Altered Plasma and Brain Disposition and Pharmacodynamics of Methadone in Abstinent Rats

The pharmacokinetics and pharmacodynamics of methadone were investigated in control and abstinent rats. Minipumps filled with saline (control group) or saline-morphine (abstinent group) solutions were used to induce physical dependence. Solutions were delivered continuously by minipumps for 6 days. The physical dependence was evaluated 12 h after minipump removal by measuring specific withdrawal signs. Animals from the abstinent group showed clear withdrawal signs such as hostility on handling and weight loss. Plasma and brain disposition and pharmacodynamics of methadone were evaluated after a 0.35 mg/kg i.v. bolus dose administered 12 h after minipump removal. Plasma clearance, distribution clearance, and volume of distribution at steady-state were significantly decreased (P < 0.05) in the abstinent group. Plasma levels of alpha1-acid glycoprotein and plasma protein binding were significantly increased (P < 0.05) in the abstinent group. The estimates of pharmacokinetic parameters based on unbound plasma concentrations did not differ between groups, with the sole exception of the unbound apparent volume of distribution. The access of methadone to the brain was significantly faster (P < 0.05) in the abstinent group, although the extent of distribution in the brain was diminished in comparison with the control group. Analgesia recorded with tail-flick was used as the pharmacodynamic endpoint. Analgesic response and effect compartment concentrations of methadone were related by the sigmoidal Emax model. Estimates of C50 [steady-state plasma concentrations eliciting half of maximum effect (Emax)]] based on unbound concentrations did not differ between groups. On the other hand, the estimate of Emax had decreased by 65% in the abstinent group

Predicting circulating biomarker response and its impact on the survival of advanced melanoma patients treated with adjuvant therapy

Advanced melanoma remains a disease with poor prognosis. Several serologic markers have been investigated to help monitoring and prognostication, but to date only lactate dehydrogenase (LDH) has been validated as a standard prognostic factor biomarker for this disease by the American Joint Committee on Cancer. In this work, we built a semi-mechanistic model to explore the relationship between the time course of several circulating biomarkers and overall or progression free survival in advanced melanoma patients treated with adjuvant high-dose interferon-[Formula: see text]. Additionally, due to the adverse interferon tolerability, a semi-mechanistic model describing the side effects of the treatment in the absolute neutrophil counts is proposed in order to simultaneously analyze the benefits and toxic effects of this treatment. The results of our analysis suggest that the relative change from baseline of LDH was the most significant predictor of the overall survival of the patients. Unfortunately, there was no significant difference in the proportion of patients with elevated serum biomarkers between the patients who recurred and those who remained free of disease. Still, we believe that the modelling framework presented in this work of circulating biomarkers and adverse effects could constitute an additional strategy for disease monitoring in advance melanoma patients

Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effects of main active metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, in rats.

The pharmacokinetics and pharmacodynamics of the two main metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, were studied in rats. Pharmacodynamic endpoints evaluated were respiratory depression, measured as the change in arterial blood pCO(2), pO(2), and pH levels; and antinociception, measured by the tail-flick technique. The administration of 10 mg/kg (+)-O-desmethyltramadol in a 10-min i.v. infusion significantly altered pCO(2), pO(2), and pH values in comparison with baseline and lower-dose groups (P <.05). However, 2 mg/kg administered in a 10-min i.v. infusion was enough to achieve 100% antinociception without respiratory depression. Moreover, the beta-funaltrexamine pretreatment completely eliminated the antinociception of the 2-mg/kg dose, suggesting that such an effect is due to mu-opioid receptor activation. To describe and adequately characterize the in vivo antinociceptive effect of the drug, (+)-O-desmethyltramadol was given at different infusion rates of varying lengths (10-300 min). Pharmacokinetics was best described by a two-compartmental model. The time course of response was described using an effect compartment associated with a linear pharmacodynamic model. The estimates of the slope of the effect versus concentration relationship were significantly decreased (P <. 05) as the length of infusion was increased, suggesting the development of tolerance. Doses of up to 8 mg/kg (-)-O-desmethyltramadol given in 10-min i.v. infusion did not elicit either antinociception in the tail-flick test or respiratory effects. These in vivo results are in accordance with the opiate and nonopiate properties reported for these compounds in several in vitro studies

Modeling of the In Vivo Antinociceptive Interaction between an Opioid Agonist, (+)-O-Desmethyltramadol, and a Monoamine Reuptake Inhibitor, (—)-O-Desmethyltramadol, in Rats

