Pragmatic approach for interpreting antiretroviral drug concentrations based on a systematic review of population pharmacokinetic studies

Objectives: The study objective was to derive reference pharmacokinetic curves of antiretroviral drugs (ART) based on available population pharmacokinetic (Pop-PK) studies that can be used to optimize therapeutic drug monitoring guided dosage adjustment.¦Methods: A systematic search of Pop-PK studies of 8 ART in adults was performed in PubMed. To simulate reference PK curves, a summary of the PK parameters was obtained for each drug based on meta-analysis approach. Most models used one-compartment model, thus chosen as reference model. Models using bi-exponential disposition were simplified to one-compartment, since the first distribution phase was rapid and not determinant for the description of the terminal elimination phase, mostly relevant for this project. Different absorption were standardized for first-order absorption processes.¦Apparent clearance (CL), apparent volume of distribution of the terminal phase (Vz) and absorption rate constant (ka) and inter-individual variability were pooled into summary mean value, weighted by number of plasma levels; intra-individual variability was weighted by number of individuals in each study.¦Simulations based on summary PK parameters served to construct concentration PK percentiles (NONMEM®).¦Concordance between individual and summary parameters was assessed graphically using Forest-plots. To test robustness, difference in simulated curves based on published and summary parameters was calculated using efavirenz as probe drug.¦Results: CL was readily accessible from all studies. For studies with one-compartment, Vz was central volume of distribution; for two-compartment, Vz was CL/λz. ka was directly used or derived based on the mean absorption time (MAT) for more complicated absorption models, assuming MAT=1/ka.¦The value of CL for each drug was in excellent agreement throughout all Pop-PK models, suggesting that minimal concentration derived from summary models was adequately characterized. The comparison of the concentration vs. time profile for efavirenz between published and summary PK parameters revealed not more than 20% difference. Although our approach appears adequate for estimation of elimination phase, the simplification of absorption phase might lead to small bias shortly after drug intake.¦Conclusions: Simulated reference percentile curves based on such an approach represent a useful tool for interpretating drug concentrations. This Pop-PK meta-analysis approach should be further validated and could be extended to elaborate more sophisticated computerized tool for the Bayesian TDM of ART.

Population pharmacokinetic study of gentamicin in a large cohort of premature and term neonates.

AIM: This study aims to investigate the clinical and demographic factors influencing gentamicin pharmacokinetics in a large cohort of unselected premature and term newborns and to evaluate optimal regimens in this population. METHODS: All gentamicin concentration data, along with clinical and demographic characteristics, were retrieved from medical charts in a Neonatal Intensive Care Unit over 5 years within the frame of a routine therapeutic drug monitoring programme. Data were described using non-linear mixed-effects regression analysis ( nonmem®). RESULTS: A total of 3039 gentamicin concentrations collected in 994 preterm and 455 term newborns were included in the analysis. A two compartment model best characterized gentamicin disposition. The average parameter estimates, for a median body weight of 2170 g, were clearance (CL) 0.089 l h(-1) (CV 28%), central volume of distribution (Vc ) 0.908 l (CV 18%), intercompartmental clearance (Q) 0.157 l h(-1) and peripheral volume of distribution (Vp ) 0.560 l. Body weight, gestational age and post-natal age positively influenced CL. Dopamine co-administration had a significant negative effect on CL, whereas the influence of indomethacin and furosemide was not significant. Both body weight and gestational age significantly influenced Vc . Model-based simulations confirmed that, compared with term neonates, preterm infants need higher doses, superior to 4 mg kg(-1) , at extended intervals to achieve adequate concentrations. CONCLUSIONS: This observational study conducted in a large cohort of newborns confirms the importance of body weight and gestational age for dosage adjustment. The model will serve to set up dosing recommendations and elaborate a Bayesian tool for dosage individualization based on concentration monitoring.

Ganciclovir exposure under a 450mg daily dosage of valganciclovir for cytomegalovirus prevention in kidney transplantation: a prospective study.

