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ABSTRACT: PURPOSE: To develop a semi-mechanistic population pharmacokinetic/pharmacodynamic (PKPD) model for the selective bradycardic agent cilobradine describing simultaneously the heart rate (HR) measured at rest and just after the end of exercise sharing the same set of PKPD parameters. METHODS: Healthy subjects received cilobradine orally once daily over 2 weeks at 0.25-5 mg doses or placebo. Plasma drug concentrations and HR were measured at rest and following 3 min of exercise over the entire study period. PK and HR data were analyzed using the population approach with NONMEM VII. RESULTS: Plasma disposition of cilobradine was described with a three compartment model. Cilobradine showed dose proportional and time independent pharmacokinetics. HR response was drug concentration dependent and appeared with a significant delay with respect to PK profiles, a phenomenon modeled using two transit compartments. Perturbation in HR at rest as a consequence of exercise was described assuming that physiological processes controlling cardiac frequency were constantly increased over the period of exercise only. CONCLUSIONS: The selected model provides a useful modeling tool for cases where the PD response measured is the result of a temporal experimental induced perturbation.
Pharmaceutical Research 12/2012; · 4.09 Impact Factor
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ABSTRACT: The model-based approach was undertaken to characterize the interaction between the peripheral and central antinociceptive effects exerted by lumiracoxib. The effects of intraplantar and intrathecal administrations and of fixed ratio combinations of lumiracoxib simultaneously administered by these two routes were evaluated using the formalin test in rats. Pain-related behavior data, quantified as the number of flinches of the injected paw, were analyzed using a population approach with NONMEM 7. The pain response during the first phase of the formalin test, which was insensitive to lumiracoxib, was modeled using a monoexponential decay. The second phase, which was sensitive to lumiracoxib, was described incorporating synthesis and degradation processes of pain mediators that were recruited locally after tissue injury. Upregulation at the local level and in the central nervous system (CNS) was set to be proportional to the predicted levels of pain mediators in the local (injured) compartment. Results suggest a greater role of upregulated COX-2(Local) in generating the pain response compared to COX-2(CNS). Drug effects were described as inhibition of upregulated COX-2. The model adequately described the time course of nociception after formalin injection in the absence or presence of lumiracoxib administered locally and/or spinally. Data suggest that the overall response is the additive outcome of drug effects at the peripheral and central compartments, with predominance of peripheral mechanisms. Application of modeling opens new perspectives for understanding the overall mechanism of action of analgesic drugs.
The AAPS Journal 09/2012; 14(4):904-14. · 5.09 Impact Factor
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Iñaki F Trocóniz,
Josep-María Cendrós,
Elena Soto,
Joan Pruñonosa,
Ana Perez-Mayoral,
Concepción Peraire,
Paola Principe,
Patrick Delavault,
Frédérique Cvitkovic,
Thierry Lesimple,
Rosendo Obach
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ABSTRACT: To characterize the pharmacokinetic profile of elomotecan, a novel homocamptothecin analog, evaluate the dose-limiting toxicities, and establish the relationship between exposure and toxicity in the first Phase I study in patients with advanced malignant solid tumors. Preliminary antitumor efficacy results are also provided.
Elomotecan was administered as a 30-min intravenous infusion at doses ranging from 1.5 to 75 mg once every 3 weeks to 56 patients with advanced solid tumors. Plasma concentration data and adverse effects were modeled using the population approach.
Elomotecan showed linear pharmacokinetics, and clearance was decreased with age. The model predicts a 47 and 61 % reduction in CL for patients aged 60 and 80 years, respectively, when compared with younger patients (30 years). Neutropenia represented the dose-limiting toxicity. The maximum tolerated dose and the recommended dose (RD) were 75 and 60 mg, respectively. Elomotecan elicited a 20, 5, 2, and 2 % severe (grade 4) neutropenia, asthenia, nausea, and vomiting at the RD, respectively. Of the subjects in the RD cohort, 41.7 % had a stable disease mean duration of 123.6 ± 43.4 days.
The pharmacokinetic parameters and the toxicity pattern of elomotecan suggest that this novel homocamptothecin analog should be further explored in the clinical setting using a dose of 60 mg administered as a 30-min intravenous infusion, once every 3 weeks.
Cancer Chemotherapy and Pharmacology 06/2012; 70(2):239-50. · 2.83 Impact Factor
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ABSTRACT: 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.
European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 02/2012; 81(2):273-80. · 3.15 Impact Factor
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ABSTRACT: To elucidate whether a dose of 2 g cefoxitin as a prophylactic agent in patients undergoing elective colorectal surgery is able to maintain free drug concentrations above the minimum inhibitory concentration of the microorganisms involved in surgical site infection.