The pharmacokinetic-pharmacodynamic (pk-pd) characterization of the in vivo antinociceptive interaction between (+)-O-desmethyltramadol [(+)-M1] and (-)-O-desmethyltramadol [(-)-M1], main metabolites of tramadol, was studied in three groups of rats. (+)-M1 and (-)-M1, both with different pd properties, were studied under steady-state and nonsteady-state conditions, depending on the group. Plasma drug concentration and antinociception were simultaneously measured in each animal by using an enantioselective analytical assay and the tail-flick test, respectively. Respiratory depression also was evaluated in another series of experiments according to the same experimental conditions. The pk behavior was similar for both enantiomers and no significant (P >.05) interaction between two compounds was found at this level. However, a significant (P .05) respiratory effects were seen during or after (+)-M1 and (-)-M1 administration

Pharmacokinetic–pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase-2, in rats

Background and purpose: This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats. Experimental approach: Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg-1 of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg-1 oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI. Results: A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT = LT0/(1 + MED). LT0 is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 mg·mL-1. Conclusions: The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics

Application of different methods to formulate PEG-liposomes of oxaliplatin: Evaluation in vitro and in vivo

In this work the film method (FM), reverse-phase evaporation (REV) and the heating method (HM) were applied to prepare PEG-coated liposomes of oxaliplatin with natural neutral and cationic lipids, respectively. The formulations developed with the three methods, showed similar physicochemical characteristics, except in the loading of oxaliplatin, which was statistically lower (P<0.05) using the HM. The incorporation of a semi-synthetic lipid in the formulation developed by FM, provided liposomes with a particle size of 115 nm associated to the lowest polydispersity index and the highest drug loading, 35%, compared to the other two lipids, suggesting an increase of the membrane stability. That stability was also evaluated according to the presence of cholesterol, the impact of the temperature, and the application of different cryoprotectans during the lyophilization. The results indicated long-term stability of the developed formulation, because after its intravenous in-vivo administration to HT-29 tumor bearing mice was able to induce an inhibition of tumor growth statistically higher (P < 0.05) than the inhibition caused by the free drug. In conclusion, the FM was the simplest method in comparison with REV and HM to develop in vivo stable and efficient PEG-coated liposomes of oxaliplatin with a loading higher than those reported for REV

The Influence of Age on the Dynamic Relationship Between End-Tidal Sevoflurane Concentrations and Bispectral Index

BACKGROUND: Age is an important determinant of the pharmacokinetic profile of inhaled anesthetics. The influence of age on the dynamic profile of sevoflurane's effect has not been well described. We performed this study to characterize the influence of age and other covariates on the dynamic relationship between sevoflurane end-tidal concentration (C(ET)) and its effect measured by bispectral index (BIS). METHODS: Fifty patients, aged 3-71 yr, scheduled for minor surgery were prospectively studied. The BIS and sevoflurane C(ET) were continuously measured during the study period. During maintenance of anesthesia and after stable BIS values of 60-65 were obtained, the inspired concentration of sevoflurane was increased to 5 vol % for 5 min or until BIS <40 and then decreased. The dynamic relationship between sevoflurane C(ET) and its effect as measured by BIS during this transition period were modeled with an inhibitory E(max) model using a population pharmacokinetic-pharmacodynamic approach with NONMEM V. A predictive check method was used to validate the final model. RESULTS: The sensitivity to sevoflurane's effect as measured by BIS expressed in the C(50) [steady-state C(ET) eliciting half of maximum response (I(max))] increased with age. The speed of change of sevoflurane's effect, expressed as the effect-site equilibration half-life (t(1/2) k(e0)), increased at older ages. The predictive check analysis confirmed the adequacy of the model. CONCLUSIONS: Age significantly affects the dynamic relationship between sevoflurane C(ET) and its effect measured with BIS

Machine Learning Analysis of Individual Tumor Lesions in Four Metastatic Colorectal Cancer Clinical Studies: Linking Tumor Heterogeneity to Overall Survival

