Iñaki F. Trocóniz

Methadone: a review of its pharmacokinetic/pharmacodynamic properties

During the past decades the use of methadone has been increased as a result of the interest of optimizing its therapeutics in opioid addicts, one of the groups with higher risk for AIDS infection. However standard dose of methadone are far from being the appropriate for relief pain or prevent withdrawal signs in maintenance programs in many patients. To achieve an optimal dose regimen for an individual, the knowledge of the relationship between the pharmacokinetics/pharmacodynamics (pk/pd) drug properties and the demographic and physiopathological characteristics of the subject is required. Unfortunately, there is a lack of studies dealing with the population pk/pd properties of methadone. In the current study, a review of the pk/pd properties of methadone is presented with the aim of understanding the sources of variability in response. This will help in the design of prospective pk/pd studies; in particular, individual data including sex, weight, alpha(1)-acid glycoprotein levels in plasma, concomitant medications, time after starting treatment with methadone and previous exposure to other opioids should be requested. In addition, designs for drug administration should allow the characterization of the plasma-versus-biophase distribution and the development of tolerance processes. Because methadone is usually administered as a racemic mixture, the use of enantioselective techniques to determine both enantiomers in plasma is also highly recommended.

Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery.

Dabigatran etexilate (BIBR 1048) is an orally bioavailable double prodrug of the active principle dabigatran (BIBR 953 ZW), which exerts potent anticoagulant and antithrombotic activity. The objective of the analysis was to develop a population pharmacokinetic model characterizing and quantifying the relationship between covariates and model parameters. A total of 4604 BIBR 953 ZW plasma concentrations, obtained from 287 patients after once‐ or twice‐daily oral dosing for up to 10 days after surgery in the dose range 12.5, 25, 50, 100, 150, 200, and 300 mg BIBR 1048, were available for the analysis. All the analyses were performed with NONMEN V. Pharmacokinetics of dabigatran were best described by a 2‐compartment model. The data supported the estimation of different apparent first‐order absorption rate constants (ka) and apparent plasma clearances (CL/F) for days 0 and 1 and days 2 to 10 after surgery. Parameter estimates indicated a flip‐flop phenomenon. Age and serum creatinine influenced ka, whereas gastrin and creatinine clearance, only for days 2 to 10, affected CL/F (P < .001). The typical values for CL/F for a patient with gastrin of 34.58 pmol/L and creatinine clearance of 76.16 mL/min were 70.87 and 106.2 L/h on days 0 and 1 and days 2 to 10, respectively. The differences found in the pharmacokinetics of dabigatran during the first 24 hours after surgery are most likely due to alterations in gastric motility and pH following surgery. As a consequence, the rate of absorption is reduced and interindividual variability in drug exposure increased. On the following days, the disposition in plasma of BIBR 953 ZW is less variable.

A review of mixed-effects models of tumor growth and effects of anticancer drug treatment used in population analysis.

Population modeling of tumor size dynamics has recently emerged as an important tool in pharmacometric research. A series of new mixed‐effects models have been reported recently, and we present herein a synthetic view of models with published mathematical equations aimed at describing the dynamics of tumor size in cancer patients following anticancer drug treatment. This selection of models will constitute the basis for the Drug Disease Model Resources (DDMoRe) repository for models on oncology.

Enantiomeric separation of tramadol and its active metabolite in human plasma by chiral high-performance liquid chromatography: application to pharmacokinetic studies.

A sensitive and stereoselective high-performance liquid chromatographic assay for the quantitative determination of the analgesic tramadol and O-demethyltramadol, an active metabolite, is described in this work. Ketamine was used as internal standard. The assay involved a single tert-butymethylether extraction and liquid chromatography analysis with fluorescence detection. Chromatography was performed at 20 degrees C on a Chiracel OD-R column containing cellulose tris-(3,5-dimethylphenylcarbamate) as stationary phase, preceded by an achiral end-capped C18 column. The mobile phase was a mixture of phosphate buffer (containing sodium perchlorate (0.2 M) and triethylamine (0.09 M) adjusted to pH 6) and acetonitrile (80:20). The method developed was validated. The limit of quantitation of each enantiomer of tramadol and its active metabolite by this method was 0.5 ng/mL; only 0.5 mL of the plasma sample was required for the determination. The calibration curve was linear from 0.5 to 750 ng/mL for tramadol enantiomers, and from 0.5 to 500 ng/mL for O-demethyltramadol enantiomers. Intra and interday precision [coefficient of variation (CV)] did not exceed 10%. Mean recoveries of 95.95 and 97.87% for (+)R,R- and (-)S,S-tramadol and 97.70 and 98.79% for (+)R,R- and (-)S,S-O-demethyltramadol with CVs < 2.15% were obtained. Applicability of the method was demonstrated by a pharmacokinetic study in normal volunteers who received 100 mg of tramadol by the intravenous route.

