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Osteoarthritis is treated with COX or fosfolipase A2 inhibitors such as carprofen, a propionic acid NSAID. The enhancement of its action over the articular cartilage is mandatory to facilitate its therapeutic application. Drug uptake into... more
Osteoarthritis is treated with COX or fosfolipase A2 inhibitors such as carprofen, a propionic acid NSAID. The enhancement of its action over the articular cartilage is mandatory to facilitate its therapeutic application. Drug uptake into the cartilage requires high synovial fluid concentrations, anticipating its rapid distribution towards bloodstream. Thus, intraarticular administration improves local targeting of the drug, lining with the site of action. A pharmacokinetic study in rabbits has been performed to evaluate carprofen nanoparticles after intraarticular administration. Pharmacokinetic analysis of plasma profiles through a modelling approach, has demonstrated the rapid distribution of drug outside of synovial chamber but mainly remaining in plasma. The data modelling has demonstrated the existence of two release-absorption processes when the nanoparticles are administered in the synovial space. Additionally, results are predictive of the PK profile of some other species such as cat, dogs or humans.
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The "in vitro" transdermal absorption characteristics of various antiemetic drugs (Alizapride, Bromopride, Clebopride, Domperidone, Metoclopramide, Metopimazine) were studied. Franz diffusion glass cells were used. The skin of... more
The "in vitro" transdermal absorption characteristics of various antiemetic drugs (Alizapride, Bromopride, Clebopride, Domperidone, Metoclopramide, Metopimazine) were studied. Franz diffusion glass cells were used. The skin of hairless rat was used as a permeation membrane. The following parameters were evaluated for each drug: Permeation constant (Kp), lag time (T1), and flux (J). A comparative study of permeation characteristics of the assayed drugs was carried out. Their potential use as transdermal dosage forme was also studied. Based on the results, Bromopride and Clebopride have showed the best "in vitro" permeation profile to be used by transdermal administration.
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Background Infliximab (IFX) is a chimeric anti-TNFα monoclonal antibody used in the treatment of psoriasis. Due to the large interindividual variability in IFX, measurement of serum concentrations and correlation with disease activity and... more
Background Infliximab (IFX) is a chimeric anti-TNFα monoclonal antibody used in the treatment of psoriasis. Due to the large interindividual variability in IFX, measurement of serum concentrations and correlation with disease activity and different covariables could be useful for psoriasis management. Purpose The primary endpoint was to assess the relation between IFX trough levels (Cmin) and treatment efficacy. A secondary endpoint was to identify variables that could affect Cmin. Material and methods Prospective study of patients with psoriasis treated with IFX between October 2013 and August 2015 at a tertiary level hospital. Cmin (mg/L) and antibodies against IFX (ATI) were determined at steady state by enzyme linked immunosorbent assay (ELISA) (Promonitor). Data recorded: sex, weight, BSA, PASI, dose regimen and cigarette smoking. Dose adjusted Cmin values were statistically compared after log transformation. Statistical analysis was performed using SPSS v.19. Results 16 patients (25% women) were included. Median weight (kg) was 83.4 (Q1-Q3 65.5–93.8), median age (years) was 45 (Q1-Q3 38–54) years and median BSA (m2 ) was 1.96 (1.66–1.96). 40 serum samples were available for analysis. Median IFX dose was 5 mg/kg/8 weeks (range 4 mg/kg/8 weeks to 5 mg/kg/6 weeks). All patients receiving dose intensified IFX had a BSA >1.7 m2 . Median Cmin (mg/L) and dose adjusted Cmin (Cmin/D) (mg/L/mg/kg/month) were 1.59 (Q1-Q3 0.86–2.63) and 0.66 (Q1-Q3 0.37–1.1), respectively. 3 samples were positive for ATI. All patients who developed ATI had undetectable Cmin. Patients achieving PASI75 had a 23% higher Cmin/D compared with those not achieving PASI75. In patients with BSA >1.7 m2 , median Cmin and Cmin/D were 45% and 15% higher, respectively. Only 63% of patients with BSA >1.7 m2 achieved PASI75 (compared with 100% of patients with BSA ≤1.7, p = 0.026); patients with BSA >1.7 m2 and achieving PASI75 had a 36% higher Cmin/D compared with those not achieving PASI75. Median Cmin was 13.7% lower in cigarette smoking patients. Conclusion Higher Cmin and Cmin/D values were associated with better treatment response in all patients. Patients with SC ≥1.7 showed a tendency to lower treatment response. Lower Cmin was found in smoking patients. More studies with a higher number of patients are needed to define the target levels and assess the influence of covariables. No conflict of interest.
