Population pharmacokinetics of tapentadol immediate release (IR) in healthy subjects and patients with moderate or severe pain.
ABSTRACT 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.
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.
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.
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.
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ABSTRACT: Drugs that provide effective analgesia in cats are limited. The aim of the present study was to investigate the pharmacokinetics of the novel atypical drug tapentadol (TAP) after intravenous (IV), intramuscular (IM) and subcutaneous (SC) injection in six healthy cats using a 3×3 Latin square crossover study design. The dose rate used was 5mg/kg and the concentrations of TAP in plasma were evaluated using high-performance liquid chromatography. Some adverse effects including salivation, agitation and panting, were noted, especially following IV administration. In all three administration groups, TAP concentrations were detectable in plasma for up to 8h. Bioavailability for each route was almost complete, accounting for 94% and 90% after IM and SC administrations, respectively. Drug absorption was faster after IM than SC administration (0.25h vs. 0.63h). The half-life of the terminal portion of the plasma concentration curve was not significantly different between the three routes of administrations (2-3h). TAP appears to have some variation in its pharmacokinetic features in cats compared to other animal species. Further studies are needed to evaluate whether TAP would be suitable for use in cats that are experiencing moderate to severe pain, but are sensitive to the adverse effects of commonly prescribed opioids.The Veterinary Journal 09/2013; · 2.42 Impact Factor
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ABSTRACT: SUMMARY In the never-ending process of providing therapy with diminishing side effects, pain medicine stands out as an important area of work. Ever since the introduction of opioids and elucidation of their mechanisms pharmaceutical researchers have sought a compound that provides long-term analgesia with none of the side effects that include somnolence, lethargy, tolerance, addiction, gastrointestinal symptoms and so on. This article reviews one of the latest improvements in analgesia, the formulation of tapentadol as an extended-release medication. Despite not claiming to have eliminated all the negatives of narcotics tapentadol extended-release seems to have made inroads to that goal.Pain management. 09/2012; 2(5):451-6.
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ABSTRACT: Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4. The objective of the present study was to characterize the clinical pharmacology profile of ipilimumab using a population pharmacokinetic (PPK) approach. The PPK model was developed using 2095 ipilimumab serum concentration values from 499 patients with unresectable stage III or IV melanoma from four phase II studies, with ipilimumab doses ranging from 0.3 to 10 mg/kg. The structural PK model was determined by developing a base PPK model. The effect of covariates on model parameters was assessed by a full-covariate model, which incorporated all pre-specified covariate-parameter relationships into the base model. The final model was developed by backward elimination, followed by exclusion of covariates determined to not be of clinical relevance to ipilimumab, and was rigorously validated against both internal and external datasets. Ipilimumab PK was linear and time-invariant, with dose-proportional exposures over the available dose range, yielding a terminal half-life of approximately 15 days. Clearance of ipilimumab increased with increasing body weight and baseline serum lactate dehydrogenase levels, but was not affected by age, gender, concomitant budesonide, Eastern Cooperative Oncology Group performance status, or prior systemic anticancer therapy. Furthermore, ipilimumab exposure was not affected by moderate renal impairment or mild hepatic impairment. Ipilimumab concentration-time data were well described by a linear, two-compartment, zero-order IV infusion model. The model confirms that a body weight-normalized dosing regimen is appropriate for ipilimumab therapy in patients with advanced melanoma.British Journal of Clinical Pharmacology 01/2014; · 3.69 Impact Factor