Manuel O, Pascual M, Perrottet N, Lamoth F, Venetz J-P, Decosterd LA, Buclin T, Meylan PR. Ganciclovir exposure under a 450 mg daily dosage of valganciclovir for cytomegalovirus prevention in kidney transplantation: a prospective study. 
Clin Transplant 2010: 24: 794-800. Abstract:  This prospective study aimed at determining the ganciclovir exposure observed under a daily dosage of 450 mg valganciclovir routinely applied to kidney transplant recipients with a GFR above 25 mL/min at risk for cytomegalovirus (CMV) disease. Ganciclovir levels at trough (C(trough) ) and at peak (C(3 h) ) were measured monthly. Ganciclovir exposure (area under the curve [AUC(0-24) ]) was estimated using Bayesian non-linear mixed-effect modeling (NONMEM). Thirty-six patients received 450 mg of valganciclovir daily for three months. Median ganciclovir C(3 h) was 3.9 mg/L (range: 1.3-7.1), and C(trough) was 0.4 mg/L (range 0.1-2.7). Median AUC(0-24) of ganciclovir was 59.3 mg h/L (39.0-85.3) in patients with GFR(MDRD) 26-39 mL/min, 35.8 mg h/L (24.9-55.8) in patients with GFR(MDRD) 40-59 mL/min, and 29.6 mg h/L (22.0-43.2) in patients with GFR(MDRD)  ≥ 60 mL/min. No major differences in adverse events according to ganciclovir exposure were observed. CMV viremia was not detected during prophylaxis. After discontinuing prophylaxis, CMV viremia was seen in 8/36 patients (22%), and 4/36 patients (11%) developed CMV disease. Ganciclovir exposure after administration of valganciclovir 450 mg daily in recipients with GFR ≥60 mL/min was comparable to those previously reported with oral ganciclovir. A routine daily dose of 450 mg valganciclovir appears to be acceptable for CMV prophylaxis in most kidney transplant recipients.

Imatinib plasma concentrations variability in oncologic patients

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occurs in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P-glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualization. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after the latest dose, were measured in 59 patients receiving Glivec at diverse regimens, using a validated HPLC-UV method developed for this study. The results were analyzed by non-linear mixed effect modeling (NONMEM). A one-compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. At present, only the MDR1 polymorphism has been assessed and seems to affect the pharmacokinetic parameters of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40 %) and distribution volume (71 %). Together with intra-patient variability (34 %), this translates into an 8-fold width of the 90 %-prediction interval of plasma concentrations expected under a fixed dosing regimen. This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring program for imatinib. It may help to individualize the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients

RESUME : Objectif: Le glioblastome multiforme (GBM) est la tumeur cérébrale maligne la plus agressive qui conduit au décès de la majorité des patients moins d'une année après le diagnostic. La plupart des agents chimiothérapeutiques actuellement disponibles ne traversent pas la barrière hémato¬encéphalique et ne peuvent par conséquent pas être utilisés pour ce type de tumeur. Le Temozolomide (TMZ) est un nouvel agent alkylant récemment développé pour le traitement des gliomes malins. A ce jour, très peu d'informations sont disponibles sur la pénétration intra-cérébrale de cet agent. Au cours d'une étude pilote de phase II menée auprès de 64 patients atteints de GBM, l'administration précoce de TMZ combinée à une radiothérapie standard (RT) afin d'intervenir au plus tôt dans l'évolution de la maladie, a permis de prolonger la survie de ces patients, résultat qui pu être confirmé par la suite lors de l'étude randomisée de phase III. L'objectif de cette étude a été de déterminer les paramètres pharmacocinétique du TMZ dans le plasma et le liquide céphalo-rachidien (LCR), d'évaluer l'influence de certains facteurs individuels (âge, sexe, surface corporelle, fonction rénale/hépatique, co-médications, RT concomitante) sur ces différents paramètres, et enfin d'explorer la relation existant entre l'exposition au TMZ et certains marqueurs cliniques d'efficacité et de toxicité. Matériel et Méthode: Les concentrations de TMZ ont été mesurées par chromatographie liquide à haute performance (HPLC) dans le plasma et le LCR de 35 patients atteints de GBM nouvellement diagnostiqués (étude pilote) ou de gliomes malins en récidive (étude récidive). L'analyse pharmacocinétique de population a été réalisée à l'aide du programme NONMEM. L'exposition systémique et cérébrale, définie par les AUC (Area Under the time-concentration Curve) dans le plasma et le LCR, a été estimée pour chaque patient et corrélée à la toxicité, la survie ainsi que la survie sans progression tumorale. Résultats: Un modèle à 1 compartiment avec une cinétique d'absorption et de transfert Kplasma -> LCR de ordre a été retenu afin de décrire le profil pharmacocinétique du TMZ. Les valeurs moyennes de population ont été de 10 L/h pour la clairance, de 30.3 L pour le volume de distribution, de 2.1 h pour la 1/2 vie d'élimination, de 5.78 hE-1 pour la constante d'absorption, de 7.2 10E4 hE-1 pour Kplasma->LCR et de 0.76 hE-1 pour KLCR plasma. La surface corporelle a montré une influence significative sur la clairance et le volume de distribution, alors que le sexe influence la clairance uniquement. L'AUC mesurée dans le LCR représente ~20% de celle du plasma et une augmentation de 15% de Kplasma->LCR a été observée lors du traitement concomitant de radiochimiothérapie. Conclusions: Cette étude est la première analyse pharmacocinétique effectuée chez l'homme permettant de quantifier la pénétration intra-cérébrale du TMZ. Le rapport AUC LCR/AUC Plasma a été de 20%. Le degré d'exposition systémique et cérébral au TMZ ne semble pas être un meilleur facteur prédictif de la survie ou de la tolérance au produit que ne l'est la dose cumulée seule. ABSTRACT Purpose: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of ma¬lignant brain tumors. The purpose was to assess TNIZ phar¬macokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covari¬ates and to explore relationships between systemic or cere¬bral drug exposure and clinical outcomes. Experimental Design: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacoki¬netic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area un¬der the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival. Results: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (VD), 30.3 liters; absorption constant rate, 5.8 hE-1; elimination half-time, 2.1 h; transfer rate from plasma to CSF (Kplasma->CSF), 7.2 x 10E-4hE-1 and the backwards rate, 0.76hE-1. Body surface area signifi¬cantly influenced both clearance and VD, and clearance was sex dependent. The AU CSF corresponded to 20% of the AUCplasma. A trend toward an increased K plasma->CSF of 15% was observed in case of concomitant radiochemo-therapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect. Conclusions: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUC CSF/ AUC plasma ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.

Relations entre la pharmacocinétique de population de l'imatinib et l'alpha-1-glycoproteine acide chez des patients hémato-oncologiques

Introduction: La disposition de l'imatinib (Glivec®) implique des systèmes connus pour de grandes différences inter-individuelles, et l'on peut s'attendre à ce que l'exposition à ce médicament varie largement d'un patient à l'autre. L'alpha-1-glycoprotéine acide (AAG), une protéine circulante liant fortement l'imatinib, représente l'un de ces systèmes. Objectif: Cette étude observationnelle visait à explorer l'influence de l'AAG plasmatique sur la pharmacocinétique de l'imatinib. Méthode: Une analyse de population a été effectuée avec le programme NONMEM sur 278 échantillons plasmatiques issus de 51 patients oncologiques. L'influence des taux d'AAG sur la clairance (CL) et le volume de distribution (Vd) a ainsi été étudiée. Résultats: Un modèle à un compartiment avec absorption de premier ordre a permis de décrire les données. Une relation hyperbolique entre taux d'AAG et CL ou Vd a été observée. Une approche mécanistique a donc été élaborée, postulant que seule la concentration libre subissait une élimination du premier ordre, et intégrant la constante de dissociation comme paramètre du modèle. Cette approche a permis de déterminer une CLlibre moyenne de 1310 l/h et un Vd de 301 l. Par comparaison, la CLtotale déterminée initialement était de 14 l/h. La CLlibre est affectée par le poids corporel et le type de pathologie. Qui plus est, ce modèle a permis d'estimer in vivo la constante d'association entre imatinib et AAG (5.5?106 l/mol), ainsi que la fraction libre moyenne de l'imatinib (1.1%). La variabilité inter-individuelle estimée pour la disposition de l'imatinib (17% sur CLlibre et 66% sur Vd) diminuait globalement de moitié avec le modèle incorporant l'impact de l'AAG. Discussion-conclusion: De tels résultats clarifient l'impact de la liaison protéinique sur le devenir de l'imatinib. Des taux élevés d'AAG ont été présumés représenter un facteur de résistance à l'imatinib. Toutefois, cela est peu probable, notre modèle prédisant que la concentration libre reste inchangée. D'un autre côté, s'il est un jour démontré que l'imatinib requiert un programme de suivi thérapeutique (TDM), la mesure des concentrations libres, ou la correction des concentrations totales en fonction des taux d'AAG, devraient être envisagées pour une interprétation précise des résultats.

Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastro-intestinal stromal tumour (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occur in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after latest dose, were measured in 59 patients receiving Glivec® at diverse regimens, using a validated chromatographic method (HPLC-UV) developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one- compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T appears to affect the disposition of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen ! This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help to individualise the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Relationship between imatinib population pharmacokinetics and alpha-1-acid glycoprotein

Objectives: Considering the large inter-individual differences in the function of the systems involved in imatinib disposition, exposure to this drug can be expected to vary widely among patients. Among those known systems is alpha-1-acid glycoprotein (AGP), a circulating protein that strongly binds imatinib. This observational study aimed to explore the influence of plasma AGP on imatinib pharmacokinetics. Methods: A population pharmacokinetic analysis was performed using NONMEM based on 278 plasma samples from 51 oncologic patients, for whom both total imatinib and AGP plasma concentrations were measured. The influence of this biological covariate on oral clearance and volume of distribution was examined. Results: A one-compartment model with first-order absorption appropriately described the data. A hyperbolic relationship between plasma AGP levels and oral clearance, as well as volume of distribution was observed. A mechanistic approach was built up, postulating that only the unbound imatinib concentration was able to undergo first-order elimination through an unbound clearance process, and integrating the dissociation constant as a parameter in the model. This approach allowed determining an average (± SEM) free clearance of 1310 (± 172) L/h and a volume of distribution of 301 (± 23) L. By comparison, the total clearance previously determined was 14 (± 1) L/h. Free clearance was affected by body weight and pathology diagnosis. Moreover, this model provided consistent estimates of the association constant between imatinib and AGP (5.5?106 L/mol) and of the average in vivo free fraction of imatinib (1.1%). The variability observed (17% for free clearance and 66% for volume of distribution) was less than the one previously reported without considering AGP impact. AGP explained indeed about one half of the variability observed in total imatinib disposition. Conclusion: Such findings clarify in part the in vivo impact of protein binding on imatinib disposition and might raise again the question whether high levels of AGP could represent a resistance factor to imatinib. This remains however questionable, as it is not expected to affect free drug concentrations. On the other hand, would imatinib be demonstrated as a drug requiring therapeutic drug monitoring, either the measurement of free concentration or the correction of the total concentration by the actual AGP plasma levels should be considered for accurate interpretation of the results.

Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein

AIMS: The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma alpha1-acid glycoprotein concentrations. METHODS: A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. RESULTS: A one-compartment model with first-order absorption appropriately described the data, giving a mean (+/-SEM) oral clearance of 14.3 l h-1 (+/-1.0) and a volume of distribution of 347 l (+/-62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma alpha1-acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells. CONCLUSION: Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating alpha1-acid glycoprotein concentrations or free imatinib concentrations.

Clinical consequences of imatinib plasma concentrations variability in hemato-oncologic patients

Background: Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). Considering the large inter-individual differences in the function of the systems involved in its disposition, exposure to imatinib can be expected to vary widely among patients. This observational study aimed at describing imatinib pharmacokinetic variability and its relationship with various biological covariates, especially plasma alpha1-acid glycoprotein (AGP), and at exploring the concentration-response relationship in patients. Methods: A population pharmacokinetic model (NONMEM) including 321 plasma samples from 59 patients was built up and used to derive individual post-hoc Bayesian estimates of drug exposure (AUC; area under curve). Associations between AUC and therapeutic response or tolerability were explored by ordered logistic regression. Influence of the target genotype (i.e. KIT mutation profile) on response was also assessed in GIST patients. Results: A one-compartment model with first-order absorption appropriately described the data, with an average oral clearance of 14.3 L/h (CL) and volume of distribution of 347 L (Vd). A large inter-individual variability remained unexplained, both on CL (36%) and Vd (63%), but AGP levels proved to have a marked impact on total imatinib disposition. Moreover, both total and free AUC correlated with the occurrence and number of side effects (e.g. OR 2.9±0.6 for a 2-fold free AUC increase; p<0.001). Furthermore, in GIST patients, higher free AUC predicted a higher probability of therapeutic response (OR 1.9±0.5; p<0.05), notably in patients with tumor harboring an exon 9 mutation or wild-type KIT, known to decrease tumor sensitivity towards imatinib. Conclusion: The large pharmacokinetic variability, associated to the pharmacokinetic-pharmacodynamic relationship uncovered are arguments to further investigate the usefulness of individualizing imatinib prescription based on TDM. For this type of drug, it should ideally take into consideration either circulating AGP concentrations or free drug levels, as well as KIT genotype for GIST.