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Background Due to the large inter-patient pharmacokinetic (PK) and pharmacodynamic (PD) variability of infliximab (IFX), clinical outcomes in patients with inflammatory bowel disease (IBD) exhibit substantial inter-subject variability. An... more
Background Due to the large inter-patient pharmacokinetic (PK) and pharmacodynamic (PD) variability of infliximab (IFX), clinical outcomes in patients with inflammatory bowel disease (IBD) exhibit substantial inter-subject variability. An association between the rs1143634 C allele in interleukin 1β (IL1β) and higher serum IL1β concentrations and a lower response to IFX in patients with Crohn’s disease (CD) has been reported. Unravelling the impact of genetic polymorphisms on IFX exposure may help to refine therapy and improve clinical outcomes. Purpose To confirm the effect of the rs1143634 single nucleotide polymorphism (SNP) of IL1β on IFX exposure and PK in CD and ulcerative colitis (UC) patients. Material and methods Patients receiving IFX between July 2013 and December 2014 (n = 67) were genotyped for IL1 β polymorphisms. Associations between this SNP and pre-dose concentrations (Cmin, mg/L), dose adjusted Cmin (Cmin/D, mg/L/mg/month), area under the concentration-time curve (AUC, mg/h/L) and half-life (t1/2, days) at steady state were evaluated. Normalised by dose exposure parameters were statistically compared after log transformation. Pharmacokinetic and statistical analysis was performed using Nonmem 7.2 and SPSSv19, respectively. Results 67 patients were included (56.7% CC, 34.3% CT and 9.0% TT). All patients who developed antibodies against IFX (ATI) were carriers C (15% of carriers C). 60% of carrier C patients had Cmin <3 mg/L vs 17% of TT patients. Univariate analysis demonstrated that median Cmin was statistically lower in carrier C patients than in TT patients (CC1.38; CT 2.78; TT 6.40, p = 0.013). Cmin/D (CC 0.04; CT 0.069; TT 0.153, p = 0.019) and AUC (CC 21771; CT 27825; TT 35875, p = 0.023) were also significantly lower in C carriers than in TT patients. t1/2 was significantly lower in CC patients than in CT or TT (CC 9.5 vs CT and TT 13) patients (p = 0.038). Analysis of negative ATI patients (n = 59) showed that median Cmin (2.05 vs 6.40; p = 0.018) and Cmin/D (0.051 vs 0.135, p = 0.036) were significantly lower in C carriers than in TT patients. 55% of carriers C had a Cmin <3 mg/L versus 17% of TT patients when ATI was negative. Conclusion IL1β polymorphisms have a major influence on IFX exposure in IBD patients. The C allele was correlated with lower Cmin and Cmin/D. These results support the importance of IL1 β polymorphisms in IFX dose optimisation but further studies are needed. No conflict of interest.
