María J. Garrido

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.

Pharmacodynamics of cisplatin-loaded PLGA nanoparticles administered to tumor-bearing mice

Biodegradable poly (lactic-co-glycolic) acid (PLGA) nanoparticles incorporating cisplatin have been developed to evaluate its in vivo efficacy in tumor-bearing mice. In vitro study proved two mechanisms of action for cisplatin depending on the dose and the rate at which this dose is delivered. In vivo study, 5mg/kg of cisplatin nanoparticles administered to mice, exhibited a tumor inhibition similar to free cisplatin, although the area under cisplatin concentration-time curve between 0 and 21days (AUC(0-21)) had lower value for the formulation than for drug solution (P<0.05). This result was associated with a higher activation of apoptosis in tumor, mediated by caspase-3, after nanoparticles administration. Toxicity measured as the change in body weight, and blood urea nitrogen (BUN) plasma levels showed that cisplatin nanoparticles treatment did not induce significant changes in both parameters compared to control, while for free drug, a statistical (P<0.01) increase was observed. In addition, a good correlation was found between time profiles of tumor volume and vascular endothelial growth factor (VEGF) plasma levels, suggesting that its expression could help to follow the efficacy of the treatment. Therefore, the PLGA nanoparticles seem to provide a promising carrier for cisplatin administration avoiding its side effects without a reduction of the efficacy, which was consistent with a higher activation of apoptosis than free drug.

Liposomes, a promising strategy for clinical application of platinum derivatives

Introduction: Liposomes represent a versatile system for drug delivery in various pathologies. Platinum derivatives have been demonstrated to have therapeutic efficacy against several solid tumors. But their use is limited due to their side effects. Since liposomal formulations are known to reduce the toxicity of some conventional chemotherapeutic drugs, the encapsulation of platinum derivatives in these systems may be useful in reducing toxicity and maintaining an adequate therapeutic response. Areas covered: This review describes the strategies applied to platinum derivatives in order to improve their therapeutic activity, while reducing the incidence of side effects. It also reviews the results found in the literature for the different platinum-drugs liposomal formulations and their current status. Expert opinion: The design of liposomes to achieve effectiveness in antitumor treatment is a goal for platinum derivatives. Liposomes can change the pharmacokinetic parameters of these encapsulated drugs, reducing their side effects. However, few liposomal formulations have demonstrated a significant advantage in therapeutic terms. Lipoplatin, a cisplatin formulation in Phase III, combines a reduction in the toxicity associated with an antitumor activity similar to the free drug. Thermosensitive or targeted liposomes for tumor therapy are also included in this review. Few articles about this strategy applied to platinum drugs can be found in the literature.

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 with the lowest polydispersity index and the highest drug loading, 35%, compared with the other two lipids, suggesting an increase in the membrane stability. That stability was also evaluated according to the presence of cholesterol, the impact of the temperature, and the application of different cryoprotectants 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.

Efficient gene delivery by EGF-lipoplexes in vitro and in vivo

AIMS In this work, we have evaluated the ability of targeted lipoplexes to enhance transgene expression in EGF receptor (EGFR) overexpressing tumor cells by using lipoplexes. MATERIALS & METHODS We prepared DOTAP/cholesterol liposomes modified with EGF at 0.5/1, 1/1, 2/1 and 5/1 lipid/DNA (+/-) charge ratio by sequentially mixing the liposomes with the ligand and adding the reporter or the therapeutic plasmid gene, pCMVLuc (pVR1216) or pCMVIL12, respectively. HepG2, DHDK12proB and SW620 cells were used for in vitro experiments, which were performed in the presence of 60% serum. RESULTS The characterization of EGF-lipoplexes indicated a size close to 300 nm and a variable net surface charge as a function of the amount of EGF associated to the cationic liposomes. EGF-lipoplexes, which showed an increased transfection activity, were positively charged, noncytotoxic and highly effective in protecting DNA from DNase I attack. Transfection activity in vitro resulted in an enhancement in the luciferase and IL-12 expression by EGF-lipoplexes compared with those without ligand (plain-lipoplexes) and to naked DNA. The results observed in SW620 cells, which are deficient in EGFR, confirmed that DNA uptake was predominantly via EGFR-mediated endocytosis. In vivo transfection activity was confirmed by luciferase imaging in living mice. Bioluminiscence could be detected mainly in the lung with a maximum signal 24 h after application. The resulting EGF-lipoplexes significantly increased the level of gene expression in mice compared with control or naked DNA. CONCLUSION These findings indicate that these nanovectors may be an adequate alternative to viral vectors for gene therapy.