Population pharmacokinetics of ganciclovir in solid-organ transplant recipients receiving oral valganciclovir.

Valganciclovir (VGC) is an oral prodrug of ganciclovir (GCV) recently introduced for prophylaxis and treatment of cytomegalovirus infection. Optimal concentration exposure for effective and safe VGC therapy would require either reproducible VGC absorption and GCV disposition or dosage adjustment based on therapeutic drug monitoring (TDM). We examined GCV population pharmacokinetics in solid organ transplant recipients receiving oral VGC, including the influence of clinical factors, the magnitude of variability, and its impact on efficacy and tolerability. Nonlinear mixed effect model (NONMEM) analysis was performed on plasma samples from 65 transplant recipients under VGC prophylaxis or treatment. A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by the glomerular filtration rate (GFR), patient gender, and graft type (clearance/GFR = 1.7 in kidney, 0.9 in heart, and 1.2 in lung and liver recipients) with interpatient and interoccasion variabilities of 26 and 12%, respectively. Body weight and sex influenced central volume of distribution (V(1) = 0.34 liter/kg in males and 0.27 liter/kg in females [20% interpatient variability]). No significant drug interaction was detected. The good prophylactic efficacy and tolerability of VGC precluded the demonstration of any relationship with GCV concentrations. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of the GCV profile after treatment with oral VGC, routine TDM does not appear to be clinically indicated in solid-organ transplant recipients. However, GCV plasma measurement may still be helpful in specific clinical situations.

Cytogenetic response to imatinib in chronic myeloid leukaemia patients: concentration dependency and associated influences under field-conditions

Introduction: Imatinib, a first-line drug for chronic myeloid leukaemia (CML), has been increasingly proposed for therapeutic drug monitoring (TDM), as trough concentrations >=1000 ng/ml (Cmin) have been associated with improved molecular and complete cytogenetic response (CCyR). The pharmacological monitoring project of EUTOS (European Treatment and Outcome Study) was launched to validate retrospectively the correlation between Cmin and response in a large population of patients followed by central TDM in Bordeaux.¦Methods: 1898 CML patients with first TDM 0-9 years after imatinib initiation, providing cytogenetic data along with demographic and comedication (37%) information, were included. Individual Cmin, estimated by non-linear regression (NONMEM), was adjusted to initial standard dose (400 mg/day) and stratified at 1000 ng/ml. Kaplan-Meier estimates of overall cumulative CCyR rates (stratified by sex, age, comedication and Cmin) were compared using asymptotic logrank k-sample test for interval-censored data. Differences in Cmin were assessed by Wilcoxon test.¦Results: There were no significant differences in overall cumulative CCyR rates between Cmin strata, sex and comedication with P-glycoprotein inhibitors/inducers or CYP3A4 inhibitors (p >0.05). Lower rates were observed in 113 young patients <30 years (p = 0.037; 1-year rates: 43% vs 60% in older patients), as well as in 29 patients with CYP3A4 inducers (p = 0.001, 1-year rates: 40% vs 66% without). Higher rates were observed in 108 patients on organic-cation-transporter-1 (hOCT-1) inhibitors (p = 0.034, 1-year rates: 83% vs 56% without). Considering 1-year CCyR rates, a trend towards better response for Cmin above 1000 ng/ml was observed: 64% (95%CI: 60-69%) vs 59% (95%CI: 56-61%). Median Cmin (400 mg/day) was significantly reduced in male patients (732 vs 899ng/ml, p <0.001), young patients <30 years (734 vs 802 ng/ml, p = 0.037) and under CYP3A4 inducers (758 vs 859 ng/ml, p = 0.022). Under hOCT-1 inhibitors, Cmin was increased (939 vs 827 ng/ml, p = 0.038).¦Conclusion: Based on observational TDM data, the impact of imatinib Cmin >1000 ng/ml on CCyR was not salient. Young CML patients (<30 years) and patients taking CYP3A4 inducers probably need close monitoring and possibly higher imatinib doses, due to lower Cmin along with lower CCyR rates. Patients taking hOCT-1 inhibitors seem in contrast to have improved CCyR response rates. The precise role for imatinib TDM remains to be established prospectively.