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Background Infliximab (IFX) is a chimeric antitumour necrosis factor α monoclonal antibody used in rheumatoid arthritis (RA). It shows large interindividual variability in serum concentrations during treatment. The use of previously... more
Background Infliximab (IFX) is a chimeric antitumour necrosis factor α monoclonal antibody used in rheumatoid arthritis (RA). It shows large interindividual variability in serum concentrations during treatment. The use of previously developed population pharmacokinetic (PPK) models might help to guide dosing recommendations to improve response. External validation provides the most compelling evidence for the validity of a PPK model. Purpose To evaluate a previously developed PPK model for IFX in RA patients using an external population dataset. Material and methods RA patients receiving IFX between July 2014 and July 2015 were included. Pre-dose serum concentrations (Cmin) (mg/L) and antibodies against IFX (ATI) were determined at steady state by enzyme linked immunosorbent assay (Promonitor). Demographic, biochemical and haematologic covariates, disease activity score (DAS28), tender joints (tender28) and swollen joints (swollen28) were recorded. The PPK model reported by Ternant et al.1 was implemented in NONMEM v.7.2 and used as a Bayesian predictor. Bias and imprecision were estimated by the median prediction error and the root median squared prediction error, respectively. Prediction errors were calculated for each individual predicted concentration. Results 36 Cmin values from 17 patients were available (14 women; 6 concomitant psoriasis). IFX was administered at 3 mg/kg/8 weeks (n = 13), 3 mg/kg/10 weeks (n = 2), 3 mg/kg/6 weeks (n = 1) or 5 mg/kg/8 weeks (n = 2). Concurrent immunomodulatory therapy was given to 15 patients. The median Cmin (range) was 0.29 mg/L (0.01–3.87 mg/L). Median (range) values for the most relevant characteristics were: C reactive protein 3.5 mg/dL (0.5–60.7); serum albumin 43 g/L (38–48); leucocytes 7.15 × 109/L (3.6–12.3); erythrocyte sedimentation rate 10 mm (2–76); DAS28 2.26 (0.63–4.71); swollen28 0 (0–8); and tender28 0 (0–8). Two patients developed ATI. Bias and imprecision estimated values were -0.03 (95% CI −0.53 to 0.43 mg/L) and 0.10 (95% CI 0.01 to 0.67 mg/L, 24%), respectively. Conclusion Acceptable bias and imprecision values were provided by the PPK model of Ternant et al .1 but a further evaluation using larger datasets will be required to confirm these results. References and/or Acknowledgements Ternant D, Ducourau E, Perdriger A, et al. Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis. BJCP 2013;78:118-28 No conflict of interest.
Treatment of solid-organ transplant (SOT) patients with ganciclovir (GCV)-valganciclovir (VGCV) according to the manufacturer's recommendations may result in over- or underexposure. Bayesian prediction based on a population... more
Treatment of solid-organ transplant (SOT) patients with ganciclovir (GCV)-valganciclovir (VGCV) according to the manufacturer's recommendations may result in over- or underexposure. Bayesian prediction based on a population pharmacokinetics model may optimize GCV-VGCV dosing, achieving the area under the curve (AUC) therapeutic target. We conducted a two-arm, randomized, open-label, 40% superiority trial in adult SOT patients receiving GCV-VGCV as prophylaxis or treatment of cytomegalovirus infection. Group A was treated according to the manufacturer's recommendations. For group B, the dosing was adjusted based on target exposures using a Bayesian prediction model (NONMEM). Fifty-three patients were recruited (27 in group A and 26 in group B). About 88.6% of patients in group B and 22.2% in group A reached target AUC, achieving the 40% superiority margin ( P < 0.001; 95% confidence interval [CI] difference, 47 to 86%). The time to reach target AUC was significantly longer...
Research Interests: Microbiology, Medical Microbiology, Kidney transplantation, Medicine, Humans, and 15 moreFemale, Male, Cytomegalovirus, Anemia, Liver Transplantation, Aged, Middle Aged, Adult, Cytomegalovirus Infections, Bayes Theorem, Heart Transplantation, Area Under Curve, Antiviral Agents, Ganciclovir, and neutropenia
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The intestinal absorption rate constants of the five 6-fluoquinolones (norfloxacin, ciprofloxacin, pefloxacin, CNV 8802 and CNV 8804), have been estimated in the rat (n = 5) by means of an "in situ" intestinal perfusion method.... more
The intestinal absorption rate constants of the five 6-fluoquinolones (norfloxacin, ciprofloxacin, pefloxacin, CNV 8802 and CNV 8804), have been estimated in the rat (n = 5) by means of an "in situ" intestinal perfusion method. Remaining 6-fluoquinol one concentrations in the perfusion liquid at fixed time (15, 30, 45, 60, 75, 90 and 120 minutes) were determined using a HPLC procedure with UV detection. Absorptions rate constants were estimated according to first order kinetics. A simple non-linear correlation between Ka and log K' on the one hand and a multiple linear correlation between Ka and the structural theoretical parameters: molar volume, dipolar moment and the charge associated to nitrogen 18 on the other, were performed. Only a correlation between Ka values as dependent variable versus dipolar moment and molecular volume values has been obtained, but this correlation is not statistically significant (p = 0.1808) and not accurate enough to have predictive value.