Modeling of the Sedative and Airway Obstruction Effects of Propofol in Patients with Parkinson Disease undergoing Stereotactic Surgery

Background Functional stereotactic surgery requires careful titration of sedation since patients with Parkinson disease need to be rapidly awakened for testing. This study reports a population pharmacodynamic model of propofol sedation and airway obstruction in the Parkinson disease population. Methods Twenty-one patients with advanced Parkinson disease undergoing functional stereotactic surgery were included in the study and received propofol via target-controlled infusion to achieve an initial steady state concentration of 1 &mgr;g/ml. Sedation was measured using the Ramsay Sedation Scale. Airway obstruction was measured using a four-category score. Blood samples were drawn for propofol measurement. Individual pharmacokinetic profiles were constructed nonparametrically using linear interpolation. Time course of sedation and respiratory effects were described with population pharmacodynamic models using NONMEM. The probability (P) of a given level of sedation or airway obstruction was related to the estimated effect-site concentration of propofol (Ce) using a logistic regression model. Results The concentrations predicted by the target-controlled infusion system generally exceeded the measured concentrations. The estimates of C50 for Ramsay scores 3, 4, and 5 were 0.1, 1.02, and 2.28 &mgr;g/ml, respectively. For airway obstruction scores 2 and 3, the estimates of C50 were 0.32 and 2.98 &mgr;g/ml, respectively. Estimates of ke0 were 0.24 and 0.5 1/min for the sedation and respiratory effects, respectively. Conclusions The pharmacokinetic behavior of propofol in patients with Parkinson disease differs with respect to the population from which the model used by the target-controlled infusion device was developed. Based on the results from the final models, a typical steady state plasma propofol concentration of 0.35 &mgr;g/ml eliciting a sedation score of 3 with only minimal, if any, airway obstruction has been defined as the therapeutic target.

Pharmacokinetic-Pharmacodynamic Modelling of the Antipyretic Effect of Two Oral Formulations of Ibuprofen

ObjectiveTo analyse the population pharmacokinetic-pharmacodynamic relationships of racemic ibuprofen administered in suspension or as effervescent granules with the aim of exploring the effect of formulation on the relevant pharmacodynamic parameters.DesignThe pharmacokinetic model was developed from a randomised, crossover bioequivalence study of the 2 formulations in healthy adults. The pharmacodynamic model was developed from a randomised, multicentre, single dose efficacy and safety study of the 2 formulations in febrile children.Patients and participantsPharmacokinetics were studied in 18 healthy volunteers aged 18 to 45 years, and pharmacodynamics were studied in 103 febrile children aged between 4 and 16 years with bodyweight ≥25kg.MethodsThe pharmacokinetic study consisted of two 1-day study occasions, each separated by a 1-week washout period. On each occasion ibuprofen 400mg was administered orally as suspension or granules. The time course of the antipyretic effect was evaluated in febrile children receiving a single oral dose of 7 mg/kg in suspension or 200 or 400mg as effervescent granules. During the pharmacodynamic analysis, the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used.ResultsThe disposition of ibuprofen was described by a 2-compartment model. No statistical differences (p > 0.05) were found between the 2 formulations in the distribution and elimination parameters. Absorption of ibuprofen from suspension was adequately described by a first-order process; however, a model with 2 parallel first-order input sites was used for the drug given as effervescent granules, leading to time to reach maximum drug concentration (tmax) values of 0.9 and 1.9 hours for suspension and granules, respectively. The time course of the antipyretic effect was best described using an indirect response model. The estimates (with percentage coefficients of variation in parentheses) of Emax (maximum inhibition of the zero-order synthesis rate of the factor causing fever), EC50 (plasma concentration eliciting half of Emax), n (slope parameter) and kout (first order rate constant of degradation) were 0.055 (10), 6.16 (14) mg/L, 2.71 (18) and 1.17 (23) h−1, respectively, where T0 is the estimate of the basal temperature, 38.8 (1) °C. No significant (p > 0.05) covariate effects (including pharmaceutical formulation) were detected in any of the pharmacodynamic parameters.ConclusionsBecause of the indirect nature of the effect exerted by ibuprofen, the implications of differences found in the plasma drug concentration profiles between suspension and effervescent granules are less apparent in the therapeutic response.

