Evaluation of the effect of naltrexone coadministration on the pharmacokinetics of oxycodone in a randomized phase 1 clinical trial
.

OBJECTIVE: Oxycodone is a centrally acting µ-opioid agonist used as a strong analgesic. The opioid receptor antagonist -naltrexone is often coadministered to healthy subjects in clinical trials evaluating the pharmacokinetics (PK) of oxycodone to minimize its pharmacodynamic opioid effects. One objective of this relative bioavailability trial in healthy subjects was to investigate the effect of naltrexone on the PK of oxycodone. MATERIALS AND METHODS: A randomized, single-dose, parallel-group, within-groups crossover, clinical trial was conducted in 24 healthy subjects. 12 subjects were to receive a new oxycodone prolonged-release (PR) tablet (test) with naltrexone (T+) and without naltrexone (T) in the fasted state. Additionally, 12 subjects were to receive an Oxygesic PR tablet (reference) with naltrexone (R+) and without naltrexone (R) in the fasted state. Naltrexone was given orally 1.5 hours prior to each oxycodone administration. Pharmacokinetics, safety, and tolerability were assessed. RESULTS: The PK parameters of either oxycodone formulation were not changed with naltrexone administration under fasted conditions (point estimate T+/T (corresponding 90% confidence interval): Cmax: 103% (88 - 119%), AUC0-t: 97% (87 - 108%), AUC: 97% (88 - 108%); point estimate R+/R (corresponding 90% confidence interval): Cmax: 104% (97 - 112%), AUC0-t: 95% (88 - 102%), AUC: 94% (87 - 100%)). The safety and tolerability of both formulations was not qualitatively affected by naltrexone coadministration; however, treatment with naltrexone coadministration showed lower frequencies of adverse events. CONCLUSION: Oral naltrexone does not affect the PK of oral oxycodone under fasted conditions. A naltrexone block can be applied in oxycodone PK trials to minimize adverse opioid effects.

Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development.

Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fold lower lysosomal trapping capacity. No signs of PLD were seen with GRT2. The different profile of GRT2 relative to GRT1 is due to a structural change resulting in a reduced basicity of one amino group. Hence, by distinct chemical modifications, undesired lysosomal trapping can be separated from desired drug delivery into different organs. In summary, assessment of intracellular unbound concentrations was instrumental in delineating the intercompound and intertissue differences in PLD induction in vivo and could be applied for identification of potential lysosomotropic compounds in drug development.

Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs.

OBJECTIVE: To evaluate the analgesic potential of the centrally acting analgesics tramadol, morphine and the novel analgesic tapentadol in a pre-clinical research model of acute nociceptive pain, the tail-flick model in dogs. STUDY DESIGN: Prospective part-randomized pre-clinical research trial. ANIMALS: Fifteen male Beagle dogs (HsdCpb:DOBE), aged 12-15 months. METHODS: On different occasions separated by at least 1 week, dogs received intravenous (IV) administrations of tramadol (6.81, 10.0 mg kg(-1) ), tapentadol (2.15, 4.64, 6.81 mg kg(-1) ) or morphine (0.464, 0.681, 1.0 mg kg(-1) ) with subsequent measurement of tail withdrawal latencies from a thermal stimulus (for each treatment n = 5). Blood samples were collected immediately after the pharmacodynamic measurements of tramadol to determine pharmacokinetics and the active metabolite O-demethyltramadol (M1). RESULTS: Tapentadol and morphine induced dose-dependent antinociception with ED50-values of 4.3 mg kg(-1) and 0.71 mg kg(-1) , respectively. In contrast, tramadol did not induce antinociception at any dose tested. Measurements of the serum levels of tramadol and the M1 metabolite revealed only marginal amounts of the M1 metabolite, which explains the absence of the antinociceptive effect of tramadol in this experimental pain model in dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Different breeds of dogs might not or only poorly respond to treatment with tramadol due to low metabolism of the drug. Tapentadol and morphine which act directly on µ-opioid receptors without the need for metabolic activation are demonstrated to induce potent antinociception in the experimental model used and should also provide a reliable pain management in the clinical situation. The non-opioid mechanisms of tramadol do not provide antinociception in this experimental setting. This contrasts to many clinical situations described in the literature, where tramadol appears to provide useful analgesia in dogs for post-operative pain relief and in more chronically pain states.

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.

Pharmacokinetics of intravenous tramadol in dogs.