Intraocular penetration of penciclovir after oral administration of famciclovir: a population pharmacokinetic model.

OBJECTIVES: We developed a population model that describes the ocular penetration and pharmacokinetics of penciclovir in human aqueous humour and plasma after oral administration of famciclovir. METHODS: Fifty-three patients undergoing cataract surgery received a single oral dose of 500 mg of famciclovir prior to surgery. Concentrations of penciclovir in both plasma and aqueous humour were measured by HPLC with fluorescence detection. Concentrations in plasma and aqueous humour were fitted using a two-compartment model (NONMEM software). Inter-individual and intra-individual variabilities were quantified and the influence of demographics and physiopathological and environmental variables on penciclovir pharmacokinetics was explored. RESULTS: Drug concentrations were fitted using a two-compartment, open model with first-order transfer rates between plasma and aqueous humour compartments. Among tested covariates, creatinine clearance, co-intake of angiotensin-converting enzyme inhibitors and body weight significantly influenced penciclovir pharmacokinetics. Plasma clearance was 22.8 ± 9.1 L/h and clearance from the aqueous humour was 8.2 × 10(-5) L/h. AUCs were 25.4 ± 10.2 and 6.6 ± 1.8 μg · h/mL in plasma and aqueous humour, respectively, yielding a penetration ratio of 0.28 ± 0.06. Simulated concentrations in the aqueous humour after administration of 500 mg of famciclovir three times daily were in the range of values required for 50% growth inhibition of non-resistant strains of the herpes zoster virus family. CONCLUSIONS: Plasma and aqueous penciclovir concentrations showed significant variability that could only be partially explained by renal function, body weight and comedication. Concentrations in the aqueous humour were much lower than in plasma, suggesting that factors in the blood-aqueous humour barrier might prevent its ocular penetration or that redistribution occurs in other ocular compartments.

Tobramycin exposure from active calcium sulfate bone graft substitute.

BACKGROUND: Bone graft substitute such as calcium sulfate are frequently used as carrier material for local antimicrobial therapy in orthopedic surgery. This study aimed to assess the systemic absorption and disposition of tobramycin in patients treated with a tobramycin-laden bone graft substitute (Osteoset® T). METHODS: Nine blood samples were taken from 12 patients over 10 days after Osteoset® T surgical implantation. Tobramycin concentration was measured by fluorescence polarization. Population pharmacokinetic analysis was performed using NONMEM to assess the average value and variability (CV) of pharmacokinetic parameters. Bioavailability (F) was assessed by equating clearance (CL) with creatinine clearance (Cockcroft CLCr). Based on the final model, simulations with various doses and renal function levels were performed. (ClinicalTrials.gov number, NCT01938417). RESULTS: The patients were 52 +/- 20 years old, their mean body weight was 73 +/- 17 kg and their mean CLCr was 119 +/- 55 mL/min. Either 10 g or 20 g Osteoset® T with 4% tobramycin sulfate was implanted in various sites. Concentration profiles remained low and consistent with absorption rate-limited first-order release, while showing important variability. With CL equated to CLCr, mean absorption rate constant (ka) was 0.06 h-1, F was 63% or 32% (CV 74%) for 10 and 20 g Osteoset® T respectively, and volume of distribution (V) was 16.6 L (CV 89%). Simulations predicted sustained high, potentially toxic concentrations with 10 g, 30 g and 50 g Osteoset® T for CLCr values below 10, 20 and 30 mL/min, respectively. CONCLUSIONS: Osteoset® T does not raise toxicity concerns in subjects without significant renal failure. The risk/benefit ratio might turn unfavorable in case of severe renal failure, even after standard dose implantation.