment periods; 6 hours after dosing, mean concentrations were comparable between placebo (8.6 nmol/L) and tapentadol immediate release (IR; 43 mg, 8.8 nmol/L; 86 mg, 9.3 nmol/L), but were lower following administration of morphine IR 30 mg (5.4 nmol/L). In study 2, there were no or minimal changes in testosterone in the therapeutic dose range with tapentadol IR (75-100 mg), and there was a modest decrease that appeared to level off in the supratherapeutic range (125-175 mg); mean testosterone and LH concentrations with all doses remained within normal ranges (testosterone, 4.56-28.2 nmol/L; LH, 2.9-4.6 U/L). In study 3, the decrease in the mean [standard deviation] testosterone concentration from baseline to endpoint for male patients receiving tapentadol ER (100 mg, -1.9 [0.71] nmol/L; 200 mg, -2.1 [0.93] nmol/L) was numerically smaller compared to oxycodone CR (20 mg, -2.7 [0.93] nmol/L), but higher compared to placebo (-0.3 [1.62] nmol/L). CONCLUSIONS: These results suggest that tapentadol, which has combined MOR and NRI activities, may have a lower impact on sex hormone concentrations than pure opioid analgesics, such as morphine or oxycodone. The data and mechanistic rationale presented herein provide a justification for conducting additional hypothesis testing studies, and are not intended to be used as a basis for clinical decision making. Future studies may help elucidate whether the observed trends are clinically significant and would translate into a reduced incidence of OPIAD.

Comparative pharmacokinetics and bioavailability of tapentadol following oral administration of immediate- and prolonged-release formulations.

OBJECTIVE: To evaluate the bioavailability and pharmacokinetics of orally administered tapentadol immediate release (IR) compared with tapentadol prolonged release (PR). METHODS: Three randomized, open-label, crossover studies were conducted in subjects under fasted conditions. Studies 1 and 2 determined the absolute bioavailability and pharmacokinetics of oral tapentadol IR 86 mg and tapentadol PR 86 mg, respectively, relative to a 34-mg intravenous (IV) dose of tapentadol. Study 3 determined the relative bioavailability of tapentadol PR 86 mg vs. tapentadol IR 86 mg. Pharmacokinetic parameters were calculated using non-compartmental analysis and relative bioavailability using dose-adjusted, log-transformed analysis of variance models for maximum concentration (Cmax) and areas under the serum concentration-time curve (AUC0-t and AUC). Adverse events (AEs), vital signs, 12-lead electrocardiograms (ECGs), and laboratory parameters were assessed. RESULTS: Absolute bioavailability was estimated to be 32% (95% confidence interval (CI), 29.4 - 34.8%; n = 24) for tapentadol IR 86 mg and 32% (95% CI, 28.0 - 35.9%; n = 18) for tapentadol PR 86 mg. Based on AUC, the relative bioavailability of tapentadol PR vs. tapentadol IR was 96% (90% CI, 87.8 - 104.4%; n = 16). Following IV administration, tapentadol had an elimination half-life of about 4 hours; in Studies 1 and 2, respectively, mean tapentadol volumes of distribution were 540 and 471 l, and mean clearance was 1,531 and 1,603 ml/min. Compared to tapentadol IR 86 mg, the prolonged-release characteristics of tapentadol PR 86 mg were evident with a lower Cmax (22.5 ng/ml vs. 64.2 ng/ml), a longer time to Cmax (5.0 h vs. 1.5 h), a higher half-value duration (HVD: 12.5 h vs. 3.6 h), and a longer mean residence time (MRT: 10.6 h vs. 6.0 h). The most common AEs reported were dizziness, headache, fatigue, nausea, somnolence, and dry mouth; most AEs were mild. No clinically relevant changes in vital signs, ECG parameters, or laboratory values were observed. CONCLUSIONS: Absolute bioavailability for both tapentadol IR and tapentadol PR was ~ 32% under fasted conditions. Extent of exposure (AUC) for tapentadol PR was very similar to tapentadol IR, whereas Cmax was lower and HVD/MRT longer for the prolonged-release formulation. Overall, the pharmacokinetic characteristics of tapentadol PR enable a twice-daily dosing regimen to be used; such a regimen is expected to improve patient compliance during chronic use.

Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects.

Tapentadol is a novel, centrally acting oral analgesic with a dual mode of action that has demonstrated efficacy in preclinical and clinical models of pain relief. The present study investigated and characterized the absorption, metabolism, and excretion of tapentadol in humans. Four healthy male subjects received a single 100-mg oral dose of 3-[14C]-labeled tapentadol HCl for evaluation of the pharmacokinetics of the drug and the excretion balance of radiocarbon. The concentration-time profiles of radiocarbon in whole blood and serum and radiocarbon excretion in the urine and feces, and the expired CO2 were determined. The serum pharmacokinetics and excretion kinetics of tapentadol and its conjugates were assessed, as was its tolerability. Absorption was rapid (with a mean maximum serum concentration [Cmax], 2.45 microg-eq/ml; a time to Cmax, 1.25-1.5 h), and the drug was present primarily in the form of conjugated metabolites (conjugated:unconjugated metabolites = 24:1). Excretion of radiocarbon was rapid and complete (>95% within 24 h; 99.9% within 5 days) and almost exclusively renal (99%: 69% conjugates; 27% other metabolites; 3% in unchanged form). No severe adverse events or clinically relevant changes in vital signs, laboratory measurements, electrocardiogram recording, or physical examination findings were reported. In our study group, it was found that a single oral dose of tapentadol was rapidly absorbed, then excreted into the urine, primarily in the form of conjugated metabolites, and was well tolerated.

Pharmacokinetics of chlormadinone acetate following single and multiple oral dosing of chlormadinone acetate (2 mg) and ethinylestradiol (0.03 mg) and elimination and clearance of a single dose of radiolabeled chlormadinone acetate.

BACKGROUND: Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t(1/2,z)). MATERIALS AND METHODS: Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography-mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose. RESULTS: Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Peak plasma concentrations of CMA were approximately 1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of approximately 400-500 pg/mL for CMA and 20-40 pg/mL for EE. Mass balance factors were 1.2-1.4 for CMA and 1.6-1.7 for EE, and accumulation factors were 1.7-2 for CMA and 1.7-1.8 for EE. Mean t(1/2,z) of CMA was approximately 25 h after single dosing and 36-39 h at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3+/-6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively. CONCLUSIONS: The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t(1/2,z) of CMA was 36-39 h after multiple dosing, which is considerably shorter than the 80 h often quoted in the literature.

The effects of tramadol on static and dynamic pupillometry in healthy subjects--the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status.