The purpose of this study was to determine the pharmacokinetics of tramadol and the active metabolite mono-O-desmethyltramadol (M1) in 6 healthy male mixed breed dogs following intravenous injection of tramadol at 3 different dose levels. Verification of the metabolism to the active metabolite M1, to which most of the analgesic activity of this agent is attributed to, was a primary goal. Quantification of the parent compound and the M1 metabolite was performed using gas chromatography. Pharmacodynamic evaluations were performed at the time of patient sampling and included assessment of sedation, and evaluation for depression of heart and respiratory rates. This study confirmed that while these dogs were able to produce the active M1 metabolite following intravenous administration of tramadol, the M1 concentrations were lower than previously reported in research beagles. Adverse effects were minimal, with mild dose-related sedation in all dogs and nausea in 1 dog. Analgesia was not documented with the method of assessment used in this study. Tramadol may be useful in canine patients, but additional studies in the canine population are required to more accurately determine the effective clinical use of the drug in dogs and quantification of M1 concentrations in a wider population of patients.

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.

Determination of tapentadol and tapentadol-O-glucuronide in human serum samples by UPLC-MS/MS.

Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action, MOR agonism and noradrenaline (NA) reuptake inhibition in a single molecule. It is the first member of a new therapeutic class, MOR-NRI. A high throughput liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay was developed and validated for the quantitative analysis of tapentadol and its O-glucuronide metabolite in human serum. Simultaneous quantification was deemed to be challenging because of the large difference in concentrations between tapentadol and its O-glucuronide metabolite in clinical samples. Therefore, a method was established using a common processed sample, but with different injection volumes and chromatographic conditions for each analyte. Tapentadol and tapentadol-O-glucuronide were determined by protein precipitation of 0.100ml of the samples with acetonitrile. The internal standards used are D6-tapentadol and D6-tapentadol-O-glucuronide. The validated concentration range was 0.200-200 ng/ml (tapentadol) and 10.0-10,000 ng/ml (tapentadol-O-glucuronide). Chromatographic separation was achieved by gradient elution on a Waters Acquity UPLC BEH C18 (1.7 µm, 2.1 × 50 mm) column, with mobile phase consisting of 0.01 M ammonium formate (adjusted to pH 4 using formic acid) (A) and methanol (B). A separate injection was done for measurement of each analyte, with a different gradient and run time. The analytes were detected by using an electrospray ion source on a triple quadrupole mass spectrometer operating in positive ionization mode. The run time was 1.6 min for tapentadol and 1.5 min for tapentadol-O-glucuronide. The high sensitivity and acceptable performance of the assay allowed its application to the analysis of serum samples in clinical trials. The validated method was used for analysis of tapentadol in over 17,000 samples.

Mechanistic and functional differentiation of tapentadol and tramadol.

INTRODUCTION: Many opioid analgesics share common structural elements; however, minor differences in structure can result in major differences in pharmacological activity, pharmacokinetic profile, and clinical efficacy and tolerability. AREAS COVERED: This review compares and contrasts the chemistry, pharmacodynamics, pharmacokinetics, and CNS 'functional activity' of tapentadol and tramadol, responsible for their individual clinical utilities. EXPERT OPINION: The distinct properties of tapentadol and tramadol generate different CNS functional activities, making each drug the prototype of different classes of opioid/nonopioid analgesics. Tramadol's analgesia derives from relatively weak µ-opioid receptor (MOR) agonism, plus norepinephrine and serotonin reuptake inhibition, provided collectively by the enantiomers of the parent drug and a metabolite that is a stronger MOR agonist, but has lower CNS penetration. Tapentadol's MOR agonist activity is several-fold greater than tramadol's, with prominent norepinephrine reuptake inhibition and minimal serotonin effect. Accordingly, tramadol is well-suited for pain conditions for which a strong opioid component is not needed-and it has the benefit of a low abuse potential; whereas tapentadol, a schedule-II controlled substance, is well-suited for pain conditions requiring a strong opioid component-and it has the benefit of greater gastrointestinal tolerability compared to classical strong opioids. Both drugs offer distinct and complementary clinical options.

Population pharmacokinetics of tapentadol immediate release (IR) in healthy subjects and patients with moderate or severe pain.