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A pharmacokinetic and dynamic study of cyanamide, an inhibitor of aldehyde dehydrogenase (ALDH) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in man after oral administrations. Cyanamide plasma... more
A pharmacokinetic and dynamic study of cyanamide, an inhibitor of aldehyde dehydrogenase (ALDH) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in man after oral administrations. Cyanamide plasma levels were determined by a sensitive and specific high performance liquid chromatographic assay. Blood ALDH activity were estimated after oral administration of 0.3, 1 and 1.5 mg/kg of cyanamide. One i.v. administration of 1 mg/kg was performed in order to determine the absolute bioavailability and the main pharmacokinetic parameters. Elimination half life and total plasma clearance values were 51.7 8.8 min and 14.4 2.7 mL/kg/min respectively. After oral administrations of 0.3, 1 and 1.5 mg/kg a rapid absorption rate was estimated with a Tmax values range of 10.5 to 15.5 min. The extent of absorption was not complete, oral bioavailability being 53%, 70% and 81% respectively. The presence of a first pass-effect is suggested. The inhibitory activity of...
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This study evaluates in vivo the drug absorption profiles from potato starch-methyl methacrylate matrices(*) using theophylline as a model drug. Healthy beagle dogs under fasting conditions were used for in vivo studies and plasma samples... more
This study evaluates in vivo the drug absorption profiles from potato starch-methyl methacrylate matrices(*) using theophylline as a model drug. Healthy beagle dogs under fasting conditions were used for in vivo studies and plasma samples were analyzed by a fluorescence polarization immunoassay analysis (FPIA method). Non-compartmental and compartmental (population approach) analysis was performed to determine the pharmacokinetic parameters. The principle of superposition was applied to predict multiple dose plasma concentrations from experimental single dose data. An in vitro-in vivo correlation (IVIVC) was also assessed. The sustained absorption kinetics of theophylline from these formulations was demonstrated by comparison with two commercially available oral sustained-release theophylline products (Theo-Dur(®) and Theolair(®)). A one-compartment model with first order kinetics without lag-time best describes the absorption/disposition of theophylline from the formulations. Results revealed a theophylline absorption rate in the order FD-HSMMA≥Theo-Dur(®)≥OD-CSMMA&amp;amp;amp;amp;amp;amp;gt;Theolair(®)≥FD-CSMMA. On the basis of simulated plasma theophylline levels, a twice daily dosage (every 12h) with the FD-CSMMA tablets should be recommended. A Level C IVIVC was found between the in vitrot50% and the in vivo AUC/D, although further optimization of the in vitro dissolution test would be needed to adequately correlate with in vivo data.