Simultaneous determination of tramadol and its major active metabolite O-demethyltramadol by high-performance liquid chromatography with electrochemical detection

A novel, highly sensitive method was developed for simultaneous determination of tramadol and its main active metabolite O-demethyltramadol (ODMT) in rat plasma. The method involves a single-step extraction procedure and a specific determination by high-performance liquid chromatography with electrochemical detection, using an ethoxy analogue of tramadol (L-233) as internal standard. The dual-electrode detector was operated in the oxidation-screening mode. Absolute recoveries of tramadol and ODMT were about 80%. Calibration curves were linear over a concentration range of 10-1000 ng/ml for ODMT and 10-10000 ng/ml for tramadol with intra- and inter-day coefficients of variation not exceeding 10% and 15%, respectively. The limit of quantification for tramadol and ODMT was lower than 15 ng/ml and 10 ng/ml using 100 microl of plasma, respectively. The described method allows an adequate characterization of the plasma vs. time profiles for both compounds.

Population Pharmacokinetics of Meropenem in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

AbstractBackground and objective: Meropenem is a carbapenem antibacterial frequently prescribed for the treatment of severe infections in critically ill patients, including those receiving continuous renal replacement therapy (CRRT). The objective of this study was to develop a population pharmacokinetic model of meropenem in critically ill patients undergoing CRRT. Patients and methods: A prospective, open-label study was conducted in 20 patients undergoing CRRT. Blood and dialysate-ultrafiltrate samples were obtained after administration of 500 mg, 1000 mg or 2000 mg of meropenem every 6 or 8 hours by intravenous infusion. The data were analysed under the population approach using NONMEM version V software. Age, bodyweight, dialysate plus ultrafiltrate flow, creatinine clearance (CLCR), the unbound drug fraction in plasma, the type of membrane, CRRT and the patient type (whether septic or severely polytraumatized) were the covariates studied. Results: The pharmacokinetics of meropenem in plasma were best described by a two-compartment model. CLCR was found to have a significant correlation with the apparent total clearance (CL) of the drug during the development of the covariate model. However, the influence of CLCR on CL differed between septic and polytraumatized patients (CL = 6.63 + 0.064 × CLCR for septic patients and CL = 6.63 + 0.72 × CLCR for polytraumatized patients). The volume of distribution of the central compartment (V1) was also dependent on the patient type, with values of 15.7 L for septic patients and 69.5 L for polytraumatized patients. The population clearance was 15 L/h, and the population apparent volume of distribution of the peripheral compartment was 19.8 L. From the base to the final model, the interindividual variabilities in CL and the V1 were significantly reduced. When computer simulations were carried out and efficacy indexes were calculated, it was shown that polytraumatized patients and septic patients with conserved renal function may not achieve adequate efficacy indexes to deal with specific infections. Continuous infusion of meropenem is recommended for critically septic patients and polytraumatized patients when pathogens with a minimum inhibitory concentration (MIC) of ≥4 mg/L are isolated. Infections caused by pathogens with an MIC of ≥8 mg/L should not be treated with meropenem in polytraumatized patients without or with moderate renal failure because excessive doses of meropenem would be necessary. Conclusion: A population pharmacokinetic model of meropenem in intensive care patients undergoing CRRT was developed and validated. CLCR and the patient type (whether septic or polytraumatized) were identified as significant covariates. The population pharmacokinetic model developed in the present study has been employed to recommend continuous infusion protocols in patients treated with CRRT.