Pharmacokinetic-Pharmacodynamic Analysis of the EEG Effect of Alfentanil in Rats Followingβ-Funaltrexamine-Induced μOpioid Receptor “Knockdown”In Vivo

AbstractPurpose. The objective of this investigation was to determine theinfluence of pre-treatment with the irreversible μ-opioid receptorantagonist β-funaltrexamine (β-FNA) on thepharmacokinetic-pharmacodynamic (PK/PD) relationship of alfentanil in rats. Methods. The PK/PD correlation of alfentanil (2 mg.kg−1intravenously in 20 min) was determined in chronically instrumented ratsusing amplitudes in the 0.5–4.5 Hz frequency band of the EEG aspharmacodynamic endpoint. β-FNA was administered intravenously(10 mg.kg−1) either 35 min or 24 h prior to the PK/PD experiments. Results. Pre-treatment with β-FNA had no influence on thepharmacokinetics of alfentanil. The in vivo concentration-EEG effectrelationships, however, were steeper and shifted towards higher concentrationswith no difference between the 35-min and the 24-h pre-treatmentgroups. Analysis of the data on basis of the operational model agonismrevealed that the observed changes could be explained by a 70–80%reduction in alfentanil efficacy in β-FNA pre-treated rats. This isconsistent with results from an in vitro receptor bioassay showing a40–60% reduction in the number of specific μ-opioid binding sites inthe brain. Conclusions. This investigation confirms the validity of a previouslypostulated mechanism-based PK/PD model for the effect of syntheticopiates in rats.

Population pharmacokinetic analysis of lanreotide Autogel in healthy subjects : evidence for injection interval of up to 2 months.

Background and objectiveLanreotide 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 sustainedrelease formulation lanreotide Autogel® after deep subcutaneous administration in healthy subjects, and to explore the potential effect of covariates, especially sex and dose.Subjects and methodsThis 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 μg/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 analysisBlood 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® version VI software. The model was validated externally using data from patients with acromegaly.ResultsIn 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 <40%. To evaluate lanreotide Autogel® pharmacokinetics, the absorption rate was modelled to decrease exponentially as a function of the natural logarithm of time. The absolute bioavailability after deep subcutaneous administration of lanreotide Autogel® was 63%. The rate of absorption and bioavailability of lanreotide Autogel® were independent of the administered dose in the range from 60 to 120 mg, and no significant effect of covariates (sex, dose, age or bodyweight) was found (p > 0.05).ConclusionsPopulation analysis allows a full description of the disposition of lanreotide after rapid intravenous bolus administration of lanreotide IRF (7 μg/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.

Efficient serum-resistant lipopolyplexes targeted to the folate receptor

In this work, we have developed and evaluated a new targeted lipopolyplex (LPP), by combining polyethylenimine (PEI), 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP)/Chol liposomes, the plasmids pCMVLuc/pCMVIL-12, and the ligand folic acid (FA), able to transfect HeLa and B16-F10 cells in the presence of very high concentration of serum (60% FBS). These complexes (Fol-LPP) have a net positive surface charge. The combination of folic acid with lipopolyplexes also enhanced significantly the transfection activity of the therapeutic gene interleukin-12 (IL-12), without any significant cytotoxicity. The specificity of the folate receptor (FR)-mediated gene transfer was corroborated by employing a folate receptor deficient cell line (HepG2). This formulation improved gene delivery showed by conventional lipoplexes or polyplexes resulting an efficient, simple, and nontoxic method for gene delivery of therapeutic genes in vitro and very probably in vivo.

Hematological response of topotecan in tumor-bearing rats: modeling of the time course of different cellular populations.

AbstractPurpose. To evaluate the hematotoxicity of topotecan (TPT) in tumor-bearing rats by a pharmacokinetic/pharmacodynamic approach. Methods. DHD/K12-PROb cells were subcutaneously injected in syngenic BD-IX rats. Three weeks after implantation of cells, animals received saline or 6 mg/kg i.p. dose of TPT (group II). Thirty days later, group II was divided into groups IIA receiving a single administration of 6 mg/kg and IIB treated with 3 mg/kg for 2 consecutive days. Leukocytes, neutrophils, and mature lymphocytes were measured in peripheral blood every 48 h for 45 days after first drug administration. Pharmacokinetic characteristics of TPT were also explored. Results. Disposition of TPT in plasma was best described with a two-compartment model. A semiphysiological model discriminating between system-related and drug-effects parameters, such as the mean cell maturation or transition time (MTT) and the linear concentration-dependent inhibitory effects on cell proliferation (Slp), described adequately the time course of hematotoxicity. The estimates of MTT and Slp for the three cell populations ranged from 1.89 to 2.18 days and from 0.01 to 0.039 ml/ng, respectively. Conclusion. The time course of the hematotoxicity induced after two cycles of chemotherapy with TPT in tumor-bearing rats could be described by a semiphysiological model.

Review on modeling anti-antibody responses to monoclonal antibodies

Monoclonal antibodies (mAbs) represent a therapeutic strategy that has been increasingly used in different diseases. mAbs are highly specific for their targets leading to induce specific effector functions. Despite their therapeutic benefits, the presence of immunogenic reactions is of growing concern. The immunogenicity identified as anti-drug antibodies (ADA) production due to the continuous administration of mAbs may affect the pharmacokinetics (PK) and/or the pharmacodynamics (PD) of mAbs administered to patients. Therefore, the immunogenicity and its clinical impact have been studied by several authors using PK modeling approaches. In this review, the authors try to present all those models under a unique theoretical mechanism-based framework incorporating the main considerations related to ADA formation, and how ADA may affect the efficacy or toxicity profile of some therapeutic biomolecules.