This was a prospective study involving 56 patients electively undergoing rectal or colon surgery. All plasma concentration-time data were analyzed simultaneously using the population approach to estimate population pharmacokinetic parameters and study the influence of the subjects' demographic characteristics, disease status, surgical procedure, and clinical laboratory values on the pharmacokinetic properties of cefoxitin.
A one-compartment open model was chosen to describe plasma concentrations of cefoxitin. Since cefoxitin is eliminated almost entirely via the kidney, creatinine clearance was identified as a covariate of cefoxitin clearance. The relationship between total cefoxitin clearance (CL) and creatinine clearance (CL(CR)) was best described using a nonlinear model [CL = 11.5 × (CL(CR)/77)(0.52)]. The population apparent volume of distribution was 12 L. Computer simulations carried out to determine the probability to maintain free plasma concentrations above 8 mg/L (the concentration threshold for susceptible bacteria) 2 h after drug administration revealed that this probability decreased from 84% in patients with a CL(CR) of 40 mL/min to 28% in patients with a CL(CR) of 100 mL/min.
To ensure cefoxitin target concentrations during surgery, we recommend that cefoxitin be administered every 1.5 h in patients with a CL(CR) ≥ 60 mL/min and every hour if the CL(CR) is ≥ 100 mL/min. Administration by continuous infusion preceded by a bolus injection should also be considered.
European Journal of Clinical Pharmacology 01/2012; 68(5):735-45. · 2.85 Impact Factor
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ABSTRACT: Flibanserin is being developed for treating hypoactive sexual desire disorder in women; the main side effect is sedation. The analysis objective was to relate flibanserin plasma concentrations with acute sedative effects using a population pharmacokinetic/pharmacodynamic (PK/PD) model.
The population model was developed with NONMEM based on data from 24 healthy volunteers. "Drowsiness" was serially assessed by a Visual Analogue Scale (VAS) on a baseline day and after morning oral administration of 100 mg flibanserin together with PK sampling.
PK was best described by a three-compartment disposition model and transit compartments accounting for the lag time in absorption. VAS "drowsiness" baseline profiles were modeled using linear splines with three breakpoints located at clock times at first and last observation, and at the median of the observation time across subjects. The drug effect followed a sigmoidal E(MAX) model using predicted effect site concentrations (C(e)). The VAS vs. C(e) relationship was very steep and effect site and plasma concentration-time profiles were very similar thus suggesting little delay between the occurrence of maximum flibanserin plasma concentrations and drowsiness.
At effect site concentrations lower than ≈ 200 ng/mL that are reached approximately 4 h after administration, flibanserin shows hardly any effect on the VAS "drowsiness" scale.
Pharmaceutical Research 01/2012; 29(6):1518-29. · 4.09 Impact Factor
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ABSTRACT: Acromegaly arises from excessive levels of growth hormone (GH), many of whose effects are mediated by stimulation of secretion of insulin-like growth factor 1 (IGF-1). Synthetic somatostatin analogues inhibit GH secretion. The objective of the study was to develop a population pharmacodynamic model describing the relationship between serum concentrations of lanreotide (C(P)) and its GH and IGF-1 effects in patients with acromegaly receiving lanreotide Autogel (LA) at doses of 60, 90, or 120 mg by deep subcutaneous route every 28 days. Data were analyzed from 104 patients. The GH and IGF-1 profiles were fit simultaneously using the population approach with NONMEM. The GH vs C(P) and the IGF-1 vs GH relationships were described using inhibitory I(max) and E(max) models, respectively. Results indicated that lanreotide cannot abolish GH completely. C(P) levels of 3.4 ng/mL are required to achieve percentages of hormonal control (GH and IGF-1) of 21% and 36% in not treated and previously treated patients. If the focus is only GH, a C(P) of 3.4 ng/mL corresponds to 33% and 56% controlling rates. Simulations showed that there is a possible clinical benefit if the highest dose of 120 mg LA is administered to patients who are not well controlled by lower doses of LA.
The Journal of Clinical Pharmacology 05/2011; 52(4):487-98. · 2.91 Impact Factor
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ABSTRACT: The aim of this investigation was to compare the performance of a commonly used semi-mechanistic model for drug-related neutropenia with other semi-mechanistic models published in the literature.
After their implementation in NONMEM VI, five semi-mechanistic models were assessed using the pharmacokinetic and absolute neutrophil count data obtained from 95 patients with non-small cell lung cancer receiving either 200 mg on day 1 or 50 or 60 mg on days 1, 2 and 3 of a 21-day treatment course with the new Plk-1 inhibitor BI 2536. The model performance was compared by means of predictive (visual and numerical) checks, precision in the parameter estimates and objective function-based measures. Details of model parameterization, model stability and run times are also provided.