BACKGROUND: Tapentadol is a new, centrally active analgesic agent with two modes of action--mu opioid receptor agonism and norepinephrine reuptake inhibition--and the immediate-release (IR) formulation is approved in the US for the relief of moderate to severe acute pain. The aims of this analysis were to develop a population pharmacokinetic model to facilitate the understanding of the pharmacokinetics of tapentadol IR in healthy subjects and patients following single and multiple dosing, and to identify covariates that might explain variability in exposure following oral administration. METHODS: The analysis included pooled data from 11,385 serum pharmacokinetic samples from 1827 healthy subjects and patients with moderate to severe pain. Population pharmacokinetic modelling was conducted using nonlinear mixed-effects modelling (NONMEM) software to estimate population pharmacokinetic parameters and the influence of the subjects' demographic characteristics, clinical laboratory chemistry values and disease status on these parameters. Simulations were performed to assess the clinical relevance of the covariate effects on tapentadol exposure. RESULTS: A two-compartment model with zero-order release followed by first-order absorption and first-order elimination best described the pharmacokinetics of tapentadol IR following oral administration. The interindividual variability (coefficient of variation) in apparent oral clearance (CL/F) and the apparent central volume of distribution after oral administration were 30% and 29%, respectively. An additive error model was used to describe the residual variability in the log-transformed data, and the standard deviation values were 0.308 and 0.314 for intensively and sparsely sampled data, respectively. Covariate analysis showed that sex, age, bodyweight, race, body fat, hepatic function (using total bilirubin and total protein as surrogate markers), health status and creatinine clearance were statistically significant factors influencing the pharmacokinetics of tapentadol. Total bilirubin was a particularly important factor that influenced CL/F, which decreased by more than 60% in subjects with total bilirubin greater than 50 micromol/L. CONCLUSIONS: The population pharmacokinetic model for tapentadol IR identified the relationship between pharmacokinetic parameters and a wide range of covariates. The simulations of tapentadol exposure with identified, statistically significant covariates demonstrated that only hepatic function (as characterized by total bilirubin and total protein) may be considered a clinically relevant factor that warrants dose adjustment. None of the other covariates are of clinical relevance, nor do they necessitate dose adjustment.

Effects of acetaminophen, naproxen, and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, crossover, drug-drug interaction studies.

STUDY OBJECTIVE: To evaluate the effects of acetaminophen, naproxen, and acetylsalicylic acid on the pharmacokinetics of the centrally acting analgesic tapentadol in healthy subjects. DESIGN: Two randomized, open-label, crossover, drug-drug interaction studies. SETTING: Clinical research facilities in the United States and Belgium. PARTICIPANTS: Twenty-four healthy adults (2-way crossover study) and 38 healthy adults (3-way crossover study). INTERVENTIONS: In both studies, tapentadol immediate release (IR) 80 mg was administered as a single oral dose alone. In the 2-way crossover study, tapentadol IR was also given with the fifth of seven doses of acetaminophen 1000 mg; in the 3-way crossover study, tapentadol IR was also given with the third of four doses of naproxen 500 mg and the second of two doses of acetylsalicylic acid 325 mg. All treatments were separated by a washout period of 7-14 days. MEASUREMENTS AND MAIN RESULTS: Overall, mean serum concentrations were similar after administration of tapentadol IR alone and after coadministration with acetaminophen or acetylsalicylic acid, and the 90% confidence intervals (CIs) for the ratios of the mean area under the serum concentration-time curve (AUC) from time zero to time of the last measurable concentration (AUC(0-t)) and from time zero extrapolated to infinity (AUC(0-infinity)) and the maximum serum concentration (C(max)) of the combined treatments to those parameters of tapentadol alone were well within 80-125%, representing the accepted range for bioequivalence. Coadministration of naproxen did not significantly alter the C(max) of tapentadol, although a slightly higher serum tapentadol exposure relative to tapentadol alone was observed. Coadministration of naproxen resulted in a mean increase of 17% in AUCs, and the upper limits of the 90% CIs for the ratios of the mean AUC(0-t) and AUC(0-infinity) were slightly outside the upper limit of bioequivalence range of 80-125%(126.47%AUC(0-t) and 126.14%AUC(0-infinity)). CONCLUSION: No clinically relevant changes were noted in the serum concentrations of tapentadol, and accordingly, no dosage adjustments with respect to the investigated pharmacokinetic mechanism of interaction are warranted for the administration of tapentadol given concomitantly with acetaminophen, naproxen, or acetylsalicylic acid.

Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes.

The new analgesic tapentadol was evaluated for induction and inhibition of several cytochrome P450 enzymes in vitro, and protein binding was assessed. It was concluded that no clinically relevant drug-drug interactions are likely to occur through either mechanism.