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A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral... more
A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral administration. Cyanamide plasma levels were determined by a sensitive HPLC assay, specific for cyanamide. After intravenous administration cyanamide displayed a disposition profile according to a two-compartmental
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To develop a population pharmacokinetic model for intravenous omeprazole in critically ill children. One hundred eighty-six omeprazole concentration-time data from 40 critically ill children were analyzed using the nonlinear mixed-effects... more
To develop a population pharmacokinetic model for intravenous omeprazole in critically ill children. One hundred eighty-six omeprazole concentration-time data from 40 critically ill children were analyzed using the nonlinear mixed-effects approach with the nonlinear mixed-effects modeling software, version 7.2 software. Patients were randomized into 2 groups and received intravenous omeprazole at a dose of 0.5 or 1 mg/kg twice daily. Blood samples were drawn at 0.5, 2, 6, 12, 24, and 48 hours after the first infusion. The pharmacokinetic profile was best described by a 2-compartment model with a first-order elimination process. Between-patient variability could only be associated with plasma clearance (CL). The typical values for plasma CL were 24.9 L·h·70 kg (10.08%), with a distributional clearance of 53.9 L·h·70 kg (11.00%) and central and peripheral compartment distribution volumes of 4.23 L/70 kg (19.62%) and 674 L/70 kg (0.89%), respectively. Allometric size models seemed to predict changes adequately in all the pharmacokinetic parameters. High values of between-patient variability of CL [75.50% (2.60%)] and residual variability [130.0% (5.26%)] were still found in the final model. Model-based simulations suggested that the most suitable dose was 1 mg/kg because this yielded similar exposure (defined by the area under the concentration-time curve) to that obtained in adults after a 20-mg dose of omeprazole intravenously. An allometric size model allows changes to be predicted in all the pharmacokinetic parameters, making dose adjustment by body weight important to achieve the most effective omeprazole exposure. This is the first step toward a population pharmacokinetic study, including more data to develop a predictable model to be used during therapeutic drug monitoring.
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Research Interests: Medicine, Respiratory Disease, Animal Feed, Female, Animals, and 13 moreMale, Absorption, Lung, High Pressure Liquid Chromatography, Anti-Bacterial Agents, Amoxicillin, Swine, Respiratory Tract Infections, Veterinary Sciences, Biological Availability, Cross-Over Studies, Porcine Reproductive and Respiratory Syndrome, and Random Allocation
A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (E.C. 1.2.1.3) has been made in the beagle dog and Sprague-Dawley rat. Cyanamide plasma levels were determined by a sensitive high performance liquid... more
A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (E.C. 1.2.1.3) has been made in the beagle dog and Sprague-Dawley rat. Cyanamide plasma levels were determined by a sensitive high performance liquid chromatographic assay, specific for cyanamide. In the dog, i.v. administration of cyanamide at 1, 2 and 4 mg kg−1, produced a dose-dependent pharmacokinetic behaviour. Statistically significant changes were observed in plasma clearance values (12·6 to 19·7 mL kg−1 min−1), half life values (39 to 61 min) and mean residence times (50 to 79 min). Peak plasma concentrations, after oral administration of 4 mg kg−1 were achieved at 30 min and oral bioavailability was about 65%. In the rat after i.v. or oral administration, cyanamide (2 mg kg−1) had a half life of 30 min, a total plasma clearance of 117 mL kg−1 min−1 and a mean residence time of 26 min. Oral bioavailability was about 69%.
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Research Interests: Chemistry, Kinetics, Comparative Study, In Vitro, Mice, and 15 morePharmaceutical Sciences, Animals, Male, Calcium Channel, Skin, Absorption, Rats, Rat, Molecular weight, In Vitro Studies, Antiemetics, Calcium Channel Blockers, Skin Absorption, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
ABSTRACT An automated solid phase extraction-based procedure for the determination of ketorolac in human plasma was developed and validated. Solid phase extraction of ketorolac tromethamine and ketoprofen (internal standard) was performed... more
ABSTRACT An automated solid phase extraction-based procedure for the determination of ketorolac in human plasma was developed and validated. Solid phase extraction of ketorolac tromethamine and ketoprofen (internal standard) was performed on disposable C-18 cartridges directly from plasma samples spiked with the corresponding standards after dilution with saline. All operations were performed automatically by means of a switching-valve assembly in the sample preparation module (Prospekt system), and sample analysis were carried out by on line connection with the HPLC system. Linearity of the analytical methodology was assessed at the concentration range 25–2500 ng/mL ketorolac tromethamine. However, accurate and precise determinations at 5 and 10 ng/mL were obtained by the use of weighing in calibration curve fitting. The mean absolute recoveries for ketorolac tromethamine and the internal standard were 87.7% and 72.9% respectively. Respective intra- and inter-assay precision values were below 7.2 and 18.0%, the later at the 5 ng/mL concentration level of ketorolac tromethamine which was considered as the lower limit of quantitation (3.4 ng/mL in terms of free acid form). Intra- and inter-assay accuracy, expressed as relative error in percentage, were less than 9.5 and 8.8% respectively. The minimal sample handling and the obtained precision and accuracy at the wide range of concentration levels tested make this method suitable for routine quantitations of ketorolac in human plasma.