The time course of the drug plasma concentrations was described by a three compartment model with a first-order elimination rate. With respect to neutropenia, all models were successfully implemented in NONMEM and provided reasonable fits for the median (although not all models described all percentiles of the data well), and in general precise parameter estimates.
In the current evaluation performed in a single drug, none of the models showed superior performance compared to the most commonly used model first described by Friberg et al. (J Clin Oncol 20:4713-4721, 2002).
Cancer Chemotherapy and Pharmacology 04/2011; 68(6):1517-27. · 2.83 Impact Factor
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ABSTRACT: Acute otitis media is the most common respiratory tract infection in infancy and early childhood that is managed with antimicrobial agents. Ninety-three per cent of the cases diagnosed in Spain are treated with antibiotics, and Streptococcus pneumoniae and untypeable Haemophilus influenzae are the most frequently isolated pathogens. The aim of this work was to evaluate the usefulness of amoxicillin, amoxicillin/clavulanate and ceftriaxone for the empirical treatment of acute otitis media, looking at the pharmacokinetic variability and the antimicrobial susceptibility of paediatric strains of the two main pathogens responsible for AOM in Spain, Streptococcus pneumoniae and Haemophilus influenzae.
Free-drug plasma concentrations were simulated and the probability of target attainment at each minimum inhibitory concentration and the cumulative fraction of response (CFR) were determined. Microbiological susceptibility information was extracted from SAUCE 3 surveillance.
CFR with amoxicillin varied from 83% to 96% against S. pneumoniae and from 78% to 86% against H. influenzae. CFR was always >85% with amoxicillin/clavulanate. With the 3-day ceftriaxone regimen, the probability of achieving free concentrations above MIC at 72 hours significantly increased compared to the single dose, with which CFR ranged from 70% to 84%.
High-dose amoxicillin (at least 80 mg/kg/day) should be the first-line therapy in uncomplicated infections, whereas amoxicillin/clavulanate (40 mg/kg/day) should be the choice when additional coverage for H. influenzae is desired. Administration of 3 daily doses of ceftriaxone increases bacteriological eradication probability when compared with one-day regimen, although additional clinical evaluations are necessary to establish the best target attainment with ceftriaxone.
Enfermedades Infecciosas y Microbiología Clínica 02/2011; 29(3):167-73. · 1.49 Impact Factor
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ABSTRACT: (1) To describe the neutropenic response of BI 2536 a polo-like kinase 1 inhibitor in patients with cancer using a semi-mechanistic model. (2) To explore by simulations (a) the neutropenic effects for the maximum tolerated dose (MTD) and the dose at which dose-limiting toxicity occurred, (b) the possibility to reduce the cycle duration without increasing neutropenia substantially, and (c) the impact of the initial absolute neutrophil count (ANC) on the degree of neutropenia for different doses.
BI 2536 was administered as intravenous infusion over 60 min in the dose range from 25 to 250 mg. Three different administration schedules were explored: (a) day 1, (b) days 1, 2, and 3 or (c) days 1 and 8 within a 3 week treatment cycle. BI 2536 plasma concentrations and ANC obtained during the first treatment cycle from 104 patients were analysed using the population approach with NONMEM VI.
Neutropenia was described by a semi-mechanistic model resembling proliferation at the stem cell compartment, maturation, degradation, and homeostatic regulation. BI 2536 acts decreasing proliferation rate. Simulations showed that (1) all MTD doses showed an acceptable risk of neutropenia, (2) when BI 2536 is given as 200 mg single administration, cycle duration can be reduced from 3 to 2 weeks, and (3) baseline ANC might be considered to individualise the dose of BI 2536.
A semi-mechanistic population model was applied to describe the neutropenic effects of BI 2536. The model was used for simulations to support further clinical development.
Cancer Chemotherapy and Pharmacology 09/2010; 66(4):785-95. · 2.83 Impact Factor
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Elena Soto,
Ron J Keizer, Iñaki F Trocóniz,
Alwin D R Huitema,
Jos H Beijnen,
Jan H M Schellens,
Jantien Wanders,
Josep María Cendrós,
Rosendo Obach,
Concepción Peraire,
Lena E Friberg,
Mats O Karlsson
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ABSTRACT: In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials.