Modeling the Effect of Propofol and Remifentanil Combinations for Sedation-Analgesia in Endoscopic Procedures Using an Adaptive Neuro Fuzzy Inference System (ANFIS)

BACKGROUND:The increasing demand for anesthetic procedures in the gastrointestinal endoscopy area has not been followed by a similar increase in the methods to provide and control sedation and analgesia for these patients. In this study, we evaluated different combinations of propofol and remifentanil, administered through a target-controlled infusion system, to estimate the optimal concentrations as well as the best way to control the sedative effects induced by the combinations of drugs in patients undergoing ultrasonographic endoscopy. METHODS:One hundred twenty patients undergoing ultrasonographic endoscopy were randomized to receive, by means of a target-controlled infusion system, a fixed effect-site concentration of either propofol or remifentanil of 8 different possible concentrations, allowing adjustment of the concentrations of the other drug. Predicted effect-site propofol (Cepro) and remifentanil (Ceremi) concentrations, parameters derived from auditory evoked potential, autoregressive auditory evoked potential index (AAI/2) and electroencephalogram (bispectral index [BIS] and index of consciousness [IoC]) signals, as well as categorical scores of sedation (Ramsay Sedation Scale [RSS] score) in the presence or absence of nociceptive stimulation, were collected, recorded, and analyzed using an Adaptive Neuro Fuzzy Inference System. The models described for the relationship between Cepro and Ceremi versus AAI/2, BIS, and IoC were diagnosed for inaccuracy using median absolute performance error (MDAPE) and median root mean squared error (MDRMSE), and for bias using median performance error (MDPE). The models were validated in a prospective group of 68 new patients receiving different combinations of propofol and remifentanil. The predictive ability (Pk) of AAI/2, BIS, and IoC with respect to the sedation level, RSS score, was also explored. RESULTS:Data from 110 patients were analyzed in the training group. The resulting estimated models had an MDAPE of 32.87, 12.89, and 8.77; an MDRMSE of 17.01, 12.81, and 9.40; and an MDPE of −1.86, 3.97, and 2.21 for AAI/2, BIS, and IoC, respectively, in the absence of stimulation and similar values under stimulation. Pk values were 0.82, 0.81, and 0.85 for AAI/2, BIS, and IoC, respectively. The model predicted the prospective validation data with an MDAPE of 34.81, 14.78, and 10.25; an MDRMSE of 16.81, 15.91, and 11.81; an MDPE of −8.37, 5.65, and −1.43; and Pk values of 0.81, 0.8, and 0.8 for AAI/2, BIS, and IoC, respectively. CONCLUSION:A model relating Cepro and Ceremi to AAI/2, BIS, and IoC has been developed and prospectively validated. Based on these models, the (Cepro, Ceremi) concentration pairs that provide an RSS score of 4 range from (1.8 &mgr;g·mL−1, 1.5 ng·mL−1) to (2.7 &mgr;g·mL−1, 0 ng·mL−1). These concentrations are associated with AAI/2 values of 25 to 30, BIS of 71 to 75, and IoC of 72 to 76. The presence of noxious stimulation increases the requirements of Cepro and Ceremi to achieve the same degree of sedative effects.

Population pharmacokinetics of piperacillin and tazobactam in critically ill patients undergoing continuous renal replacement therapy: application to pharmacokinetic/pharmacodynamic analysis

OBJECTIVES To evaluate the pharmacokinetics of piperacillin/tazobactam in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to assess the success of the therapy against susceptible bacteria. PATIENTS AND METHODS Sixteen patients undergoing CRRT with different degrees of renal function were included in the study. Blood and ultrafiltrate samples were drawn after administration of piperacillin/tazobactam (4/0.5 g) every 4, 6 or 8 h. The data were analysed by a population approach using NONMEM 7.2. The probability of target attainment (PTA) of maintaining free piperacillin levels above the MIC during the entire dosing interval was estimated by simulation of intermittent and continuous infusions. RESULTS The pharmacokinetics of piperacillin and tazobactam were best described by two-compartment models where the elimination of both drugs was conditioned by renal [dependent on creatinine clearance (CLCR)], non-renal and extracorporeal clearances. A 20 min infusion of piperacillin/tazobactam administered every 6 h provided high PTAs against MICs ≤ 32 mg/L in patients with severe renal failure. In patients with normal or moderate renal function PTAs ≥ 90% were only obtained up to MICs ≤ 8 mg/L with short infusions. However, simulating continuous infusion, higher probabilities of success were obtained against MICs of 32 and 16 mg/L when CLCR was 50 and 100 mL/min, respectively. CONCLUSIONS Population pharmacokinetic models have been developed and validated for piperacillin and tazobactam. Based on the pharmacokinetic/pharmacodynamic analysis, dosing recommendations are given considering the residual renal function of the patient and the MIC for the isolated bacteria.