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An analytical method for the determination of valproic acid in human plasma and ultrafiltrated human plasma has been developed and validated. The analytical method lies in the solid phase extraction of valproic acid (VPA), followed by its... more
An analytical method for the determination of valproic acid in human plasma and ultrafiltrated human plasma has been developed and validated. The analytical method lies in the solid phase extraction of valproic acid (VPA), followed by its quantification through an LC-MS method, using benzoic acid as the internal standard. The intra-assay and inter-assay precisions of this technique ranged between 4.29%
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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)]... more
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.
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Alprazolam, a benzodiazepine widely used for the treatment of psychiatric disorders, has been aimed to be formulated in a transdermal delivery system (TDS) prototype. A series of TDS prototypes dosed in all cases at 0.35 mg·cm(-2) of... more
Alprazolam, a benzodiazepine widely used for the treatment of psychiatric disorders, has been aimed to be formulated in a transdermal delivery system (TDS) prototype. A series of TDS prototypes dosed in all cases at 0.35 mg·cm(-2) of alprazolam were prepared as a monolithic drug in adhesive matrix using acrylic pressure-sensitive adhesives (PSA) of acrylate vinyl acetate (Duro-tack(®)). The effects of several permeation enhancers as azone, transcutol, propylene glycol, dodecyl alcohol, decyl alcohol, diethanolamine, N-methyl pyrrolidone and lauric acid were studied. Prototypes have been characterized based on adhesion parameters (peel adhesion and shear adhesion), in vitro human skin permeation and in vitro drug release according to European Pharmacopoeia for the selected prototype. Best results show that a combination of permeation enhancers from different chemical groups is able to provide almost a 33 fold increase in the transdermal alprazolam flux of an aqueous saturated dispersion (from 0.054 ± 0.019 to 1.76 ± 0.21 μg h.cm(-2)). Based on these in vitro flux data, a predictive simulation of the achievable plasmatic levels was performed assuming a constant systemic infusion of drug. In summary, it is possible to obtain a prototype of a TDS of alprazolam with adequate adhesive properties (peel adhesion and shear adhesion) and able to predict sustained therapeutic plasmatic levels.
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Research Interests: Materials Science, Chemistry, Chromatography, Clinical Biochemistry, Medicine, and 10 moreHumans, Calibration, High Performance Liquid Chromatography, High Pressure Liquid Chromatography, Reproducibility of Results, Drug Stability, Antiviral Agents, Ganciclovir, Medical biochemistry and metabolomics, and limit of detection
Research Interests: Nonlinear dynamics, Adolescent, Tacrolimus, Humans, Child, and 14 moreFemale, Male, Infant, Liver Transplantation, Cyclosporine, Age Factors, Combination drug therapy, Bayes Theorem, Area Under Curve, Child preschool, Immunosuppressive Agents, Tissue distribution, Mycophenolic Acid, and Pharmacology and pharmaceutical sciences
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A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then... more
A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then 900 mg of valganciclovir (16 days), both twice daily with dose adjustment for renal function. A total of 382 serum concentrations from days 5 and 15 were analyzed with NONMEM VI. Renal function given by creatinine clearance (CLCR) was the most influential covariate in CL. The final pharmacokinetic parameters were as follows: ganciclovir clearance (CL) was 7.49·(CLCR/57) liter/h (57 was the mean population value of CLCR); the central and peripheral distribution volumes were 31.9 liters and 32.0 liters, respectively; intercompartmental clearance was 10.2 liter/h; the first-order absorption rate constant was 0.895 h−1; bioavailability was 0.825; and lag time was 0.382 h. The CLCR was the best predictor of CL, making dose adjustment by this covariate im...