Investigational New Drugs 05/2010; 29(5):984-95. · 3.36 Impact Factor
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ABSTRACT: Microdialysis is used to determine the concentrations of substances in the extracellular fluid of tissues. To date, it has not been used to measure rocuronium concentrations in human muscle. We determined the ability of microdialysis to recover rocuronium from muscle interstitial tissue for the purpose of assessing the effect of chronic phenytoin therapy on muscle concentrations of rocuronium.
In a first phase, an in vitro study was performed to establish the ability of the assay to recover rocuronium. In a second phase, 17 patients undergoing brain surgery were enrolled. Eight patients were on chronic phenytoin therapy and the remaining 9 patients were not taking any antiepileptic agent (controls). Rocuronium was administered intravenously and muscle tissue samples for microdialysis were collected.
The recovery rate of the in vitro assay was 36% at a pump rate of 1 microL/min. Rocuronium muscle tissue concentrations could be measured in 25 microdialysate samples. Rocuronium concentrations were similar in patients treated with phenytoin and in controls, although the doses required to obtain a similar effect were significantly higher in patients on chronic phenytoin treatment.
Quantification of drug concentrations in muscle by means of microdialysis is technically feasible in the clinical setting and it might help in studying pharmacologic mechanisms of drug action. Based on our results the decrease in the degree of effect of rocuronium in the presence of chronic phenytoin therapy might seem to be due mainly to a pharmacokinetic mechanism.
Journal of neurosurgical anesthesiology 04/2010; 22(2):163-9. · 2.41 Impact Factor
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ABSTRACT: Since gene therapy started over 20 years ago, more than one-thousand clinical trials have been carried out. Nonviral vectors present interesting properties for their clinical application, but their efficiency in vivo is relatively low, and further improvements in these vectors are needed. Elucidating how nonviral vectors behave at the intracellular level is enlightening for vector improvement and optimization. Model-based approach is a powerful tool to understand and describe the different processes that gene transfer systems should overcome inside the body. Model-based approach allows for proposing and predicting the effect of parameter changes on the overall gene therapy response, as well as the known application of the pharmacokinetic/pharmacodynamic modelling in conventional therapies. The objective of this paper is to critically review the works in which the time-course of naked or formulated DNA have been quantitatively studied or modelled.
Pharmaceutical Research 04/2010; 27(8):1487-97. · 4.09 Impact Factor
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ABSTRACT: To develop a semi-physiological-based model describing simultaneously the time course of immature and mature B-lymphocytes after topotecan (TPT) administration to tumor-bearing rats.
Twenty-four tumor-bearing BDIX male rats received a single 6 mg/kg intra-peritoneal dose of TPT or saline. Mature and immature B-cell levels were measured every two days during three weeks and showed a very different temporal pattern. Both B-cell populations declined rapidly, reaching the nadir at 3-4 days after TPT administration; however, mature cells returned to baseline at day 8, while immature B-cells stayed at nadir until day 9 instead. Data were modeled using the population approach with NONMEM VI.
The model developed maintains the proliferation, maturation and degradation elements of previous published models for myelosuppresion. In order to describe the rapid recovery of mature cells, it includes a peripheral compartment providing a constant supply of mature cells to the bloodstream.
The major contribution of the model is its new structure and the dynamical consequences, demonstrating an independent behavior between mature and immature B-cells during recovery. The final model could represent a good basis for the optimization of cytotoxic drugs oriented to attain a maximum antitumor efficacy while minimizing hematological toxicity.
Pharmaceutical Research 03/2010; 27(3):431-41. · 4.09 Impact Factor
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ABSTRACT: To establish an in vitro-in vivo level A correlation (IVIVC) for pramipexole slow-release formulations.
The IVIVC was developed based on data from an immediate-release (IR) and three slow-release (SR) formulations of pramipexole; a fourth SR formulation was used for validation purposes. In vitro dissolution profiles were obtained from all SR formulations. Fifteen volunteers received all pramipexole formulations in a randomized cross-over trial. Data were analyzed using the population modelling approach as implemented in NONMEM VI.
Dissolution profiles of the SR formulations were described by the Weibull model. The pharmacokinetics of the IR formulation were described by a two-compartment disposition model with first-order absorption. Difference between the in vivo and in vitro estimates of the release rate constants (k(d)) from the Weibull function suggests the release process occurs faster in vivo. Pharmacokinetic profiles for SR formulations were described based on the in vitro release model with k(d) increased in 0.058 h(-1) and the population pharmacokinetic model developed from the IR formulation.
A level A IVIVC was established and evaluated for the pramipexole SR formulations, which can be used in the future as a surrogate to avoid certain bioequivalence studies.