OBJECTIVES: The main objective of the present study was to provide information on whether static and dynamic pupillometry can be used for pharmacodynamic profiling, particularly when investigating opioid-like drugs, such as tramadol. METHODS: Healthy subjects (n = 26) participated in this randomised, double-blind, placebo-controlled, crossover Phase 1 study. Of these, 20 extensive metabolisers (EMs) with respect to polymorphic isoenzyme cytochrome P450 2D6 (CYP2D6) received up to 150 mg of tramadol-HCl and placebo. The 6 poor metabolisers (PMs) with respect to CYP2D6 received 100 mg tramadol-HCl and placebo. RESULTS: In EMs, serum concentrations of the enantiomers of tramadol and of O-demethylated metabolite (M1) increased with increasing doses. Comparing the 100-mg dose between EMs and PMs, the latter exhibited higher serum concentrations of both enantiomers of tramadol. Serum concentrations of (+)-M1 remained below the lower limit of quantification, and that of (-)-M1 were lower than those in EMs. In EMs, doses from 100 mg tramadol-HCl on induced a significant (P<0.05) miosis as compared with placebo. The maximum mean differences from placebo after dosing with 50, 100 and 150 mg tramadol-HCL were -0.5, -0.8 and -1.1 mm, respectively, indicating a dose-dependent character of the changes. Dynamic pupillometry revealed significant (P<0.05) effects for the amplitude, latency and duration of reaction. The amplitude and velocity of constriction were decreased only at the highest dose; whereas, the changes of the amplitude reached statistical significance (P<0.05). Both the latency and reaction duration behaved in a dose-dependent manner. For the latency, significant changes compared with placebo (P<0.05) were found at the 150-mg dose level, while the reaction duration was already significantly (P<0.05) decreased from the 100-mg dose on. The velocity of redilatation did not respond at all. In PMs, no effect on the initial pupil diameter was found. Although the statistical analysis failed to demonstrate any significant change from placebo for the dynamic pupillometry, the effect-time profiles of EMs and PMs were comparable. For both metaboliser groups, a decrease of amplitude, velocity of constriction and reaction duration as well as an increase of latency was observed. In principle, the direction and magnitude of changes were comparable between EMs and PMs. Most important was the finding that the time course of effects was completely different between both groups of metabolisers. In EMs, effects slowly reached a maximum between 4 h and 10 h after dosing and diminished until 24 h; whereas, in PMs, both maximum effects and the return to baseline occurred much earlier, at approximately 3 h and 8 h, respectively. CONCLUSIONS: The EMs and PMs of CYP2D6 treated with tramadol behaved differently in static and dynamic pupillometry. The reason for this could largely be explained with the aid of the metaboliser status and the pharmacokinetic properties of tramadol. In EMs, the pupillometric response was mainly driven by the (+)-M1, which comprises the mu action component of tramadol; whereas, in PMs, the non-mu component appears to play an important role. Thus, pupillometry was found to be useful in pharmacodynamic profiling and provides a good correlation with the pharmacokinetics.

Oral bioavailability of gatifloxacin in healthy volunteers under fasting and fed conditions.

The effect of food on the pharmacokinetics of gatifloxacin given as a single oral dose of 400 mg under fasting and fed conditions was determined in 18 healthy male volunteers in an open, two-way, randomised cross-over study. Concomitant food intake did not significantly alter the peak plasma concentrations (C(max)) or the area under the plasma concentration-time curve (AUC) of gatifloxacin. The mean C(max) levels under fasting and fed conditions were 3.5 and 3.2 mg/l, respectively, after the 400-mg single dose of gatifloxacin. The corresponding mean AUC data were 32.8 mg x h/l (fasted) and 30.5 mg x h/l (fed). Moreover, the rate of absorption was not affected by food intake. The median T(max) value was 2 h in both treatment periods. No clinically relevant adverse effects or changes in clinical laboratory test results, ECGs or physical examinations were observed. The results of this study indicate that gatifloxacin given as a single 400-mg oral dose was well tolerated in the presence or absence of food. Concomitant administration of a continental breakfast with a caloric content of 1,050 kcal had no effect on the bioavailability of gatifloxacin. It is suggested that gatifloxacin can be given without regard to meals.

Multiple-dose pharmacokinetics and excretion balance of gatifloxacin, a new fluoroquinolone antibiotic, following oral administration to healthy Caucasian volunteers.

The multiple-dose pharmacokinetics and excretion balance of gatifloxacin were evaluated in 42 healthy Caucasian volunteers. Following multiple oral doses of 400 and 600 mg, the pharmacokinetics of gatifloxacin were similar on days 1 and 15, suggesting no therapeutically relevant time-dependent changes in the pharmacokinetics of gatifloxacin at the doses and duration of dosing studied. Gatifloxacin was rapidly absorbed and a favourable elimination half-life of 7-8 h was evaluated. Saliva concentrations were similar to plasma concentrations. The main route of excretion is the urine. After a single dose of 400 mg of gatifloxacin, the recovery in urine was 83% and 5.2% in faeces. Following multiple doses of 400 or 600 mg, the renal excretion was 80 and 77%, respectively. The drug was well tolerated.