Total tumor size (TS) metrics used in TS models in oncology do not consider tumor heterogeneity, which could help to better predict drug efficacy. We analyzed individual target lesions (iTLs) of patients with metastatic colorectal carcinoma (mCRC) to determine differences in TS dynamics by using the ClassIfication Clustering of Individual Lesions (CICIL) methodology. Results from subgroup analyses comparing genetic mutations and TS metrics were assessed and applied to survival analyses. Data from four mCRC clinical studies were analyzed (1781 patients, 6369 iTLs). CICIL was used to assess differences in lesion TS dynamics within a tissue (intra-class) or across different tissues (inter-class). First, lesions were automatically classified based on their location. Cross-correlation coefficients (CCs) determined if each pair of lesions followed similar or opposite dynamics. Finally, CCs were grouped by using the K-means clustering method. Heterogeneity in tumor dynamics was lower in the intra-class analysis than in the inter-class analysis for patients receiving cetuximab. More tumor heterogeneity was found in KRAS mutated patients compared to KRAS wild-type (KRASwt) patients and when using sum of longest diameters versus sum of products of diameters. Tumor heterogeneity quantified as the median patient’s CC was found to be a predictor of overall survival (OS) (HR = 1.44, 95% CI 1.08–1.92), especially in KRASwt patients. Intra- and inter-tumor tissue heterogeneities were assessed with CICIL. Derived metrics of heterogeneity were found to be a predictor of OS time. Considering differences between lesions’ TS dynamics could improve oncology models in favor of a better prediction of OS

Intrahepatic injection of recombinant adeno-associated virus serotype 2 overcomes gender-related differences in liver transduction

The liver is an attractive organ for gene therapy because of its important role in many inherited and acquired diseases. Recombinant adeno-associated viruses (rAAVs) have been shown to be good candidates for liver gene delivery, leading to long-term gene expression. We evaluated the influence of the route of administration on rAAV-mediated liver transduction by comparing levels of luciferase expression in the livers of male and female mice after injection of rAAV serotype 2, using three different routes of administration: intravenous (IV), intraportal (IP), or direct intrahepatic (IH) injection. To determine transgene expression we used a noninvasive optical bioluminescence imaging system that allowed long-term in vivo analysis. After IV injection dramatic differences in liver transgene expression were observed, depending on gender. When IP injection was used the differences were reduced although they were still significant. Interestingly, direct intrahepatic injection of rAAV vectors was associated with the fastest and strongest onset of luciferase expression. Moreover, no gender differences in liver transduction were observed and luciferase expression was confined to the site of injection. Thus, direct intrahepatic injection of rAAV offers specific advantages, which support the potential of this route of administration for future clinical applications

Population Pharmacokinetic Analysis of Lanreotide Autogel® in Healthy Subjects: evidence for injection interval of up to 2 months

BACKGROUND AND OBJECTIVE: Lanreotide is a somatostatin analogue used for the treatment of acromegaly and neuroendocrine tumours. The objective of this study was to develop a pharmacokinetic model for the sustained-release formulation lanreotide Autogel after deep subcutaneous administration in healthy subjects, and to explore the potential effect of covariates, especially sex and dose. SUBJECTS AND METHODS: This was an open-label, single-centre, randomized, dose-ranging, parallel-group study, with a follow-up period of 4-7 months following drug administration in healthy subjects. Healthy Caucasian subjects aged 18-45 years were included. Subjects received a rapid intravenous bolus of 7 microg/kg of an immediate-release formulation of lanreotide (lanreotide IRF). After a 3-day washout period, participants were randomized to receive a single deep subcutaneous injection of lanreotide Autogel at a dose of 60, 90 or 120 mg. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Blood samples for lanreotide determination were obtained during the first 12 hours after the intravenous bolus injection and during the 4- to 7-month follow-up period after deep subcutaneous administration of lanreotide Autogel. Data after intravenous and subcutaneous administration were fitted simultaneously using the population approach in NONMEM((R)) version VI software. The model was validated externally using data from patients with acromegaly. RESULTS: In total, 50 healthy subjects (24 women and 26 men) received a single intravenous dose of lanreotide IRF. Of these, 38 subjects (18 women and 20 men) received a single subcutaneous dose of lanreotide Autogel 3 days after intravenous lanreotide IRF. The disposition of lanreotide was described by a three-compartment open model. The estimates of the total volume of distribution and serum clearance were 15.1 L and 23.1 L/h, respectively. The estimates of interindividual variability were 0.05). CONCLUSIONS: Population analysis allows a full description of the disposition of lanreotide after rapid intravenous bolus administration of lanreotide IRF (7 microg/kg) and the pharmacokinetics of lanreotide Autogel after a single deep subcutaneous injection (60, 90 or 120 mg) in healthy subjects. The model-based simulations provide support for the feasibility of extending the dosing interval for lanreotide Autogel to 56 days when given at 120 mg. The absorption profile of lanreotide Autogel was independent of the dose and was not affected by sex