Pharmaceutical Research 02/2010; 27(2):340-9. · 4.09 Impact Factor
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ABSTRACT: The aim of this conceptual framework paper is to contribute to the further development of the modelling of effects of drugs or toxic agents by an approach which is based on the underlying physiology and pathology of the biological processes. In general, modelling of data has the purpose (1) to describe experimental data, (2a) to reduce the amount of data resulting from an experiment, e.g. a clinical trial and (2b) to obtain the most relevant parameters, (3) to test hypotheses and (4) to make predictions within the boundaries of experimental conditions, e.g. range of doses tested (interpolation) and out of the boundaries of the experimental conditions, e.g. to extrapolate from animal data to the situation in man. Describing the drug/xenobiotic-target interaction and the chain of biological events following the interaction is the first step to build a biologically based model. This is an approach to represent the underlying biological mechanisms in qualitative and also quantitative terms, thus being inherently connected in many aspects to systems biology. As the systems biology models may contain variables in the order of hundreds connected with differential equations, it is obvious that it is in most cases not possible to assign values to the variables resulting from experimental data. Reduction techniques may be used to create a manageable model which, however, captures the biologically meaningful events in qualitative and quantitative terms. Until now, some success has been obtained by applying empirical pharmacokinetic/pharmacodynamic models which describe direct and indirect relationships between the xenobiotic molecule and the effect, including tolerance. Some of the models may have physiological components built in the structure of the model and use parameter estimates from published data. In recent years, some progress toward semi-mechanistic models has been made, examples being chemotherapy-induced myelosuppression and glucose-endogenous insulin-antidiabetic drug interactions. We see a way forward by employing approaches to bridge the gap between systems biology and physiologically based kinetic and dynamic models. To be useful for decision making, the 'bridging' model should have a well founded mechanistic basis, but being reduced to the extent that its parameters can be deduced from experimental data, however capturing the biological/clinical essential details so that meaningful predictions and extrapolations can be made.
Basic & Clinical Pharmacology & Toxicology 08/2009; 106(1):2-12. · 2.18 Impact Factor
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ABSTRACT: A biopharmaceutic-pharmacodynamic model is proposed to characterize the antiproliferative effect of controlled release formulations of cisplatin in cancer cell culture. In vitro release profiles from PLGA [poly(d,l-lactide-co-glycolide)] systems were described using a model based on the characterization of two drug release processes: diffusion and matrix degradation. Cytotoxicity data available consisting of the number of survival cells after a continuous exposure to free or encapsulated cisplatin were simultaneously modeled under the Gompertz framework incorporating the drug release model. The release model parameters showed that particle size was inversely related to the diffusion rate. The antiproliferative effect was described as a function of drug concentrations and exposure times. Two mechanisms were included: (i) an inhibition of cell proliferation, where cisplatin released from PLGA systems was mainly involved, followed by (ii) stimulation of cell death due to cisplatin activity and mediated by the activation of a signal transduction process. Cell accumulation in G2/M phase of the cell cycle followed by the activation of caspase-3, supported both mechanisms. The selected drug-effect model and its model parameters were independent from the formulation, which makes it a suitable tool to explore in silico, alternative in vitro and in vivo scenarios to optimize these delivery systems.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 07/2009; 37(3-4):341-50. · 2.61 Impact Factor
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ABSTRACT: Suppressed expression of transgene is a major obstacle in gene therapy. Understanding of the mechanisms involved in expression and silencing of exogenous genes is required to overcome gene therapy hurdles.
To develop a semi-mechanistic model describing the effects of transgenes over the activity of an expression cassette.
Twelve Balb/c mice received 40microg of plasmid DNA. Animals were assigned to one of the following treatments: (I) 20microg of the plasmid expressing luciferase (pEF-Luc) and 20microg of "empty" plasmid; (II) pEF-Luc (20microg) and 20microg of plasmid expressing murine interferon alpha (IFNalpha); and (III) pEF-Luc (20microg), and 20microg of plasmid expressing beta-galactosidase (pCMVbeta). The expression of luciferase over time, quantified by a noninvasive method, was used as a measured of pEF-Luc activity and modelled using NONMEM.
The selected model suggests the co-existence of two forms of active DNA differing in their transcription efficiencies. The core model was expanded to describe reversible and irreversible silencing processes, induced by the coexpression of IFNalpha or beta-galactosidase, respectively.
Coupling noninvasive in vivo imaging and mathematical modelling allows quantitative description of gene transfer, providing a tool to select the best regulatory elements to construct a therapeutic expression cassette.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 07/2009; 37(3-4):418-26. · 2.61 Impact Factor
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ABSTRACT: 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.
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.
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 <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).
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.
Clinical Pharmacokinetics 01/2009; 48(1):51-62. · 5.40 Impact Factor
